Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:11]2[NH:10][C:9](=[O:14])[N:8]3[CH2:15][CH2:16][N:17]=[C:7]3[C:6]=2[CH:5]=1)([O-])=O.[OH-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:1][C:4]1[CH:13]=[CH:12][C:11]2[NH:10][C:9](=[O:14])[N:8]3[CH2:15][CH2:16][N:17]=[C:7]3[C:6]=2[CH:5]=1
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2C2=NCCN12
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc2c(c1)C1=NCCN1C(=O)N2
Temperature: 60 °C

Procedure:
4.6 g of 9-nitro-5-oxo-2,3,5,6-tetrahydroimidazo-[1,2-c]-quinazoline were dissolved in 4.8 g (0.12 mol) of NaOH in 80 ml of H2O. 10.5 g of sodium dithionite were added to the mixture, during which the temperature increased to 60° C. The mixture was then heated to boiling for a short time. After the mixture had been cooled, the precipitated crystals were filtered off under suction, washed with H2O and finally thoroughly stirred in 1N NaOH. The mixture was then again filtered off under suction, and the residue was washed with water, ethanol and ether, and dried.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:30]1[S:34][N:33]=[CH:32][N:31]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=2I)=[CH:12][C:11]=1[F:29])(=[O:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].C(OC[N:51]1[C:55](B2OC(C)(C)C(C)(C)O2)=[CH:54][CH:53]=[N:52]1)C.FC(F)(F)C(O)=O>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:29][C:11]1[CH:12]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=2[C:53]2[NH:52][N:51]=[CH:55][CH:54]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:30]1[S:34][N:33]=[CH:32][N:31]=1)(=[O:9])=[O:8]
Reactant: CCOCn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ccc(C(F)(F)F)cc3I)cc2F)c(OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: O
Product: O=S(=O)(Nc1ncns1)c1cc(F)c(Oc2ccc(C(F)(F)F)cc2-c2ccn[nH]2)cc1F
Temperature: 80 °C
Reaction time: 16 h
Yield: 9 %

Procedure:
A suspension of N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-[2-iodo-4-(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 363, 100 mg, 0.14 mmol), potassium carbonate (48 mg, 1.12 mmol) and 1-(ethoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 337, 70 mg, 0.28 mmol) in 1,4-dioxane (5 mL) and water (2 mL) was degassed and palladium tetrakis (16 mg, 0.014 mmol) added before heating at 80° C. for 16 hours. Dicholoromethane (20 mL) and water (10 mL) were added and the organics separated and evaporated in vacuo to afford the crude product. Dicholoromethane (10 mL) and trifluoroacetic acid (5 mL) were added and the reaction mixture was stirred at room temperature for 16 hours before concentrating in vacuo. Hydrochloric acid (4 M in 1,4-dioxane, 10 mL) was added and the reaction mixture was stirred for 16 hours before concentrating in vacuo. The residue was purified by reverse phase chromatography to afford the desired product, 6 mg, 9% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[C:14]2[C:7]([NH:8][CH:9]=[C:10]2[CH2:11][CH2:12][NH2:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:16](OC(=O)C)(=[O:18])[CH3:17]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:15]=[C:14]2[C:7](=[CH:6][CH:5]=1)[NH:8][CH:9]=[C:10]2[CH2:11][CH2:12][NH:13][C:16](=[O:18])[CH3:17])([O-:3])=[O:2]
Reactant: NCCc1c[nH]c2ccc([N+](=O)[O-])cc12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NCCc1c[nH]c2ccc([N+](=O)[O-])cc12

Procedure:
5-Nitrotryptamine (6 mmol) is dissolved in pyridine (15 ml) and treated with acetic anhydride (7 mmol) 20 min at 27° C. The solvents are removed in vacuo, the residue taken into a small amount of methanol and passed through a short plug of silica with 5% methanol-chloroform eluent. Product-containing fractions are pooled, evaporated and dried thoroughly at <0.1 mm Hg.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[NH2:6][C@@H:7]([CH3:29])[CH2:8][O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[C:12]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([Cl:28])[CH:22]=1)=[N:13][CH:14]=[N:15]2>>[Cl:28][C:23]1[CH:22]=[C:21]([NH:20][C:12]2[C:11]3[C:16](=[CH:17][CH:18]=[CH:19][C:10]=3[O:9][CH2:8][C@@H:7]([NH:6][C:1](=[O:5])[CH2:2][OH:3])[CH3:29])[N:15]=[CH:14][N:13]=2)[CH:26]=[CH:25][C:24]=1[OH:27]
Reactant: O=C(O)CO
Reactant: C[C@H](N)COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Product: C[C@@H](COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12)NC(=O)CO
Yield: 73 %

Procedure:
The procedure described in Example 3 (preparation of starting materials) was repeated using glycolic acid and 4-[(5-{[(2S)-2-aminopropyl]oxy}quinazolin-4-yl)amino]-2-chlorophenol to give N-[(1S)-2-({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)-1-methylethyl]-2-hydroxyacetamide in 73% yield; Mass spectrum MH+ 403.0.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:16])[CH3:15])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].CO>[CH3:15][N:14]([CH3:16])[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: [H][H]
Reactant: CN(C)C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CN(C)C1CCNCC1

Procedure:
A solution of the 1-benzyl-4-dimethylaminopiperidine in 125 ml. of methanol was shaken with 1.0 gm. of 10 percent palladium on carbon under 50 psi of hydrogen at 50°C. until one equivalent of hydrogen was consumed. The suspension was filtered and the filtrate concentrated at atmospheric pressure. The residue was distilled at 20 mm. Hg. to give 4-dimethylaminopiperidine, b.p. 90°-92°C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.[C:11](Cl)(Cl)=[S:12].[OH-].[Na+]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]2[O:9][C:11](=[S:12])[O:8][C:6]=2[CH:7]=1
Reactant: S=C(Cl)Cl
Reactant: Oc1cc(Br)cc(F)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Fc1cc(Br)cc2oc(=S)oc12
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
5-Bromo-3-fluorobenzene-1,2-diol (2.0 g, 9.7 mmol, prepared according to Lu, Hejun; Tang, Peng Cho; Chen, Yiqian; Wang, Shenglan; Wang, Hua; Zhang, Lei; Li, Jun, WO 2011140936 A1) was dissolved in chloroform (25 mL), treated with thiophosgene (1.2 g, 11 mmol) and cooled to 0-5° C. Sodium hydroxide (10% aqueous, 8.9 g, 22 mmol) was added dropwise with vigorous stirring over 30 min. After 1 h, the chloroform was removed under vacuum and the pH was adjusted to 2 by addition of 6 M HCl. The solid that was formed was taken up in ethyl acetate (120 mL), washed with saturated NaCl (30 mL), dried (Na2SO4) and evaporated. The material was purified by flash chromatography using a 0-30% ethyl acetate-hexane gradient to give the title compound as a tan solid (1.5 g, 62%): mp 41-42° C.; 1H NMR (400 MHz, CDCl3) δ 7.35-7.30 (m, 1H), 7.29 (d, J=1.6 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −128.93; EIMS m/z 248/250.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6]O)=[CH:2]1.C1(P([N:22]=[N+:23]=[N-:24])(C2C=CC=CC=2)=O)C=CC=CC=1.CCCCCCC=CCCC>C1(C)C=CC=CC=1>[N:22]([CH2:6][C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)=[N+:23]=[N-:24]
Reactant: OCc1ccoc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCCC=CCCCCCC
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NCc1ccoc1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
To a 50 mL round-bottomed flask equipped with a magnetic stirbar was added 3-furan methanol (1.00 g, 10.2 mmol) and a solution of diphenyl phosphoryl azide (3.37 g, 12.2 mmol) in toluene (30 mL). The stirring solution is allowed to cool to 0° C., in which 1,8 Diazabycyclo [5.4.0.] undec-7-ene (1.86 g, 12.2 mmol) was added dropwise. The reaction is allowed to slowly warm to ambient temperature for an additional 16 hours of stirring. After this period, the reaction mixture is washed with water (2×20 mL) and then with 5% HCl (20 mL). Volatiles are evaporated under reduced pressure. The resulting residue is then purified by column chromatography (1:9 ethyl acetate/hexane) providing 3-azidomethyl furan (1.19 g, 95%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.46 (d, 1H), δ 7.44 (s, 1H), δ 6.42 (d, 1H), δ 4.20 (s, 2H). ppm; 13C NMR (75 MHz, CDCl3) δ 144.1, 141.1, 110.4, 92.1, 45.8 ppm; LRMS (EI) calcd for C5H5N3O (M+) 123. Found 123.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[CH2:8][C:9]3[C:21]4[NH:20][C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[C:13]=4[C:12]4[C:22](=[O:25])[NH:23][CH2:24][C:11]=4[C:10]=3[C:4]=2[CH:3]=1.C[Si]([C:30]#[CH:31])(C)C.C(N(CC)CC)C>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:30]([C:2]1[CH:7]=[CH:6][C:5]2[CH2:8][C:9]3[C:21]4[NH:20][C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[C:13]=4[C:12]4[C:22](=[O:25])[NH:23][CH2:24][C:11]=4[C:10]=3[C:4]=2[CH:3]=1)#[CH:31]
Reactant: O=C1NCc2c3c(c4[nH]c5ccccc5c4c21)Cc1ccc(Br)cc1-3
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#Cc1ccc2c(c1)-c1c3c(c4c([nH]c5ccccc54)c1C2)C(=O)NC3
Temperature: 25 °C
Reaction time: 24 h
Yield: 8.2 %

Procedure:
To a solution of 3-bromo-5H,6H,12H,13H-indeno[2,3-a]pyrrolo[3,4-c]carbazole-7(7H)one (Compound I-9) (435 mg, 1.1 mmol), trimethylsilylacetylene (0.47 ml, 3.3 mmol) and triethylamine (1.0 mL) in DMF (11 mL) was added bis(triphenylphosphine)palladium(II)chloride (17 mg). The solution was heated in a sealed reaction tube at 100°-110° C. for 24 h. The mixture was cooled to ambient temperature, filtered through a pad of celite then the solvent concentrated at reduced pressure. The product was dissolved in DMF (8 mL), MeOH (8 mL) cesium fluroide (370 mg, 2.4 mmol) added and the mixture stirred at ambient temperature 24 h. The solvent was concentrated at reduced pressure to give a dark solid. Purification by column chromatography (silica gel, EtOAc:MeOH; 10:1, Rf =0.53) give 30 mg of a tan solid. The compound was further purified by preparative TLC (silica gel, EtOAc:hexane; 3:1) to give Compound I-36 as a tan solid, mp>300° C. 1H NMR (DMSO-d6, 300 MHz): d 4.2 (s, 2H), 5.0 (s, 2H), 7.38-7.46 (m, 3H), 7.58-7.75 (m,4H), 8.15 (s, 1H), 9.42 (d, 1H, J=9 Hz), 12.19 (s, 1H; MS m/e=335 (m+).
Reaction SMILES: [S:1]([NH:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22](=[O:26])[CH2:23][CH2:24][CH3:25])[CH2:17]2)[C:7]=1[C:8]#[N:9])(=[O:4])(=[O:3])[NH2:2].[OH-].[Na+].Cl>CCO>[NH2:9][C:8]1[C:7]2[C:10]([O:14][CH2:15][C@H:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:22](=[O:26])[CH2:23][CH2:24][CH3:25])[CH2:17]3)=[CH:11][CH:12]=[CH:13][C:6]=2[NH:5][S:1](=[O:3])(=[O:4])[N:2]=1
Reactant: CCCC(=O)N1CCC[C@H](COc2cccc(NS(N)(=O)=O)c2C#N)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCC(=O)N1CCC[C@H](COc2cccc3c2C(N)=NS(=O)(=O)N3)C1
Yield: 63.2 %

Procedure:
To a stirred solution of (S)-2-sulfamoylamino-6-((1-butyrylpiperidin-3-yl)methoxy)benzonitrile (Example 1a, 9.5 g. 24.97 mmol) in EtOH (65 mL) was added at room temperature aq.NaOH (2.0 N, 37 mL. 74.91 mmol). The reaction mixture was refluxed for 4 hrs then cooled to 0° C. and neutralized carefully with 2N HCl. The precipitate was collected by filtration, re-crystallized from EtOHH2O, and dried under vacuum to give the title compound as a white solid (6 g) in 63% yield. 1H NMR (400 MHz, DMSO-d6,) δ 0.82-0.86 (m, 3H), 1.30-1.51 (m, 4H), 1.65 (m, 1H), 1.82 (m, 1H), 2.01-2.21 (m, 2H), 2.22-2.27 (m, 2H), 2.71-3.12 (m, 2H), 3.63-3.86 (m, 1H), 4.03 (m, 2H), 4.12 (m, 1H), 6.60 (m, 1H), 6.75 (t, J=8.0 Hz, 1H), 7.43-7.45 (m, 1H), 7.77 (d, J=20 Hz, 1H), 8.36 (m, 1H), 10.91 (s, 1H). MS 381 (MH+). Elem. Anal. Calcd.: C, 53.67%; H, 6.36%; N, 14.73%. Found: C, 53.64%; H, 6.63%; N, 14.73%
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[CH2:18]([O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Br:1])[CH:3]=1)[CH3:19]
Reactant: O=C(O)Cc1ccc(F)c(Br)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc(F)c(Br)c1

Procedure:
3-Bromo-4-fluorophenylacetic acid (2.35 g, 9.0 mmol) was treated with concentrated sulfuric acid (2 mL) in ethanol (100 mL) at reflux for 2 hours. Purification by silica gel chromatography provided the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:4][C:5]([O:12]C)=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.Br.C(=O)(O)[O-].[Na+].ClC1C(N2CCCCC2)=CC(O)=C(CC(O)=O)C=1>O>[Cl:1][C:2]1[C:3]([N:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[CH:4][C:5]2[O:12][C:9](=[O:11])[CH2:8][C:6]=2[CH:7]=1
Reactant: COc1cc(N2CCCCC2)c(Cl)cc1CC(=O)O
Agent: Br
Agent: O=C(O)Cc1cc(Cl)c(N2CCCCC2)cc1O
Agent: O=C([O-])O
Solvent: O
Product: O=C1Cc2cc(Cl)c(N3CCCCC3)cc2O1

Procedure:
A solution of 8.5 g (30 mmoles) of 5-chloro-2-methoxy-4-(piperidin-1-yl)-phenylacetic acid in 150 ml of 48% strength hydrobromic acid is boiled under reflux for 15 hours. The reaction mixture is cooled, diluted with water and adjusted to a pH of 3-4 with saturated sodium bicarbonate solution. The mixture is then extracted with ethyl acetate, and the combined organic phases are washed with water, dried over sodium sulphate and concentrated by evaporation in a high vacuum rotary evaporator. There is obtained a dark-grey foam comprising 5-chloro-2-hydroxy-4-(piperidin-1-yl)-phenylacetic acid, which is reacted, without being purified, to form 5-chloro-6-(piperidin-1-yl)-benzofuran-2(3H)-one.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][O:14][C:15]2[CH:16]=[N:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([O:29]CC)=[O:28])=[CH:23][CH:22]=3)=[CH:19][CH:20]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:3].[OH-].[Na+].Cl>C(O)C>[CH3:3][CH:2]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([OH:29])=[O:28])=[CH:25][CH:26]=3)=[N:17][CH:16]=2)[CH2:11][CH2:12]1)=[O:6])[CH3:1]
Reactant: CCOC(=O)c1ccc(-c2ccc(OCC3CCN(C(=O)OC(C)C)CC3)cn2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(C(=O)O)cc3)nc2)CC1
Reaction time: 8 h

Procedure:
1-Methylethyl-4-{[(6-{4-[(ethyloxy)carbonyl]phenyl}-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate (0.3 g, 0.70 mmol) was added to a solution of NaOH (0.06 g, 1.4 mmol) in ethanol (10 mL). The reaction mixture was stirred overnight, neutralized with 1N HCl and freeze-dried to give 4-(5-{[(1-{[(1-methylethyl)oxy]carbonyl}-4-piperidinyl)methyl]oxy}-2-pyridinyl)benzoic acid, which was used without further purification. 1H NMR (400 MHz, DMSO-d6): δ 8.38 (d, 1H, J=3.0 Hz), 8.12 (d, 2H, J=8.7 Hz), 8.01-7.97 (m, 3H), 7.53-7.49 (m, 1H), 4.77-4.71 (m, 1H), 4.04-3.94 (m, 4H), 2.07 (bs, 3H), 1.80-1.72 (m, 2H), 1.19-1.13 (m, 8H); LRMS (ESI), m/z 399 (M+H).
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[OH:22][C@H:23]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@@H:25]([C:35]([O:37][CH3:38])=[O:36])[CH2:24]1>ClCCl>[O:22]=[C:23]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[C@@H:25]([C:35]([O:37][CH3:38])=[O:36])[CH2:24]1
Reactant: COC(=O)[C@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)[C@H]1CC(=O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 131 %

Procedure:
To slurry of pyridinium dichromate (9.97 g, 26.5 mmol) in dichloromethane (60 mL) at rt was added (2R,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (5.00 g, 20.39 mmol) in several portions. The resulting mixture was stirred overnight at rt. Celite (5 g) was added and the mixture stirred for 40 min, filtered and the filter cake was rinsed with additional dichloromethane (50 mL×3). The resulting filtrate was concentrated and toluene (40 mL) was added followed by concentration again under vacuum to give ˜6.5 g of a brown syrup as the crude product. Purification by flash silica gel chromatography (120 g column, EtOAc in hexane, 0 to 100% gradiant, 85 mL/min) afforded 4.18 g (84%) of the title compound as a white solid. LCMS (condition A): m/z 144 (M-Boc) −ve. 1H NMR (400 MHz, CDCl3) δ ppm 4.64-4.89 (1 H, m), 3.84-3.96 (2 H, m), 3.77 (3 H, s), 2.81-3.10 (1 H, m), 2.59 (1 H, dd, J=18.93, 1.76 Hz), 1.52 (9 H, s).
Reaction SMILES: [CH2:1]=[N:2][C:3]([CH3:10])([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]([C:25]([CH3:27])=[O:26])[C:20]([O:22]CC)=O>C1(C)C(C)=CC=CC=1>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[C:20](=[O:22])[N:2]([C:3]([CH3:10])([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:1][O:26][C:25]=1[CH3:27]
Reactant: C=NC(C)(C)C(=O)OCC
Reactant: CCOC(=O)C(C(C)=O)c1ccccc1OC
Solvent: Cc1ccccc1C
Product: CCOC(=O)C(C)(C)N1COC(C)=C(c2ccccc2OC)C1=O
Reaction time: 3 h
Yield: 117.4 %

Procedure:
A solution of ethyl 2-(N-methyleneamino)-2-methylpropionate (10.3 g) in xylene was added during 1 hour to a solution of ethyl 2-(2-methoxyphenyl)acetoacetate (8.51 g) in xylene whilst heating under reflux. The rate of addition was controlled so as to equal the rate of azeotropic distillation (via a Dean and Stark separator). Additional xylene was then added and distillation continued for 3 hours. The mixture was evaporated in vacuo to give ethyl 2-[2,3-dihydro-5-(2-methoxyphenyl)-6-methyl-4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanoate (14.1 g), NMR 1.25(t,3H), 1.55(s,6H), 1.8(s,3H), 3.75(s,3H), 4.1 5(m,2H), 5.3(s,2H), 6.9-7.3(m,4H).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:6][C:5]2[C:7]([CH3:19])=[C:8]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.Br[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([CH3:29])[CH:23]=1>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([N:16]2[CH2:15][CH2:14][N:13]([C:8]3[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]4[O:3][C:2]([CH3:20])([CH3:1])[CH2:6][C:5]=4[C:7]=3[CH3:19])[CH2:18][CH2:17]2)=[CH:23][C:24]=1[CH3:29]
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Reactant: Cc1cc(Br)ccc1Cl
Product: Cc1cc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(C)O4)CC2)ccc1Cl
Yield: 15 %

Procedure:
By using 1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (274 mg, 1.00 mmol) synthesized in Reference example 61 and 4-bromo-1-chloro-2-methylbenzene (308 mg, 1.50 mmol), the reaction was carried out in the same manner as Example 23 to obtain the title compound 60 mg (yield 15%).
Reaction SMILES: CN(C)CCNCCNC1C=CC([N+]([O-])=O)=CN=1.[N:19]1([CH2:25][CH2:26][N:27]([CH2:40][CH2:41][NH:42][C:43]2[CH:48]=[CH:47][C:46]([N+:49]([O-:51])=[O:50])=[CH:45][N:44]=2)S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[N:19]1([CH2:25][CH2:26][NH:27][CH2:40][CH2:41][NH:42][C:43]2[CH:48]=[CH:47][C:46]([N+:49]([O-:51])=[O:50])=[CH:45][N:44]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: O=[N+]([O-])c1ccc(NCCN(CCN2CCOCC2)S(=O)(=O)c2ccccc2[N+](=O)[O-])nc1
Agent: CN(C)CCNCCNc1ccc([N+](=O)[O-])cn1
Product: O=[N+]([O-])c1ccc(NCCNCCN2CCOCC2)nc1

Procedure:
Made using the same procedure as for polymer-bound dimethyl[2-({2-[(5-nitro(2-pyridyl))amino]ethyl}amino)ethyl]amine except that resin-bound (2-morpholin-4-ylethyl){2-[(5-nitro(2-pyridyl))amino]ethyl}[(2-nitrophenyl)sulfonyl]amine was used.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>CN(C)C=O>[CH2:18]([N:11]1[CH2:12][CH2:13][C:9]([C:4]2[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=2)([O:14][CH3:15])[CH2:10]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC1(c2cc(F)cc(F)c2)CCNC1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(c2cc(F)cc(F)c2)CCN(Cc2ccccc2)C1
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
To a solution of 3-(3,5-difluorophenyl)-3-methoxypyrrolidine (1.3 g, 6.1 mmol) in dry dimethyl formamide (5 mL), was added sodium hydride (60% dispersion in mineral oil, 0.27 g, 6.7 mmol). The mixture was stirred for 15 min after which a solution of benzylbromide (0.725 mL, 6.1 mmol) in dry dimethyl formamide (5 mL) was added dropwise. The mixture was stirred for 30 min, hydrochloric acid (10%, 50 ml) was added and the aqueous phase was extracted with diethylether (50 mL), the aqueous phase was made basic with Na2CO3 and extracted with ethyl acetate (3×50 mL). The combined organic phase was washed with aqueous LiCl (5%, 50 mL), dried (Na2SO4), filtered and evaporated. Purification by flash column chromatography on silica gel (ethyl acetate) gave the title compound (1.15 g, 62%). MS m/z (rel. intensity, 70 eV) 273 (10), 133 (42), 132 (23), 91 (bp), 65 (11).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[OH:24].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.O1CCOCC1>[F:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[O:24][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(Cl)ccnc2c1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COc1ccc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2c1
Temperature: 110 °C
Yield: 50 %

Procedure:
To 4-chloro-7-methoxyquinoline (0.900 g, 4.6 mmol), 2-fluoro-4-nitrophenol (2.3 g, 14 mmol), and N,N-dimethylpyridin-4-amine (0.068 g, 0.56 mmol) was added dioxane (10 mL) and pyridine (6.4 ml, 79 mmol). The resulting mixture was heated at 110° C. in an argon-purged sealed tube for 16 hours. An aliquot was analyzed by LCMS and indicated the presence of desired product. The reaction mixture was concentrated in vacuo and diluted with 2 N NaOH. The resulting solid was filtered, and the filtrate was extracted with CH2Cl2. The organic layers were dried over sodium sulfate and filtered through a pad of silica gel along with the solids using 10% MeOH/CH2Cl2 as eluent. The collected fractions were concentrated in vacuo to yield 4-(2-fluoro-4-nitrophenoxy)-7-methoxyquinoline (0.900 g, 2.3 mmol, 49% yield) as a brownish solid. Calcd for C16H11FN2O4: [M]+=314. Found: [M+H]+=315.
Reaction SMILES: [CH3:1][O:2][S:3]([O-:6])(=[O:5])=[O:4].[CH3:7][N+:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-])=O.[H][H]>O.[Pd]>[CH3:1][O:2][S:3]([O-:6])(=[O:5])=[O:4].[NH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][CH2:15][CH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][N+:8]=1[CH3:7]
Reactant: C[n+]1ccccc1CCOc1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: COS(=O)(=O)[O-]
Solvent: O
Product: C[n+]1ccccc1CCOc1ccccc1N
Reaction time: 2 h

Procedure:
3.7 g (10 mmol) of the compound from Step 3.2 was hydrogenated in 25 mL of water in the presence of 0.3 g of Pd/C (10%) under 9 bar of hydrogen pressure. After 2 hours, the catalyst was filtered off, and the solution obtained was directly subjected to further reaction.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1.[CH3:12]I>CN(C)C=O>[CH3:12][O:9][CH2:8][C:7]1[CH:10]=[CH:11][C:4]([Br:3])=[CH:5][CH:6]=1
Reactant: OCc1ccc(Br)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 60% sodium hydride (1.6 g) in dimethylformamide (50 ml) was added 4-bromobenzyl alcohol (5.00 g) under ice-water cooling and the mixture was stirred at 0° C. for 0.5 hour. To the mixture was added methyl iodide (2 ml) under ice-water cooling and the mixture was stirred at 0° C. for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with hexane to give 4-(methoxymethyl)bromobenzene as colorless oil (3.63 g).