Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[O-].[Na+].[CH3:4][O:5][CH:6]([CH2:11][CH:12]=[CH2:13])[CH2:7][CH:8]=[N:9][OH:10]>ClCCl>[CH3:4][O:5][CH:6]1[CH2:7][C:8]2=[N:9][O:10][CH2:13][CH:12]2[CH2:11]1
Reactant: C=CCC(CC=NO)OC
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: COC1CC2=NOCC2C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 51.8 %

Procedure:
A sodium hypochlorite solution (5% available chlorine, 9.36 mL) was added dropwise to a solution of 3-methoxy-5-hexenal oxime (450 mg) in dichloromethane (20 mL) at 0° C., and the mixture was stirred at 0° C. to room temperature for 1.5 hours. The reaction solution was poured into ice water, followed by extraction with dichloromethane. The extract was washed with a saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under normal pressure. The resulting crude product was purified by silica gel column chromatography to obtain the less polar title compound (230 mg) and the more polar title compound (150 mg).
Reaction SMILES: [I:1][C:2]1[C:3](N)=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2.N([O-])=O.[Na+].[ClH:19]>O.Cl[Cu]>[Cl:19][C:3]1[C:2]([I:1])=[CH:11][C:10]2[C:5]([CH:4]=1)=[CH:6][C:7]([O:12][CH3:13])=[CH:8][CH:9]=2
Reactant: COc1ccc2cc(I)c(N)cc2c1
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc2cc(I)c(Cl)cc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of 3-iodo-7-methoxynaphthalen-2-amine (see Intermediate 6, product of step 3) (1.0 g, 3.34 mmol) in water (20 mL) and conc. HCl (20 mL) was added a solution of NaNO2 (230 mg, 3.34 mmol) in water (10 mL) dropwise at 0° C. and the reaction was stirred at 0° C. for 1 hour. Then CuCl (400 mg, 4.04 mmol) was added and the mixture was stirred at 20° C. for 2 hours. An aqueous/EtOAc workup was followed by purification by silica gel column (PE/EtOAc=100/1) to give 3-chloro-2-iodo-6-methoxynaphthalene (900 mg, yield 85%) as off-white solid. 1H NMR (CDCl3 300 MHz TMS): δ 8.29 (s, 1H), 7.84 (s, 1H), 7.60 (d, J=9.0 Hz, 1H), 7.13 (dd, J=9.0, 2.7 Hz, 1H), 6.99 (d, J=2.4 Hz, 1H), 3.91 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][C:16]([C:22]3[CH:23]=[N:24][NH:25][CH:26]=3)=[CH:15]4)=[N:9][N:10]=2)[N:7]=1.[H-].[Na+].Br[CH2:30][C:31]([NH2:33])=[O:32]>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][C:16]([C:22]3[CH:23]=[N:24][N:25]([CH2:30][C:31]([NH2:33])=[O:32])[CH:26]=3)=[CH:15]4)=[N:9][N:10]=2)[N:7]=1
Reactant: Cc1ccc2nnc(Cc3ccc4ncc(-c5cn[nH]c5)cc4c3)n2n1
Reactant: NC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2nnc(Cc3ccc4ncc(-c5cnn(CC(N)=O)c5)cc4c3)n2n1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
6-(6-Methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-3-(1H-pyrazol-4-yl)-quinoline (65 mg, 0.19 mmol, 1 equiv) was dissolved in dimethylformamide (0.5 mL) and NaH (60% in oil, 1.2 equiv, 0.228 mmol, 9 mg) was added. The solution was stirred under nitrogen for 30 min and then 2-bromoacetamide (26 mg, 0.19 mmol, 1 equiv) was added and the solution heated at 90° C. for 18 h. The product was extracted into dichloromethane and washed with water. The organic phase was concentrated to dryness to afford the title compound (40 mg, 52% yield). Analytical data presented in Table 2.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1([CH3:11])[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1>CO>[Br:1][CH:6]1[CH2:5][C:4]([CH3:11])([CH3:3])[CH2:9][CH2:8][C:7]1=[O:10]
Reactant: BrBr
Reactant: CC1(C)CCC(=O)CC1
Solvent: CO
Product: CC1(C)CCC(=O)C(Br)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
1.71 g (10.7 mmol) of bromine were added in one portion to a solution of 1.35 g (10.7 mmol) of 4,4-dimethyl-cyclohexanone in methanol (10 ml) at −10° C. The reaction mixture was then stirred for 10 min at −10° C., for 30 min at 0° C. and finally for 8 h at RT. The reaction was then quenched by addition of water (5 ml) and stirred overnight at RT. Additional water was added (20 ml) leading to the formation of a precipitate that was collected by filtration. The crude 2-bromo-4,4-dimethyl-cyclohexanone (1.72 g, 78%) that was obtained as an orange solid was used in the next reaction step without further purification. 1HNMR (CDCl3, 300 MHz): δ 1.09 (s, 3H), 1.23 (s, 3H), 1.75 (m, 2H), 2.09 (t, J=13.1 Hz, 1H), 2.34 (ddd, J=13.3 and 6.1 and 2.8 Hz, 1H), 2.59 (m, 2H), 4.77 (dd, J=12.9 and 5.9 Hz, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][C:10]([F:13])([F:12])[F:11].Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)=[CH:20][CH:19]=1)=[O:16]>>[F:32][C:31]([F:34])([F:33])[C:28]1[CH:29]=[CH:30][C:25]([O:24][C:21]2[CH:22]=[CH:23][C:18]([O:17][C:15](=[O:16])[N:2]([CH3:1])[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[O:9][C:10]([F:11])([F:12])[F:13])=[CH:19][CH:20]=2)=[N:26][CH:27]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CNc1ccccc1OC(F)(F)F
Product: CN(C(=O)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)c1ccccc1OC(F)(F)F

Procedure:
The title product was prepared from N-methyl-2-(trifluoromethoxy)-aniline and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, preparative H PLC (method C) (49%, colourless oil). HPLC-MS m/z=473.2 (M+1), Rt: 5.18 min.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[I:22][C:23]1[N:24]=[CH:25][NH:26][CH:27]=1>>[I:22][C:23]1[N:24]=[CH:25][N:26]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:3]=2)[CH:27]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(Br)n2)cc1
Reactant: Ic1c[nH]cn1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(-n3cnc(I)c3)n2)cc1

Procedure:
The title compound was prepared 2-bromo-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (example A.19) (2.22 g, 6 mmol) and commercially available 4-iodo-imidazole (1.28 g, 6.6 mmol) according to the general procedure IVa. Obtained as a white solid (2.70 g, 86%, 92% purity). MS (ISP) 484.2 [(M+H)+].
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[N+:11]([CH3:14])([O-:13])=[O:12].[OH-].[Na+]>CO>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2](/[CH:1]=[CH:14]/[N+:11]([O-:13])=[O:12])=[CH:3][CH:4]=1
Reactant: C[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(/C=C/[N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a cool (0° C.), stirred solution of 4-anisaldehyde (1.75 mL, 14.3 mmol), nitromethane (2.0 mL, 36.9 mmol) in MeOH (6.0 mL) was added NaOH (1M, 40 mL), and allowed to warm to room temperature. After 2.5 hours, ice water was added with stirring, extracted with DCM (3×), the combined extracts were dried (MgSO4), filtered, concentrated and purified on Biotage Horizon to provide the product as a solid: 1H NMR (400 MHz, CDCl3) δ ppm: 7.97 (1H, d, J=13.64 Hz), 7.51 (1H, d, J=13.64 Hz), 7.50 (1H, d, J=8.84 Hz), 6.95 (2H, d, J=8.84 Hz), 3.86 (3H, s).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C@@H:25]1[C@@H:65]([CH2:66][O:67]C(=O)C)[O:64][C@@H:28]([O:29][N:30]2[CH:34]=[C:33]([CH2:35][O:36][C@H:37]3[CH2:61][CH2:60][C@@:59]4([CH3:62])[CH:39]([CH2:40][CH2:41][C@@H:42]5[C@@H:58]4[CH2:57][CH2:56][C@@:55]4([CH3:63])[C@H:43]5[CH2:44][CH2:45][C@@H:46]4[C@H:47]([CH3:54])[CH2:48][CH2:49][CH2:50][CH:51]([CH3:53])[CH3:52])[CH2:38]3)[N:32]=[N:31]2)[C@H:27]([O:71]C(=O)C)[C@H:26]1[O:75]C(=O)C)(=O)C.C[O-].[Na+].CO>CO.C(Cl)(Cl)Cl.CO>[C@@H:6]1([O:24][C@@H:25]2[C@@H:65]([CH2:66][OH:67])[O:64][C@@H:28]([O:29][N:30]3[CH:34]=[C:33]([CH2:35][O:36][C@H:37]4[CH2:61][CH2:60][C@@:59]5([CH3:62])[CH:39]([CH2:40][CH2:41][C@@H:42]6[C@@H:58]5[CH2:57][CH2:56][C@@:55]5([CH3:63])[C@H:43]6[CH2:44][CH2:45][C@@H:46]5[C@H:47]([CH3:54])[CH2:48][CH2:49][CH2:50][CH:51]([CH3:53])[CH3:52])[CH2:38]4)[N:32]=[N:31]3)[C@H:27]([OH:71])[C@H:26]2[OH:75])[O:7][C@H:8]([CH2:19][OH:20])[C@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](O[C@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](On3cc(CO[C@H]4CC[C@@]5(C)C(CC[C@H]6[C@@H]7CC[C@H]([C@H](C)CCCC(C)C)[C@@]7(C)CC[C@@H]65)C4)nn3)O[C@@H]2COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4C[C@@H](OCc5cn(O[C@@H]6O[C@H](CO)[C@@H](O[C@@H]7O[C@H](CO)[C@H](O)[C@H](O)[C@H]7O)[C@H](O)[C@H]6O)nn5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dry N-glycoside 91 (100 mg, 0.092 mmol) was dissolved in anhydrous CH3OH and a solution of NaOMe/CH3OH (11M, 30 μL) was added dropwise to the mixture at 0° C. under argon. The solution was allowed to stir at RT overnight. After monitoring by TLC, additional anhydrous CH3OH (2 mL) and NaOMe/CH3OH (11M, 50 μL) was added and the reaction mixture found to be pH 11. Upon completion, the reaction was neutralised to pH 6 by the addition of Dowex H+ ion-exchange resin, and the resulting suspension dissolved in CHCl3/CH3OH (1:1) at 40° C. The solution was filtered, concentrated and dried over P2O5 to yield the crude product.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.CS(O[CH2:17][C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=O)=O>>[S:19]1[CH:20]=[CH:21][CH:22]=[C:18]1[CH2:17][N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: CS(=O)(=O)OCc1cccs1
Reactant: O=Cc1cccc2[nH]ccc12
Product: O=Cc1cccc2c1ccn2Cc1cccs1

Procedure:
The same procedures used in Example 1 were repeated except for using 725 mg of indole-4-carbaldehyde and 2-thienylmethyl methanesulfonate instead of the benzyl bromide used in Example 1 to give 392 mg of 1-(2-thienylmethyl)indole-4-carbaldehyde as pale yellow crystals. The yield thereof was found to be 33%.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][CH:22]=[C:21]([C:24]([OH:26])=O)[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([NH:40][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[CH:8]=[C:9]([F:14])[C:10]([O:12][CH3:13])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:16]=3[NH:23][CH:22]=2)=[O:26])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c[nH]c23)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)c[nH]c23)cc1F

Procedure:
Starting from 4-(2-Cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A80) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:10]1[N:11]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH3:32])=[CH:26][CH:25]=2)[C:12](=[O:23])[C:13]2[CH2:19][CH2:18][CH2:17][N:16]([C:20](=[O:22])[CH3:21])[C:14]=2[N:15]=1)[CH3:9])(C)(C)C.ClCCl>FC(F)(F)C(O)=O>[C:20]([N:16]1[C:14]2[N:15]=[C:10]([C@H:8]([NH2:7])[CH3:9])[N:11]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH3:32])=[CH:26][CH:25]=3)[C:12](=[O:23])[C:13]=2[CH2:19][CH2:18][CH2:17]1)(=[O:22])[CH3:21]
Reactant: CCOc1ccc(-n2c([C@@H](C)NC(=O)OC(C)(C)C)nc3c(c2=O)CCCN3C(C)=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1ccc(-n2c([C@@H](C)N)nc3c(c2=O)CCCN3C(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
D3 (268 mg, 0.59 mmol) was dissolved in 1:1 trifluoroacetic acid:dichloromethane (10 mL). The reaction stirred at room temperature for 30 min. The solvent was removed in vacuo, then 10% aqueous ammonium hydroxide was added until the aqueous pH=9. The aqueous layer was extracted three times with dichloromethane, then the combined organic layer was washed with saturated aqueous sodium bicarbonate and brine. It was dried over magnesium sulfate, filtered, and concentrated in vacuo, recovering 170 mg of D4. MS (MH+): 357.1. 1H NMR (400 MHz; CDCl3; T=298 K): δ 7.13 (ddd, 2H, J=18.9, 1.4, 1.1 Hz), 7.02 (ddd, 2H, J=9.0, 1.2, 0.8 Hz), 4.09 (dq, 2H, J=6.9, 1.2 Hz), 3.98-3.80 (ddq, 2H, J=62.6, 5.3, 1.0 Hz), 3.73 (dd, 1H, J=6.6, 1.2 Hz), 2.60 (s, 3H), 1.92 (m, 2H), 1.82 (broad s, 2H), 1.45 (ddd, 3H, J=8.3, 6.1, 1.3 Hz), 1.28-1.21 (m, 5H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)(O)[CH3:13])[C:6]3[CH2:22][CH2:23][N:24]([CH3:26])[CH2:25][C:5]=3[C:4]=2[CH:3]=1.S(=O)(=O)(O)O.[OH-].[K+]>>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:11]=[C:12](/[C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)\[CH3:13])[C:6]3[CH2:22][CH2:23][N:24]([CH3:26])[CH2:25][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2c(c3cc(F)ccc3n2CC(C)(O)c2ccc(F)cc2)C1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: C/C(=C\n1c2c(c3cc(F)ccc31)CN(C)CC2)c1ccc(F)cc1
Temperature: 0 °C

Procedure:
1-(8-Fluoro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(4-fluorophenyl)propan-2-ol (1 g, 2.80 mmol, 1 equiv.) was refluxed with 25% sulfuric acid (7 mL) for 2 h. The reaction mixture was cooled to 5° C. in ice-water bath. KOH (15% aqueous solution) was added dropwise to the reaction mixture until pH 9-10 was achieved. The reaction mixture was extracted with EtOAc (3×10 mL). The combined organic layer was washed with water (10 mL) followed by brine, dried over sodium sulfate and evaporated under vacuum. The crude product was purified by silica gel chromatography (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%) to obtain a mixture of isomers, which were separated by HPLC. 1H NMR (DMSO-d6, oxalate salt) δ (ppm): 7.75 (m, 2H), 7.38-7.20 (m, 4H), 7.10 (s, 1H), 7.0 (t, 1H), 4.30 (m, 2H), 3.05 (s, 3H), 2.90 (m, 4H), 1.90 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:16]>CCOCC>[F:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N+:6]([O-:16])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1cnc2[nH]ccc2c1
Solvent: CCOCC
Product: [O-][n+]1cc(F)cc2cc[nH]c21
Temperature: 5 °C
Reaction time: 3 h
Yield: 77.3 %

Procedure:
To a stirred solution of 5-fluoro-1H-pyrrolo[2,3-b]pyridine (5.00 g, 36.73 mmol) in Et2O (120 mL), under a nitrogen atmosphere, is added 3-chloroperoxybenzoic acid (11.09 g, 64.28 mmol) portionwise over 5 minutes and the reaction stirred for 3 h. The reaction is then cooled to 5° C., filtered and the solid washed with Et2O (ca. 100 mL). This is dried in vacuo to give the title compound as a pale green crystalline solid (4.317 g, 28.38 mmol). MS (m/z): 153 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH:16]([C:19]1[CH:27]=[CH:26][C:25]([CH3:28])=[C:21]([C:22]([OH:24])=[O:23])[C:20]=1[OH:29])([CH3:18])[CH3:17].Cl>[N+](C1C=CC=CC=1)([O-])=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:26]2[C:25]([CH3:28])=[C:21]([C:22]([OH:24])=[O:23])[C:20]([OH:29])=[C:19]([CH:16]([CH3:18])[CH3:17])[CH:27]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(C)C)c(O)c1C(=O)O
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1c(S(=O)(=O)c2ccc(Cl)cc2)cc(C(C)C)c(O)c1C(=O)O
Temperature: 0 °C

Procedure:
4-Chlorophenylsulphonyl chloride (6.3 g.) is added to a mixture of aluminium chloride (8.1 g.) and 3-isopropyl-6-methylsalicylic acid (5.7 g.) in dry nitrobenzene (3 ml.). The mixture is heated at 95°-100° C. for 4 hours and is then stirred into a mixture of ice (250 g.) and concentrated hydrochloric acid (30 ml.). The mixture is subsequently extracted with ethyl acetate (3 × 250 ml.). The extracts are washed with water and are then concentrated in vacuo. Residual nitrobenzene is removed by steam distillation. The oily solid, which remains after decantation of the water from the distillation residue, is crystallised from a mixture of xylene and petroleum ether (b.p. 60°-80° C.) to give 5-(4-chlorophenylsulphonyl)-3-isopropyl-6-methylsalicylic acid, m.p. 165°-166° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:5][C:4]=1[C:16]([F:19])([F:18])[F:17]>C(#N)C.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[S:7][C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:5][C:4]=1[C:16]([F:18])([F:17])[F:19])=[O:1]
Reactant: CC(C)(C)OC(=O)Nc1nc(C(F)(F)F)c(CO)s1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1nc(C(F)(F)F)c(C=O)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.3 %

Procedure:
Manganese dioxide (1.0 g, 11.5 mmol) was added to a stirred solution of crude (5-hydroxymethyl-4-trifluoromethylthiazol-2-yl)carbamic acid, 1,1-dimethylethyl ester (Example 29; 480 mg, 1.6 mmol) in acetonitrile (20 mL). The mixture was allowed to stir at room temperature for 1 h and then a further portion of manganese dioxide (0.50 g, 5.75 mmol) was added. The reaction mixture was stirred at room temperature for 1 h, it then it was filtered through Celite® and the filter pad was washed with acetonitrile. The filtrate was evaporated to dryness to give (5-formyl-4-trifluoromethylthiazol-2-yl)carbamic acid, 1,1-dimethylethyl ester (480 mg). Examination of the crude product by NMR indicated the presence of approximately 33% of (5-ethoxycarbonyl-4-trifluoromethylthiazol-2-yl)carbamic acid, 1,1-dimethylethyl ester. This mixture was used without further purification in a subsequent transformation.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][CH2:21][CH2:22][CH2:23][N:24]([CH3:32])[C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][N:26]=1>>[CH3:19][O:20][CH2:21][CH2:22][CH2:23][N:24]([CH3:32])[C:25]1[N:26]=[CH:27][C:28]([NH:31][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:29][CH:30]=1
Reactant: COCCCN(C)c1ccc(N)cn1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: COCCCN(C)c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(3-methoxy-propyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N2-(3-methoxy-propyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C21H21F3N4O3 (m/e) 434, obsd 435 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[O:18][CH2:19][CH:20]([OH:23])[CH2:21][OH:22])[CH:5]=[CH:4][N:3]=1.[CH3:24][C:25]1[O:29][N:28]=[C:27]([C:30]([OH:34])([C:32]#[CH:33])[CH3:31])[CH:26]=1.C(N(CC)CC)C>CS(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([C:33]#[C:32][C:30]([OH:34])([C:27]4[CH:26]=[C:25]([CH3:24])[O:29][N:28]=4)[CH3:31])[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[O:18][CH2:19][CH:20]([OH:23])[CH2:21][OH:22])[CH:5]=[CH:4][N:3]=1
Reactant: C#CC(C)(O)c1cc(C)on1
Reactant: Nc1nccc(-n2c(OCC(O)CO)nc3ccc(Br)cc32)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1cc(C(C)(O)C#Cc2ccc3nc(OCC(O)CO)n(-c4ccnc(N)n4)c3c2)no1
Temperature: 70 °C
Reaction time: 5 h
Yield: 24.3 %

Procedure:
A mixture of 3-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]propane-1,2-diol (80 mg, 0.21 mmol), 2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol (160 mg, 1.06 mol), bis(triphenylphosphine)palladium(II) dichloride (160 mg, 0.22 mmol) and triethylamine (1 mL) in DMSO (2 mL) was stirred for 5 h at 70° C. under nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered through a frit filter. The filtrate was purified by preparative HPLC to afford 23 mg (24%) of 3-[[1-(2-aminopyrimidin-4-yl)-6-[3-hydroxy-3-(5-methyl-1,2-oxazol-3-yl)but-1-yn-1-yl]-1H-1,3-benzodiazol-2-yl]oxy]propane-1,2-diol as a white solid. 1H NMR (300 MHz, DMSO) delta 8.38 (d, J=5.4 Hz, 1H), 8.20 (s, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.28 (d, J=8.1 Hz, 1H), 7.07-7.05 (m, 3H), 6.46 (s, 1H), 6.38 (s, 1H), 5.19 (d, J=5.4 Hz, 1H), 4.83-4.80 (m, 1H), 4.64 (d, J=3.6 Hz, 1H), 4.52 (d, J=6.3 Hz, 1H), 3.93 (d, J=4.5 Hz, 1H), 3.52-3.49 (m, 3H), 2.40 (s, 3H), 1.82 (s, 3H); LC-MS: m/z=451 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:2]([CH3:4])[CH3:3].[CH3:17][O:18]C(Cl)Cl.O>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH:17]([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[C:7]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:8]=1)=[O:18]
Reactant: COC(=O)Cc1ccccc1OCC(C)C
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COC(=O)Cc1cc(C=O)ccc1OCC(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 10 ml of methylene chloride is dissolved 1.00 g of methyl 2-(2-isobutoxyphenyl)acetate. After successively adding 0.99 ml of titanium tetrachloride and 0.45 ml of α,α-dichloromethyl methyl ether at 5-10° C., the mixture thus obtained is stirred at ambient temperature for 30 minutes. The reaction mixture is added to a mixture of methylene chloride and water, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue is purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=95:5) to obtain 0.80 g of methyl 2-(5-formyl-2-isobutoxyphenyl)acetate as a colorless oily product.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:15][C:16]2[C:21]([N+:22]([O-])=O)=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)(=[O:3])[CH3:2]>[Pd].CO.O1CCOCC1>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:15][C:16]2[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(NC(C)=O)cc(Nc2ncccc2[N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1cc(NC(C)=O)cc(Nc2ncccc2N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.8 %

Procedure:
A mixture of 2-(3-acetylamino-5-methoxycarbonylphenylamino)-3-nitropyridine (1.20 g) and 10% palladium on carbon (0.25 g) in methanol (15 ml) and 1,4-dioxane (15 ml) was stirred under hydrogen (3 atm) at room temperature for 3 hours. The catalyst was removed by filtration and the solvent was evaporated. The resulting solid was collected and washed with isopropyl ether to give 2-(3-acetylamino-5-methoxycarbonylphenylamino)-3-aminopyridine (1.10 g).