Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[O:9][CH3:10].[CH2:11]1[CH2:15][O:14][CH2:13][CH2:12]1.C([Mg]Cl)(C)C.C1(=O)CCC1>CCOCC>[F:8][C:4]1[C:3]([O:9][CH3:10])=[C:2]([C:15]2([OH:14])[CH2:11][CH2:12][CH2:13]2)[CH:7]=[CH:6][CH:5]=1
Reactant: C1CCOC1
Reactant: COc1c(F)cccc1Br
Agent: CC(C)[Mg]Cl
Agent: O=C1CCC1
Solvent: CCOCC
Product: COc1c(F)cccc1C1(O)CCC1
Temperature: 0 °C
Yield: 49 %

Procedure:
To a 500 mL round-bottomed flask were added a stir bar, 2-bromo-6-fluoroanisol (11.03 g, 53.8 mmol) and dry THF (215 mL). The flask was purged with nitrogen and cooled to 0° Celsius before adding 2.0 M i-PrMgCl in THF (60 mL, 120 mmol) over the course of 3 min. The resultant mixture was stirred for 2 h before adding cyclobutanone (5.0 mL, 67 mmol). The resultant mixture was stirred for 0.5 hour before diluting with Et2O (500 mL) and washing with saturated NH4Cl followed by brine. The organic layer was isolated, dried over MgSO4, filtered and concentrated to dryness to give a pale-yellow oil. Subjecting the residue to FCC yielded 1-(3-fluoro-2-methoxyphenyl)cyclobutanol as a pale-yellow oil (5.18 g, 49%). 1H NMR (600 MHz, CDCl3) δ 7.07-7.03 (m, 1H), 7.03-6.98 (m, 1H), 6.98-6.94 (m, 1H), 3.99 (d, J=2.4, 3H), 3.39 (s, 1H), 2.57-2.45 (m, 2H), 2.41-2.31 (m, 2H), 2.17-2.05 (m, 1H), 1.75-1.65 (m, 1H).
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4](=[O:14])[CH2:3][CH2:2]1.[OH-].[Na+]>[Ni].O>[OH:14][C:4]1[C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH:1]=[CH:2][CH:3]=1
Reactant: O=C1CCCc2[nH]c3ccccc3c21
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1cccc2[nH]c3ccccc3c12

Procedure:
To a reactor containing water (1 L) was added Raney nickel (35 g) followed by 1,2,3,9-tetrahydrocarbazole-4-one (50 g) and sodium hydroxide (15 g). The contents were heated to reflux and maintained for about 20 hours. The catalyst was filtered off and the filtrate was acidified to obtain a solid, which was filtered and dried to obtain the title compound. When necessary, the title compound was further purified by dissolving in 10% sodium hydroxide solution, treating with activated charcoal and precipitation from dilute hydrochloric acid to give off-white to grey crystals of 4-hydroxy carbazole in 50% yield.
Reaction SMILES: CCCCCC.[Li][CH2:8][CH2:9][CH2:10][CH3:11].O=C1CC[CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[CH2:11]=[C:10]1[CH2:9][CH2:8][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1
Reactant: [Li]CCCC
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: O
Product: C=C1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45.9 %

Procedure:
A 2.5 M hexane solution of n-BuLi (4.86 mL, 12.15 mmol) was added to a suspension of methyltriphenylphosphonium bromide (4.34 g, 12.15 mmol) in Et2O (100 mL) at 0° C. The mixture was stirred at room temperature for 10 min. A solution of tert-butyl 3-oxopiperidine-1-carboxylate (2.2 g, 11.04 mmol) in ether (10 mL) was added dropwise. The resultant mixture was stirred at room temperature for 1 h, at reflux for 30 min, and cooled to room temperature. After the addition of water (30 mL), the two phases were separated. The aqueous phase was extracted with ether (3×60 mL). The combined ether extracts were washed with brine (20 mL), dried (MgSO4) and concentrated. Silica gel chromatography, eluting with 0 to 15% ethyl acetate in hexane, gave a colorless liquid (1.0 g, 46%). 1H NMR (400 MHz, chloroform-d) δ ppm 4.61-4.96 (2H, m), 3.87 (2H, s), 3.25-3.55 (2H, m), 2.09-2.39 (2H, m), 1.54-1.73 (2H, m), 1.46 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH3:16])[C:12]([N+:17]([O-])=O)=[CH:11][N:10]=2)=[CH:4][CH:3]=1.CN(C)C=O.[H][H]>CO.[Pt]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH3:16])[C:12]([NH2:17])=[CH:11][N:10]=2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CNc1nc(Nc2ccc(Cl)cc2)ncc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CN(C)C=O
Solvent: CO
Product: CNc1nc(Nc2ccc(Cl)cc2)ncc1N
Reaction time: 0.5 h

Procedure:
3.0 g of 2-(4-chlorophenylamino)-4-methylamino-5-nitro-pyrimidine are hydrogenated in 300 ml of methanol and 150 ml of dimethylformamide in the presence of 1 g of platinum on charcoal (5% platinum) for one hour at a hydrogen pressure of 50 psi. The reaction mixture is filtered and the filtrate is evaporated to dryness in vacuo. The residue is combined with 40 ml water and stirred for 30 minutes. The solid is suction filtered, washed with water and dried.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6](Cl)=[O:7].[OH:29][CH:30]([CH2:35][CH3:36])[C:31]([O:33][CH3:34])=[O:32].C(N(CC)CC)C.CCOCC>C(Cl)Cl>[F:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]([O:29][CH:30]([C:31]([O:33][CH3:34])=[O:32])[CH2:35][CH3:36])=[O:7]
Reactant: CCC(O)C(=O)OC
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1F
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC(CC)C(=O)OC)cc1F
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 10.0 g 3-fluoro-4-(hexadecylamino)benzoyl chloride hydrochloride in 200 ml methylene chloride is added dropwise a solution of 3 g. methyl α-hydroxybutyrate and 5 g triethylamine in 100 ml. ether. After 17 hours stirring at room temperature, the precipitate is collected and washed with several portions of ether. The ether solution is washed with water, dried and evaporated to yield 1-(methoxycarbonyl)propyl 3-fluoro-4-(hexadecylamino)benzoate as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[H-].[Na+].I[CH2:22][CH2:23][CH3:24]>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:22][CH2:23][CH3:24])[N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1
Reactant: COc1ccc(-c2n[nH]c3c(F)cccc23)cc1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Product: CCCn1nc(-c2ccc(OC)cc2)c2cccc(F)c21
Yield: 52.1 %

Procedure:
Prepared according to Method D step B from 7-fluoro-3-(4-methoxyphenyl)-1H-indazole (0.121 g, 0.5 mmol), sodium hydride (60% in oil, 0.024 g, 0.6 mmol) and 1-iodopropane (0.096 mL, 1.0 mmol) to give the title compound (0.074 g) as a white solid.
Reaction SMILES: [CH:1]1[CH2:2][C:3](=O)[CH:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2.[OH2:12]>>[CH3:4][CH:5]1[C:10](=[O:12])[C:2]2=[CH:1][C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[CH:4]=[C:3]2[CH2:6]1
Reactant: O
Reactant: O=C1C=c2ccccc2=CC1
Product: CC1Cc2cc3c(cc2C1=O)CCCC3

Procedure:
The reaction is diluted with water and extracted with dichloromethane. After drying (Na2SO4) the solvent is removed to give an oil. The product is purified by chromatography (silica, ethyl acetate/hexane) to give a geometrical mixture of isomers containing 2-Methyl-1,2,6,7,8,9-hexahydro-cyclopenta[.a.]naphthalen-3-one and the title compound.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1I)[C:8](=[O:11])[O:9][CH3:10].C(=O)([O-])[O-].[K+].[K+].O1[CH2:44][CH2:43][O:42][CH2:41]C1>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[C:25]1[CH:26]=[C:3]([CH2:4][CH3:5])[CH:2]=[CH:44][C:43]=1[O:42][CH3:41])[C:8](=[O:11])[O:9][CH3:10]
Reactant: C1COCCO1
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1I
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: [Pd+2]
Solvent: ClCCl
Product: CCc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)c1

Procedure:
A mixture of methyl [3,5-bis(trifluoromethyl)benzyl](2-iodo-5-trifluoromethyl-benzyl)carbamate (105 mg, 0.18 mmol) (Example 5), the title compound from Step B (58 mg, 0.22 mmol), anhydrous potassium carbonate (50 mg, 0.36 mmol), dichloro[1,1′-bis(diphenylphospino)ferrocene]palladium(II) dichloromethane adduct (14.7 mg, 0.018 mmol), and a catalytic amount of palladium acetate in anhydrous dioxane were stirred at 80° C. for approximately 40 hours. The solvent was removed in vacuo, and the title compound was obtained by preparative thin layer chromatography using 60% CH2Cl2/hexane. 1H NMR (CDCl3, 600 MHz) δ 7.71 (s, 1H), 7.56 (d, J=7.8 Hz, 1H), 7.45 (m, 2H), 7.32 (d, J=7.8 Hz, 1H), 7.25 (m, 1H), 7.21 (m, 1H), 6.88 (d, J=2.4 Hz, 1H), 6.87 (m, 1H), 4.23-4.56 (m, 4H), 3.74 (m, 3H), 3.68 (s, 3H), 2.60 (m, 2H), 1.24 (m, 3H). LC-MS (M+1) 594.0 (4.76 min).
Reaction SMILES: FC(F)(F)C(O)=O.[I:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([NH2:18])[CH:16]=2)[N:11]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:10]=1.C(N(CC)CC)C.[CH2:35]([N:37]=[C:38]=[O:39])[CH3:36]>ClCCl>[CH2:35]([NH:37][C:38]([NH:18][C:15]1[CH:16]=[C:17]2[C:9]([I:8])=[CH:10][N:11]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:12]2=[N:13][CH:14]=1)=[O:39])[CH3:36]
Reactant: Nc1cnc2c(c1)c(I)cn2S(=O)(=O)c1ccccc1
Reactant: CCN=C=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNC(=O)Nc1cnc2c(c1)c(I)cn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of Example 226a (120 mg, 0.234 mmol) in 5 mL dichloromethane was added triethylamine (0.326 mL, 2.34 mmol) followed by addition of ethyl isocyanate (0.074 mL, 0.935 mmol). The reaction mixture was stirred 16 hours at room temperature and then concentrated to dryness. The residue was partitioned with sodium bicarbonate solution and ethyl acetate. The organics were concentrated to dryness and the residue purified by silica gel flash chromatography eluting with 15% ethyl acetate, 85% dichloromethane to give the title compound as a pink-brown powder in quantitative yield. MS (ESI+) m/z 471.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4[N:18]=[N:19][NH:20][CH:21]=4)=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.IC.[C:24](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4[CH:21]=[N:20][N:19]([CH3:24])[N:18]=4)=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc(-n2ccc3cc(-c4c[nH]nn4)ccc32)cc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: Cn1ncc(-c2ccc3c(ccn3-c3ccc(F)cc3)c2)n1

Procedure:
A mixture of 1-(4-fluorophenyl)-5-triazol-4-yl-1H-indole (6.0 g), iodomethane (6.7 mL), potassium carbonate (6.0 g) and acetone (100 mL) was boiled under weak reflux for 18 hours. The reaction mixture was filtered and the volatile solvents evaporated in vacuo. The mixture of 1-methyl- and 2-methyl-substituted triazoles was separated by column chromatography on silica gel (ethyl acetate/heptane 1:1). Evaporation of the fastest eluting fractions in vacuo afforded pure 1-(4-fluorophenyl)-5-(2-methyltriazol-4-yl)-1H-indole (20a) as an oil: (2.1 g): 1H NMR (CDCl3) δ 4.25 (s, 3H), 6.70 (d, 1H), 7.20 (t, 2H), 7.30 (d, 1H), 7.40-7.55 (m, 3H), 7.65 (broad d, 1H), 7.85 (s, 1H), 8.10 (broad s, 1H). Evaporation of the slowest eluting fractions in vacuo afforded pure 1-(4-fluorophenyl)-5-(1-methyltriazol-4-yl)-1H-indole (20b) as an oil (0.8 g): 1H NMR (CDCl3) δ 4.15 (s, 3H), 6.70 (d, 1H), 7.20 (t, 2H), 7.30 (d, 1H), 7.50 (dd, 2H), 7.55 (d, 1H), 7.70 (broad d, 1H), 7.75 (s, 1H), 8.10 (broad s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25](=[O:42])(=[O:41])[NH:26][C:27]3[CH:32]=[CH:31][C:30]([N:33]([CH3:35])[CH3:34])=[C:29]([C:36]4[O:37][CH:38]=[CH:39][CH:40]=4)[CH:28]=3)[CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:34][N:33]([CH3:35])[C:30]1[CH:31]=[CH:32][C:27]([NH:26][S:25]([C:21]2[CH:20]=[C:19]([S:16]([NH:15][CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)(=[O:18])=[O:17])[CH:24]=[CH:23][CH:22]=2)(=[O:42])=[O:41])=[CH:28][C:29]=1[C:36]1[O:37][CH:38]=[CH:39][CH:40]=1
Reactant: CN(C)c1ccc(NS(=O)(=O)c2cccc(S(=O)(=O)NCC3CCN(C(=O)OC(C)(C)C)CC3)c2)cc1-c1ccco1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1ccc(NS(=O)(=O)c2cccc(S(=O)(=O)NCC3CCNCC3)c2)cc1-c1ccco1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 103 %

Procedure:
To a solution (10 ml) of Y244 (332 mg, 0.53 mmol) produced in Example 5 in dichloromethane was added trifluoroacetic acid (3 ml), and the mixture was stirred at room temperature for 20 min. Then, the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol (8:1-3:1)) to give the title compound (283 mg, 87%).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:19]1[CH:20]=[C:21]([NH:25][C:26]([O:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH:37]([NH:41][C:42]3[CH:43]=[C:44]4[C:49](=[CH:50][CH:51]=3)[C:48]([N:52]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])=[N:47][CH:46]=[CH:45]4)[C:38]([OH:40])=[O:39])=[CH:33][C:32]=2[CH3:67])=[O:27])[CH:22]=[CH:23][CH:24]=1)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=O)C1C=CC=CC=1>CO.Cl.[Pd]>[NH2:11][C@H:12]([C:19]1[CH:20]=[C:21]([NH:25][C:26]([O:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH:37]([NH:41][C:42]3[CH:43]=[C:44]4[C:49](=[CH:50][CH:51]=3)[C:48]([N:52]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[C:60]([O:62][C:63]([CH3:66])([CH3:64])[CH3:65])=[O:61])=[N:47][CH:46]=[CH:45]4)[C:38]([OH:40])=[O:39])=[CH:33][C:32]=2[CH3:67])=[O:27])[CH:22]=[CH:23][CH:24]=1)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C[C@H](NC(=O)OCc1ccccc1)c1cccc(NC(=O)OCCc2ccc(C(Nc3ccc4c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc4c3)C(=O)O)cc2C)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCOC(=O)C[C@H](N)c1cccc(NC(=O)OCCc2ccc(C(Nc3ccc4c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc4c3)C(=O)O)cc2C)c1
Yield: 79.5 %

Procedure:
A solution of 34F (670 mg, 0.96 mmol) in MeOH (60 mL) and HCl (2.5 mL, 1.0 M aqueous) and Pd/C (60 mg) was stirred under an atmosphere of H2 (60 psi) for 8 h. The solution was filtered and concentrated in vacuo to yield 34G (600 mg, 89%) as a yellow solid. MS (ESI) m/z 786.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[N+:29]([O-:31])=[O:30])[C:6]([C:8]1[N:16]2[C:11]([CH:12]=[CH:13][CH:14]=[CH:15]2)=[C:10]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:9]=1[CH3:25])=[O:7].[H-].[Na+].CI.[C:36](=O)(O)[O-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[N+:29]([O-:31])=[O:30])[C:6]([C:8]1[N:16]2[C:11]([CH:12]=[CH:13][CH:14]=[CH:15]2)=[C:10]([N:17]([CH3:36])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:21])[CH3:22])[C:9]=1[CH3:25])=[O:7]
Reactant: COc1cc(C(=O)c2c(C)c(NC(=O)OC(C)(C)C)c3ccccn23)ccc1[N+](=O)[O-]
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1cc(C(=O)c2c(C)c(N(C)C(=O)OC(C)(C)C)c3ccccn23)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
3.05 g (7.2 mmol) of tert-butyl 3-(3-methoxy-4-nitrobenzoyl)-2-methylindolizin-1-ylcarbamate in solution in 50 ml of tetrahydrofuran are added dropwise to 315 mg (7.9 mmol) of sodium hydride (at 60% as a dispersion in oil) in suspension in 10 ml of tetrahydrofuran, cooled to 0° C. After stirring for 1 hour at 0° C., 0.59 ml (9.5 mmol) of methyl iodide is added while the medium is maintained at 0° C. It is allowed to return to room temperature and it is stirred for 1 hour. The reaction medium is poured over a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase is separated after settling out, washed with a saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. 3.47 g of an orange-coloured foam are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([NH:15][NH2:16])=[O:14])=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[OH:17][C:18]([CH3:23])([CH3:22])[C:19](O)=O>>[NH2:1][C:2]1[C:3]([C:13]2[O:14][C:19]([C:18]([OH:17])([CH3:23])[CH3:22])=[N:16][N:15]=2)=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CC(C)(O)C(=O)O
Reactant: NNC(=O)c1nc(Br)c(C(F)(F)F)cc1N
Product: CC(C)(O)c1nnc(-c2nc(Br)c(C(F)(F)F)cc2N)o1

Procedure:
The title compound was prepared from 3-amino-6-bromo-5-(trifluoromethyl)picolinohydrazide (Intermediate H) and 2-hydroxy-2-methylpropanoic acid analogously to Example 10 (leave out step 4);
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][OH:7])[C@H:3]([CH3:5])[OH:4].N1C=CN=C1.[Si:13](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C.CCOC(C)=O>[NH2:1][C@@H:2]([CH2:6][O:7][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C@@H:3]([OH:4])[CH3:5]
Reactant: C[C@H](O)[C@@H](N)CO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](O)[C@@H](N)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 49.1 %

Procedure:
D-threoninol (2 g, 19.02 mmol) was dissolved in DMF (15 ml), treated with imidazole (3.89 g, 57.1 mmol) and stirred at RT for 5 min. Then, TBDPS-Cl (5.13 ml, 19.97 mmol) was added dropwise to the reaction solution under argon. The reaction solution was stirred for 16H at RT. Then it was diluted in EtOAc and washed twice with saturated NaHCO3 solution and once with brine. Organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (heptane/EtOAc: 100%→0% heptane.) to give the title compound (3.21 g, 47%). tR: 0.98 min (LC-MS 1); ESI-MS: 344.3 [M+H]+ (LC-MS 1).
Reaction SMILES: [C:1]12([CH2:10][NH2:11])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.N1C=CC=CC=1.[Br:18][CH2:19][C:20](Br)=[O:21]>CCOCC>[Br:18][CH2:19][C:20]([NH:11][CH2:10][C:1]12[C:7]([CH3:8])([CH3:9])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2)=[O:21]
Reactant: O=C(Br)CBr
Reactant: CC1(C)C2CCC1(CN)CC2
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC1(C)C2CCC1(CNC(=O)CBr)CC2
Temperature: 25 °C

Procedure:
10-Bornanamine (0.5 g) in dry ether (30 ml) containing pyridine (C.45 ml) was treated at -80° with a solution of bromoacetyl bromide (0.3 ml) in ether (5 ml) over one minute with stirring. The mixture was allowed to warm to room temperature and after a further 30 min. it was partitioned between ether and water. The organic layer was washed with 2N-hydrochloric acid solution and then water. It was dried (MgSO4) and evaporated. The residue (0.73 g.) was purified by preparative layer chromatography and by crystallisation from petroleum ether (bp. 60°-80°) to give the title compound (0.48 g) mp. 89°, (Found: C, 52.4; H, 7.3; Br, 28.9; N, 5.0; C12H20BrNO requires C, 52.55; H, 7.35; Br, 29.1; N,5.1%).
Reaction SMILES: [F:1][C:2]([N:5]=[C:6]=[O:7])([F:4])[F:3].[CH3:8][C:9]1[CH:10]=[C:11]([NH:15][OH:16])[CH:12]=[CH:13][CH:14]=1>C(OCC)C>[F:1][C:2]([F:4])([F:3])[NH:5][C:6]([N:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([CH3:8])[CH:10]=1)[OH:16])=[O:7]
Reactant: Cc1cccc(NO)c1
Reactant: O=C=NC(F)(F)F
Solvent: CCOCC
Product: Cc1cccc(N(O)C(=O)NC(F)(F)F)c1
Reaction time: 1 h

Procedure:
A solution of trifluoromethyl isocyanate (11.1 grams; 0.1 mol) in diethyl ether (50 ml) is added dropwise, with stirring, to a solution of N-(3-methylphenyl) hydroxylamine (12.3 grams; 0.1 mol) in diethyl ether (50 ml) at room temperature. Stirring is continued for a period of about 1 hour resulting in the formation of a precipitate. The precipitate is recovered by filtration, is washed and dried to yield 1-trifluoromethyl-3-(3'-methylphenyl)-3-hydroxyurea.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][CH:12]=[CH:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(OCC)=O)C.[C:20]([C:22]1[CH:29]=[CH:28][C:25](C=O)=[CH:24][CH:23]=1)#[N:21].C(OCC)(=O)C>O1CCCC1.[Cl-].[Na+].O>[C:20]([C:22]1[CH:29]=[CH:28][C:25]([CH:11]=[CH:12][CH:13]=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:24][CH:23]=1)#[N:21]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CCOC(=O)CC=CCP(=O)(OCC)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C=CC=Cc1ccc(C#N)cc1
Temperature: -10 °C
Yield: 29 %

Procedure:
The mixture of 60% sodium hydride (7.92 g) in tetrahydrofuran (100 ml) was stirred at -10° C. under nitrogen gas. To reaction mixture was poured ethyl 5-diethoxyphosphoryl-3-pentenoate (49.61 g) and stirred for 1 hour at -10° C. To reaction mixture was poured p-cyanobenzaldehyde (20.00 g) in tetrahydrofuran (50 ml) and stirred for 3 hours at 0° C. The reaction mixture was poured into a mixture of brine and ethyl acetate. The separated organic layer was dried over magnesium sulfate and treated with activated charcoal. After filtration, the filtrate was evaporated in vacuo. The residue was subjected to column chromatography on silica gel and eluted with ethyl acetate/n-hexane=1:4. The fractions containing the object compound were combined and evaporated in vacuo, and give ethyl 5-(4-cyanophenyl)-2,4-pentadienoate (10.04 g).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[OH:13])([CH3:3])[CH3:2].[Br:14]Br>C(O)(=O)C>[Br:14][C:6]1[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[OH:13]
Reactant: BrBr
Reactant: CC(C)c1ccc(O)c(C(C)C)c1
Solvent: CC(=O)O
Product: CC(C)c1cc(Br)c(O)c(C(C)C)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100.7 %

Procedure:
To a solution of 2,4-diisopropyl-phenol (Intermediate 1, 10.0 g, 56 mmol) in acetic acid (20 mL) was added bromine (3.5 mL, 67 mmol) at 0° C. The mixture was stirred at 0° C. for 15 min, quenched with water and extracted with EtOAc. The organic layer was washed successively with NaOH (4M, 85 mL), NaHSO3, and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (hexanes) to yield the title compound as a light yellow oil (14.5 g, 100%).