Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:20]([OH:22])=O)=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])[N:5]2[C:10]=1[CH:9]=[CH:8][N:7]=[CH:6]2.[CH3:23][C:24]1([CH3:32])[O:28][C@@H:27]([CH2:29][O:30][NH2:31])[CH2:26][O:25]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:23][C:24]1([CH3:32])[O:28][C@@H:27]([CH2:29][O:30][NH:31][C:20]([C:3]2[C:2]([Cl:1])=[C:10]3[CH:9]=[CH:8][N:7]=[CH:6][N:5]3[C:4]=2[NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[O:22])[CH2:26][O:25]1
Reactant: CC1(C)OC[C@H](CON)O1
Reactant: O=C(O)c1c(Cl)c2ccncn2c1Nc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](CONC(=O)c2c(Cl)c3ccncn3c2Nc2ccc(I)cc2F)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.9 %

Procedure:
5-Chloro-7-(2-fluoro-4-iodo-phenylamino)-pyrrolo[1,2-c]pyrimidine-6-carboxylic acid (145 mg, 0.34 mmol), O—((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (50 mg, 0.34 mmol), HOBt (50 mg, 0.37 mmol), EDCI hydrochloride (71 mg, 0.37 mmol) and DIPEA (63 μL, 0.37 mmol) were dissolved in DMF (3 mL). The reaction was stirred at room temperature for 3 hours then concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 25-100% ethylacetate in cyclohexane) to yield the title compound as a brown solid (57 mg, 25%). LCMS (Method B): RT=3.63 min, M+H+=561.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:12]([C:18](=[CH2:23])[C:19]([O:21][CH3:22])=[O:20])=[C:13]([CH3:17])[S:14][C:15]=3[CH3:16])=[CH:10][C:5]=2[CH2:4][CH2:3][CH2:2]1.[C:24]([Li])([CH3:27])([CH3:26])[CH3:25].CCCCC>O1CCCC1>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:12]([CH:18]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]([O:21][CH3:22])=[O:20])=[C:13]([CH3:17])[S:14][C:15]=3[CH3:16])=[CH:10][C:5]=2[CH2:4][CH2:3][CH2:2]1
Reactant: C=C(C(=O)OC)c1c(C)sc(C)c1-c1ccc2c(c1)CCCO2
Reactant: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: COC(=O)C(CC(C)(C)C)c1c(C)sc(C)c1-c1ccc2c(c1)CCCO2
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 76 %

Procedure:
Under a nitrogen atmosphere, a solution of methyl 2-[4-(3,4-dihydro-2H-1-benzopyran-6-yl)-2,5-dimethylthiophen-3-yl]prop-2-enoate (42c) (114 mg, 0.35 mmol) in anhydrous tetrahydrofuran (5 mL) was cooled to −78° C. tert-Butyllithium 1.6M in pentane (0.24 mL, 0.38 mmol) was added dropwise and the reaction mixture was stirred at −78° C. for 20 minutes before being quenched with brine (3 mL). The mixture was extracted with dichloromethane (2×6 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (cyclohexane/ethyl acetate 70/30) to provide the desired product (42d) (102 mg, 0.26 mmol, 76%) as a light yellow oil.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[C:5]([O:13][CH2:14][CH2:15][C@@H:16]2[CH2:18][C@@H:17]2[CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[CH2:21][CH2:20]2)=[N:6][CH:7]=[C:8]([N+:10]([O-])=O)[CH:9]=1>CO.C(Cl)Cl.Cl[Ni]Cl>[NH2:10][C:8]1[CH:9]=[C:4]([CH3:3])[C:5]([O:13][CH2:14][CH2:15][C@@H:16]2[CH2:18][C@@H:17]2[CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:26])[CH2:21][CH2:20]2)=[N:6][CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1OCC[C@@H]1C[C@@H]1C1CCN(C(=O)OCc2ccccc2)CC1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(N)cnc1OCC[C@@H]1C[C@@H]1C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 0.08 h

Procedure:
To the solution of NiCl2 (Nickel (II) Chloride-hexahydrate, 1.03 g, 4.32 mmol) in 40 ml of methanol was added 150 mg of NaBH4 (it turned dark) at RT and the mixture stirred 5 minutes. Benzyl 4-((1R,2S)-2-{-[(3-methyl-5-nitropyridin-2-yl)oxy]ethyl}cyclopropyl)piperidine-1-carboxylate (1.90 g, 4.32 mmol) in 15 ml of DCM was added followed by the addition of another 116 mg of NaBH4 in 3 portions. The resulting mixture was then stirred for 40 minutes. The reaction was then diluted with DCM and filtered through a celite and silica gel pad. The filtrate was concentrated in vacuo and the residue was partitioned between saturated NaHCO3 aqueous solution and DCM. The organics were separated, dried over sodium sulfate, filtered and the filtrate concentrated under reduced pressure to afford the title compound as a crude product which was used for the next step. LC/MS (m/z): 410 (M+H)+.
Reaction SMILES: [CH3:1][NH2:2].C(O)C.Br[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][C:17]([C:19]3[C:20]([NH2:37])=[N:21][CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([S:31]([CH:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])=[CH:27][CH:26]=4)[N:24]=3)=[N:16][N:15]=2)=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CO>[CH:34]([S:31]([C:28]1[CH:29]=[CH:30][C:25]([C:23]2[N:24]=[C:19]([C:17]3[O:18][C:14]([C:11]4[CH:10]=[CH:9][C:8]([CH2:7][NH:2][CH3:1])=[CH:13][CH:12]=4)=[N:15][N:16]=3)[C:20]([NH2:37])=[N:21][CH:22]=2)=[CH:26][CH:27]=1)(=[O:33])=[O:32])([CH3:35])[CH3:36]
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccc(CBr)cc4)o3)n2)cc1
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: CNCc1ccc(-c2nnc(-c3nc(-c4ccc(S(=O)(=O)C(C)C)cc4)cnc3N)o2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
MeNH2 in ethanol (184.9 g, 243.6 mL of 33% w/w, 1.965 mol) was added in one portion to a stirred solution of 3-[5-[4-(bromomethyl)phenyl]-1,3,4-oxadiazol-2-yl]-5-(4-isopropylsulfonylphenyl)pyrazin-2-amine (10.11 g, 19.65 mmol) in CH2Cl2 (1.01 L) and methanol (1.01 L) and the resulting mixture stirred overnight at room temperature. Nitrogen was bubbled through reaction for 2 h and then the reaction mixture was concentrated in vacuo. The crude material was stirred in K2CO3 (393.0 mL of 0.25 M, 98.25 mmol) for 2 h and then isolated by filtration and washed with water. Triturated with warm acetonitrile to leave the product as a yellow solid (7.19 g, 75% yield); 1H NMR (400 MHz, DMSO) d 1.19-1.21 (d, 6H), 2.30 (m, 3H), 3.35-3.49 (m, 1H), 3.77 (m, 2H), 7.61-7.63 (d, 2H), 7.97-7.99 (d, 2H), 8.11-8.13 (d, 2H), 8.39-8.41 (d, 2H) and 9.06 (s, 1H) ppm; MS (ES+) 465.4
Reaction SMILES: [Cl-].[NH4+:2].[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:11]>O.CO.[Fe]>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:2])=[CH:6][C:5]=1[O:10][CH3:11]
Reactant: COc1ccccc1Br
Reactant: [NH4+]
Agent: [Fe]
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: COc1cc(N)ccc1Br
Temperature: 75 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
A suspension of iron powder (40.8 g, 0.730 mol), ammonium chloride (64.7 g, 1.21 mol) and 2-bromoanisole (50 g, 0.215 mol) in water (1.5 L) and MeOH (1 L) was stirred overnight at 75° C. The solid was filtered off and the liquid was diluted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and the solvents were evaporated under vacuum. 43.1 g of the title compound were obtained. Brown solid, ISP-MS: m/e=203.1 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])=[O:5].[Cl:22][CH2:23][C:24](Cl)=O>C(O)(=O)C>[Cl:22][CH2:23][C:24]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:4](=[O:5])[C:3]2[C:2](=[C:17]([C:18]([F:21])([F:19])[F:20])[CH:16]=[CH:15][CH:14]=2)[N:1]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1c(C(=O)Nc2ccccc2Cl)cccc1C(F)(F)F
Solvent: CC(=O)O
Product: O=c1c2cccc(C(F)(F)F)c2nc(CCl)n1-c1ccccc1Cl
Yield: 60.5 %

Procedure:
Prepared according to Procedure B with 1m (500 mg, 1.59 mmol) and chloroacetyl chloride (0.38 mL, 4.77 mmol) in acetic acid (10 mL). Purified by recrystallization from isopropanol to afford 359 mg of a white crystalline solid (61%). 1H NMR (CDCl3) δ: 8.51 (dd, J=1.0, 8.0 Hz, 1H); 8.14 (d, J=7.3 Hz, 1H); 7.65 (dd, J=2.5, 5.6 Hz, 1H); 7.62 (d, J=3.9 Hz, 1H); 7.48-7.60 (m, 3H); 4.44 (d, J=12 Hz, 1H), 4.12 (d, J=12 Hz, 1H). MS (ES): m/z 373.0 (M+).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)[CH3:10])[CH:5]=[CH:4][CH:3]=1.[CH3:18][S-:19].[Na+]>CS(C)=O>[CH3:18][S:19][C:5]1[C:6]([O:8][CH:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)[CH3:10])=[N:7][CH:2]=[CH:3][CH:4]=1
Reactant: C[C@@H](Oc1cccc(F)n1)c1ccnc(N)n1
Reactant: C[S-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CSc1cccnc1OC(C)c1ccnc(N)n1
Temperature: 140 °C
Reaction time: 0.08 h
Yield: 51.9 %

Procedure:
To a solution of (R)-4-(1-(6-fluoro-pyridin-2-yloxy)ethyl)pyrimidin-2-amine (389 mg) (prepared as described for (R)-4-(1-(6-fluoro-pyridin-2-yloxy)ethyl)pyrimidin-2-amine but starting from 1-(2-aminopyrimidin-4-yl)ethanol) in dry dimethylsulfoxide (10 mL) was added sodium methanethiolate (582 mg) the solution was stirred for 5 min and then heated with microwave irradiation at 140° C. for 300 sec. The resulting mixture was quenched into water (300 mL) the resulting solid was filtered and washed with water and dried. The solid was triturated with heptane and further to give the title compound (226 mg) as a pale brown solid, MS (ES): m/z 263 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:7](C(O)=O)=[CH:6][N:5]=[C:4]([OH:11])[CH:3]=1.P(=O)(O)(O)O.C(O)(=O)C.[N+:21]([O-])([OH:23])=[O:22].O>>[OH:11][C:4]1[C:3]([N+:21]([O-:23])=[O:22])=[C:2]([OH:1])[CH:7]=[CH:6][N:5]=1
Reactant: O=C(O)c1cnc(O)cc1O
Reactant: O=[N+]([O-])O
Agent: O=P(O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1c(O)ccnc1O
Temperature: 90 °C
Reaction time: 4.5 h
Yield: 55.5 %

Procedure:
A 3-neck 22 L flask equipped with a temperature probe with a chart recorder, mechanical stirrer, a Dean-Stark apparatus and a reflux condenser is charged with 4,6-dihydroxy nicotinic acid (88 %, 2.0 Kg, 12.81 mol), phosphoric acid (85%. 6 L, 103.15 mol). The off gases from the condenser are scrubbed by bubbling into 50% aqueous NaOH. The suspension is heated until a sufficient amount of water has been removed (about 1.2 L), i.e., dehydration of the phosphoric acid. Without the dehydration of the phosphoric acid, the carboxylation does not occur. For the internal temperature to reach 210° C.±5° C., a mantle temperature of 290° C. is applied over an elapsed time of 3.5 hours. After being stirred for 4-5 hours at that temperature, the disappearance of the starting material is confirmed by HPLC. The reaction mixture is then allowed to cool down to a temperature of less than 100° C., at which point acetic acid (6 L, 104.81 mol) is added and the temperature is maintained at 90° C. To this mixture is added nitric acid (485 mL, 12.11 mol) at a constant rate (5-6 mL/minute) until HPLC shows no more 4,6-dihydroxy nicotinic acid present. Water (6 L, 333.3 mol) is then added to the reaction and heating is stopped. A yellow solid starts appearing at a temperature of less than 80° C. and is allowed to precipitate with stirring overnight. Filtration in a scintered glass funnel (course porosity) yields a yellow solid which is then washed with 2.5 L of isopropyl alcohol. The resulting cake is air-dried for 48 hours and then put in a drying oven under vacuum (20 in. Hg with a air bleed) at 50° C. for 3 days. 2,4-dihydroxy-3-nitropyridine (1.050 Kg) is obtained in 60% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@@H:4]1[CH2:8][C@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:20])[C@@H:4]1[CH2:8][C@H:7]([O:9][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:6][N:5]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OCc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.59 g (5.7 mmol) of N-benzyloxycarbonyl-4-hydroxy-L-cis-proline methyl ester are dissolved in 50 ml of abs. pyridine and cooled to 0° C. 0.6 ml (7.7 mmol) of methanesulphonyl chloride is added dropwise at 0° C., and the mixture is subsequently stirred at room temperature for 3 hours. The mixture is then concentrated and 100 ml of methylene chloride are added to the residue, and this latter mixture is then extracted 2 x by shaking with a 10% solution of NaHCO3, dried over sodium sulphate and concentrated once again, with the residue being subsequently distilled repeatedly with toluene. Yield: quantitative Rf : 0.33, eluent, toluene/EtOH (10:1)
Reaction SMILES: [C:1]([O:4][C@@H:5]1[N:8]([Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[C:7](=[O:16])[C@H:6]1[NH2:17])(=[O:3])[CH3:2].[Br:18][CH:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](O)=[O:21]>>[C:1]([O:4][C@@H:5]1[N:8]([Si:9]([C:12]([CH3:13])([CH3:15])[CH3:14])([CH3:10])[CH3:11])[C:7](=[O:16])[C@H:6]1[NH:17][C:20](=[O:21])[CH:19]([Br:18])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:3])[CH3:2]
Reactant: O=C(O)C(Br)c1ccccc1
Reactant: CC(=O)O[C@H]1[C@H](N)C(=O)N1[Si](C)(C)C(C)(C)C
Product: CC(=O)O[C@H]1[C@H](NC(=O)C(Br)c2ccccc2)C(=O)N1[Si](C)(C)C(C)(C)C
Yield: 58.9 %

Procedure:
Following the procedure of Reference Example 16B but using 0.385 g of (3S,4S)-4-acetoxy-3-amino-1-t-butyldimethylsilyl-2-oxoazetidine and 0.384 g of 2-bromo-2-phenylacetic acid there is obtained 0.40 g of (3S,4S)-4-acetoxy-3-(2-bromo-2-phenylacetamido)-1-t-butyldimethylsilyl-2-oxoazetidine.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:9]
Reactant: Nc1ccccc1
Reactant: O=C(O)c1cc(Br)ccc1O
Product: O=C(Nc1ccccc1)c1cc(Br)ccc1O
Yield: 68.8 %

Procedure:
Using 5-bromosalicylic acid and aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[CH3:2].[N:15]([CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[N+:16]=[N-:17]>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[N:15]([CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:16]=[N:17][C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=1)=[O:14])[CH3:2]
Reactant: CCOC(=O)C#Cc1ccc(F)cc1
Reactant: C[Si](C)(C)CN=[N+]=[N-]
Solvent: c1ccccc1
Product: CCOC(=O)c1c(-c2ccc(F)cc2)nnn1C[Si](C)(C)C
Reaction time: 5 h
Yield: 41.2 %

Procedure:
To a solution of (4-fluoro-phenyl)-propynoic acid ethyl ester (1.45 g, 7.55 mmol) in benzene (25 mL) was added azidomethyl-trimethyl-silane (1.17 g, 9.05 mmol) and the reaction mixture was refluxed under nitrogen for 72 h. A subsequent batch of azidomethyl-trimethyl-silane (0.29 g, 2.26 mmol) was added and refluxing was continued for 5 h. The mixture was then evaporated and purification by chromatography (silica, 0 to 50% ethyl acetate in heptane) afforded the title compound (1.0 g, 41%) as a yellow oil. MS: m/e=322.2 [M+H]+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(C)(C)C.[C:21]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]2[C:33]3[CH:42]=[CH:41][C:40]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=4[C:49]([F:52])([F:51])[F:50])=[N:39][C:34]=3[N:35]=[C:36]([Cl:38])[N:37]=2)=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22]>C(#N)C>[C:21]([C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:32]2[C:33]3[CH:42]=[CH:41][C:40]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=4[C:49]([F:52])([F:51])[F:50])=[N:39][C:34]=3[N:35]=[C:36]([Cl:38])[N:37]=2)=[CH:29][CH:30]=1)([CH3:24])([CH3:22])[CH3:23].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)Nc1ccccc1
Agent: CC(C)(C)c1ccc(Nc2nc(Cl)nc3nc(-c4ccccc4C(F)(F)F)ccc23)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Nc1ccccc1
Temperature: 80 °C

Procedure:
To a mixture of diisopropylethylamine (260 mg, 2.0 mmol) in acetonitrile (5 mL), add t-butylaniline (124 mg, 1.0 mmol) followed by (4-tert-Butyl-phenyl)-[2-chloro-7-(2-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidin-4-yl]-amine (310 mg, 1.0 mmol). Heat the mixture to 80° C. for six hours. Evaporate the solvent, and partition between 1M NaOH and EtOAc. Dry the solvent (Na2SO4) and evaporate. Purify by silica gel chromatography (1:1 hexanes/EtOAc to furnish the monoaniline (4-tert-Butyl-phenyl)-[2-chloro-7-(2-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidin-4-yl]-amine as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:12])[C:7](=[O:11])[N:8]2[CH3:13])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1Nc2cc(Br)ccc2C1=O
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CN1C(=O)C(=O)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 6-bromoisatin (CAS#6326-79-0, 4.52 g, 20.0 mmol) in acetonitrile (150 mL) was added potassium carbonate (11.1 g, 80 mmol) followed by iodomethane (2.75 mL, 44.0 mind). The reaction was then placed at 60° C. and stirred for 40 minutes. The reaction was then cooled to room temperature, filtered and concentrated to 10% of the original volume. The reaction was then diluted with dichloromethane, water, and brine. The layers were separated and the aqueous layer was extracted two additional times with dichloromethane. The organic extracts were combined, dried over anhydrous sodium sulfate filtered and concentrated to provide 6-bromo-1-methyl-1H-indole-2,3-dione as an orange solid without the need for further purification. The 6-bromo-1-methyl-1H-indole-2,3-dione (1.0 g, 4.2 mmol) was then treated with hydrazine hydrate (7.0 mL, 225 mmol). The reaction was heated to 130° C. and stirred for 80 minutes, at which time the reaction was placed at room temperature and cooled by the addition of ice. Once the reaction was cooled to room temperature it was diluted with dichloromethane and water and the layers were separated. The aqueous layer was extracted an additional two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethanol-dichloromethane 0 to 2%) to afford 6-bromo-1-methyl-1,3-dihydro-indol-2-one; MS: (ES+) m/z 225.9 (M+H)+.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[OH-].[Na+:12]>>[C:1]([O-:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Na+:12]
Reactant: O=C(O)c1ccccc1O
Agent: [Na+]
Agent: [OH-]
Product: O=C([O-])c1ccccc1O

Procedure:
A blend of 17% by weight of sodium salicylate and 83% by weight of condensate were prepared by mixing 100 grams of 40% by weight of condensate, 8 grams of salicylic acid and 19 grams of dilute sodium hydroxide (1.3 grams in 100 grams water). The mixture contained 38.8% by weight solids and had a pH of 8.5.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][N:11]([CH2:18][CH2:19][OH:20])[C:12]1[N:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:10][N:11]([CH2:18][CH2:19][O:20][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:12]1[N:13]=[CH:14][CH:15]=[CH:16][N:17]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CN(CCO)c1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CN(CCOc1ccc(C=O)cc1)c1ncccn1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
A mixture of 4-fluorobenzaldehyde (12 ml) and 2-[N-methyl-N-(2-pyrimidinyl)amino]ethanol (10.05 g) in dry dimethyl sulphoxide (50 ml) containing anhydrous potassium carbonate (15 g) was stirred at 120° C. for 6 hours. The mixture was cooled to room temperature and added to water (200 ml). The aqueous solution was extracted with ethyl acetate (2×300 ml), the organic extracts washed with brine, dried (MgSO4) and evaporated. The title compound was obtained as an oil following chromatography on silica-gel in 2% methanol in dichloromethane.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([OH:14])[CH:8]=[CH:7]2.I[CH2:16][CH2:17][CH2:18][CH3:19].CN(C=O)C>C1COCC1.O>[Br:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH2:16][CH2:17][CH2:18][CH3:19])[CH:10]=2)[CH:5]=1
Reactant: CCCCI
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CCCCOc1ccc2cc(Br)ccc2c1
Yield: 92.2 %

Procedure:
An oil dispersion of 480 mg (50%, 10 mmol, Alfa) of sodium hydride was washed three times with petroleum ether then the residue covered with 5 ml of dry THF. To the resulting stirred slurry was added dropwise a solution of 2.00 g (8.97 mmol, Aldrich) of 6-bromo-2-naphthol, in 10 ml of THF over 10 minutes. The reaction mixture was stirred for 30 minutes then 1.70 g (9.23 mmol, Aldrich) of 1-iodobutane and 15 ml of sieve-dried DMF were added. The resulting solution was heated to 60° for two hours, then cooled, added to 100 ml of H2O and extracted with 50 ml of petroleum ether. The organic extract was washed with an additional 100 ml of H2O, dried (MgSO4) and concentrated in vacuo to give a solid. The crude material was purified by flash chromatography (15×5 cm, pet ether) to afford 2.31 g (92%) of title compound as a white solid, m.p. 48°-50°.
Reaction SMILES: C(C1C=C(C2O[N:12]=[C:11]([C:14]3[CH:29]=[C:28]([CH3:30])[C:17]([O:18][CH2:19][CH:20]([OH:27])[CH2:21][NH:22][C:23](=[O:26])[CH2:24][OH:25])=[C:16]([CH3:31])[CH:15]=3)[N:10]=2)C=CC=1)=O.[CH:32]([C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=O)=[CH:36][C:35]=1[CH3:43])=[O:33].OCC(NCC(O)COC1C(C)=CC(C(=N)NO)=CC=1C)=O>>[CH:32]([C:34]1[CH:42]=[CH:41][C:37]([C:38]2[O:40][N:12]=[C:11]([C:14]3[CH:15]=[C:16]([CH3:31])[C:17]([O:18][CH2:19][CH:20]([OH:27])[CH2:21][NH:22][C:23](=[O:26])[CH2:24][OH:25])=[C:28]([CH3:30])[CH:29]=3)[N:10]=2)=[CH:36][C:35]=1[CH3:43])=[O:33]
Reactant: Cc1cc(-c2noc(-c3cccc(C=O)c3)n2)cc(C)c1OCC(O)CNC(=O)CO
Reactant: Cc1cc(C(=O)O)ccc1C=O
Agent: Cc1cc(C(=N)NO)cc(C)c1OCC(O)CNC(=O)CO
Product: Cc1cc(-c2nc(-c3cc(C)c(OCC(O)CNC(=O)CO)c(C)c3)no2)ccc1C=O

Procedure:
The title compound was prepared in analogy to rac-N-(3-{4-[5-(3-formyl-phenyl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide, starting from 4-formyl-3-methyl benzoic acid and rac-2-hydroxy-N-{2-hydroxy-3-[4-(N-hydroxycarbamimidoyl)-2,6-dimethyl-phenoxy]-propyl}-acetamide.
Reaction SMILES: [I:1][C:2]1[C:3]([OH:12])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH2:19](I)[CH2:20][CH3:21].O>CN(C=O)C>[CH3:11][O:10][C:4]1[CH:5]=[C:6]([CH:9]=[C:2]([I:1])[C:3]=1[O:12][CH2:19][CH2:20][CH3:21])[CH:7]=[O:8]
Reactant: COc1cc(C=O)cc(I)c1O
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1c(I)cc(C=O)cc1OC
Temperature: 25 °C
Yield: 933.7 %

Procedure:
5-Iodovanillin (25 g, 0.009 mol) in DMF (100 mL) was treated with potassium carbonate (32 g, 0.23 mol) and n-propyl iodide (52 g, 0.3 mol, 31 mL) and heated for 16 hours. The solution was allowed to cool to room temperature and then poured into water (500 mL) and extracted with ether (3×250 mL). The organic layers were combined and washed with water and saturated sodium chloride solution, and then dried over magnesium sulfate. The organic layer was evaporated by distillation under diminished pressure to an oil, and then purified by column chromatography (silica, 7:3 petroleum ether-ethyl acetate), to provide an amber colored solid (26.9 g, 93%).