Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](=[O:15])(=[O:14])[NH:12][CH3:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:17]1C=CC(S(O)=O)=CC=1C(O)=O.C(N)C>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](=[O:15])(=[O:14])[NH:12][CH2:13][CH3:17])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(S(=O)O)ccc1Cl
Reactant: CNS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Agent: CCN
Product: CCNS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Yield: 78 %

Procedure:
The title compound was synthesised according to the procedure described for 2-Chloro-5-methylsulfamoyl-benzoic acid from 2-Chloro-5-sulfino-benzoic acid and ethylamine and obtained in 78% yield. MS (m/e): 262.2 (MH−, 100%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([C:8]1[CH:9]=[C:10]([C:13]([NH:15][N:16]([CH2:32][C@@H:33]([OH:37])[C:34]([OH:36])=[O:35])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=3[F:31])=[CH:20][CH:19]=2)=[O:14])[NH:11][N:12]=1)(=[O:7])[CH3:6].C1COCC1>>[C:1]([O:37][C@H:33]([CH2:32][N:16]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=2[F:31])=[CH:20][CH:19]=1)[NH:15][C:13]([C:10]1[NH:11][N:12]=[C:8]([C:5](=[O:7])[CH3:6])[CH:9]=1)=[O:14])[C:34]([OH:36])=[O:35])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)[nH]n1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Product: CC(=O)O[C@H](CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(C(C)=O)n[nH]1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
Acetyl chloride (30 μL, 421.2 μmol) and (R)-3-[N′-(5-acetyl-2H-pyrazole-3-carbonyl)-N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid (20.0 mg, 42.1 μmol) were combined in THF (205 μL, 2.5 mmol), and stirred overnight at room temperature. The solvent was evaporated and the residue was purified (reverse phase HPLC column) to yield the title compound (12.2 mg) as a TFA salt. MS m/z [M+H]+ calc'd for C24H22ClFN4O6, 517.12. found 517.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=1.[ClH:37].C(O)C.C(=O)([O-])[O-].[NH4+:45].[NH4+]>ClCCl.C(O)C>[ClH:37].[ClH:37].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:20]=[CH:21][C:22]([C:25](=[NH:45])[NH2:26])=[CH:23][CH:24]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1cccnc1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1cccnc1
Yield: 86 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 86% of theory, C27H29N7O3 (499.6) Rf value: 0.09 (silica gel; dichloromethane/ethanol=4:1 EKA mass spectrum: (M+H)+ =500
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH2:17][CH2:18][CH3:19])=[O:15])=[C:12]([CH3:20])[NH:11][C:10]2[CH2:21][O:22][C:23](=[O:24])[C:9]1=2.[OH-].[K+].[CH3:27]I>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH2:17][CH2:18][CH3:19])=[O:15])=[C:12]([CH3:20])[N:11]([CH3:27])[C:10]2[CH2:21][O:22][C:23](=[O:24])[C:9]1=2
Reactant: CI
Reactant: CCCOC(=O)C1=C(C)NC2=C(C(=O)OC2)C1c1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCOC(=O)C1=C(C)N(C)C2=C(C(=O)OC2)C1c1ccccc1Cl
Reaction time: 2 h

Procedure:
50 mmol of propyl 4-(2-chlorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro-[3,4-b]pyridine-3-carboxylate are dissolved in 150 ml of dimethyl sulphoxide, and 7 g of potassium hydroxide powder and 50 mmol of methyl iodide are added. After 2 hours at room temperature, the mixture is poured onto ice-water and extracted with CH2Cl2, the extract is dried and evaporated down, and the residue is recrystallized.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([Cl:11])[N:3]=1.[H-].[Na+].I[CH:15]([CH3:17])[CH3:16].O>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:15]([CH3:17])[CH3:16])=[C:4]([Cl:11])[N:3]=1
Reactant: CC(C)I
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Temperature: 10 °C
Reaction time: 1 h

Procedure:
To 2,6-dichloro-9H-purine (a) (998 g, 5.28 mol) dissolved in anhydrous DMF (5.0 L) was added sodium hydride (60% dispersion, 254 g, 6.35 mol) with stirring at 10° C. over 1 hr. 2-iodopropane (1595 g) was added and the mixture was stirred at rt for 24 hr. Water (5.0 L) was added, and the resulting solid precipitate was collected and washed with water (500 ml) and heptane (2×2.5 L). The crude solid was crystallized from isopropyl acetate (2.1 L) to provide the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[O:3]1.[H-].[Na+].[CH3:19][O:20][CH2:21][CH2:22]Br>CN(C=O)C>[CH3:19][O:20][CH2:21][CH2:22][O:15][C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (150 mg, 0.682 mmol) in DMF (5 mL) was added 60% NaH (136 mg, 3.41 mmol) and 2-bromoethyl methyl ether (0.13 mL, 1.363 mmol). The resulting solution was stirred at 50° C. overnight, cooled to ambient temperature, quenched with water, and extracted with EtOAc. The combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography to give the title compound (114 mg, 60% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[C:25]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH3:33])[N:27]=4)=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:15][CH:14]=2)=[N:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:39]1[S:40][CH:41]=[CH:42][N:43]=1)CCC>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>[CH3:33][NH:32][C:28]1[N:27]=[C:26]([C:25]2[C:20]([O:19][C:16]3[CH:17]=[CH:18][C:13]([NH:12][C:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C:2]([C:39]5[S:40][CH:41]=[CH:42][N:43]=5)=[N:3][N:4]=4)=[CH:14][CH:15]=3)=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:31]=[CH:30][N:29]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(Cl)c4ccccc34)cc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CNc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(-c4nccs4)c4ccccc34)cc2)n1
Temperature: 110 °C

Procedure:
A resealable pressure tube, purged with argon, was charged with 4-chloro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amine (150 mg, 0.329 mmol), tetrakis(triphenylphosphine)palladium (38 mg, 0.033 mmol), and 2-(tributylstannyl)thiazole (0.207 mL, 0.658 mmol). This mixture was purged with argon for 10 minutes, followed by addition of toluene (1.6 ml, 0.2 M). Tube was sealed and mixture heated to 110° C. overnight. Next day LC/MS shows completion of reaction. The reaction was stopped, cooled to RT and concentrated under reduced pressure to a brown residue. This residue was purified by Gilson reverse phase chromatography (10% to 90% CH3CN/H2O/0.1% TFA). The product-containing fractions were combined, basified by addition of aq. NaHCO3 and extracted with ethyl acetate. The organic portion was dried with Na2SO4, filtered, and concentrated to afford pure N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-(thiazol-2-yl)phthalazin-1-amine as a yellow solid. MS m/z=505 [M+H]+. Calc'd for C27H20N8OS: 504.57.
Reaction SMILES: [CH2:1]([C:3]1[NH:9][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH:4]=1)[CH3:2].[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][CH2:21][Cl:22]>CN(C)C=O>[Cl:22][CH2:21][CH2:20][CH2:19][CH2:18][N:9]1[C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH:4]=[C:3]1[CH2:1][CH3:2]
Reactant: CCC1=COc2ccccc2C(=O)N1
Reactant: ClCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC1=COc2ccccc2C(=O)N1CCCCCl
Reaction time: 0.5 h

Procedure:
430 mg of 4,5-dihydro-3-ethyl-1,4-benzoxazepin-5-one was dissolved in 10 ml of dimethylformamide, then 110 mg (1.2 equivalents) of 60% sodium hydride was added under ice cooling. This was agitated for 30 minutes, then 480 mg (1.2 equivalents) of 1-bromo-4-chlorobutane was added and the resultant mixture was agitated at room temperature for 6 hours.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[S:3]([O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH2:11][C@H:12]3[NH:23][CH2:22][CH2:21][C@@:18]4([C:19]=2[CH:20]=1)[C@H:13]3[CH2:14][CH2:15][CH2:16][CH2:17]4)(=[O:5])=[O:4].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[CH2:26]([N:23]1[CH2:22][CH2:21][C@@:18]23[C:19]4[CH:20]=[C:7]([O:6][S:3]([C:2]([F:1])([F:24])[F:25])(=[O:5])=[O:4])[CH:8]=[CH:9][C:10]=4[CH2:11][C@@H:12]1[C@@H:13]2[CH2:14][CH2:15][CH2:16][CH2:17]3)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=S(=O)(Oc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3)C(F)(F)F
Reactant: BrCc1ccccc1
Solvent: ClCCl
Product: O=S(=O)(Oc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(Cc1ccccc1)CC3)C(F)(F)F
Reaction time: 5 h
Yield: 84.3 %

Procedure:
To a solution of compound 38 (50 mg, 0.13 mmol) and TEA (74 μL, 0.53 mmol) in dry CH2Cl2 (2 mL) was slowly added benzyl bromide (32 μL, 0.27 mmol) at 0° C. and stirred for 5 h. Solvent was removed under reduced pressure. The crude product was purified on a silica gel column chromatography (90:5 CH2Cl2/MeOH) to give a colorless oil (51 mg, 84% yield): 1H NMR (300 MHz, CDCl3) 1.05˜1.72 (m, 9H); 1.74˜1.85 (m, 1H); 1.90˜1.94 (m, 1H); 1.96˜2.05 (m, 1H); 2.31 (d, J=13.0 Hz, 1H); 2.48˜2.52 (m, 1H); 2.88˜2.91 (m, 1H); 3.12 (d, J=18.6 Hz, 1H); 3.67 (dd, J=13.4 Hz, 2H); 7.03˜7.38 (m, 8H).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>C1COCC1>[CH:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH:7][C:22](=[O:23])[C:21]1[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=1[C:19]([F:18])([F:29])[F:30])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CC(C)c1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)c1cccc(NC(=O)c2ccccc2C(F)(F)F)c1
Temperature: 0 °C

Procedure:
One gram of 3-isopropylaniline and 0.8 gram of triethylamine were dissolved in 50 ml of THF, cooled to 0° C. and agitated. A solution prepared by dissolving 1.54 grams of 2-trifluoromethylbenzoyl chloride in 20 ml of THF were dropwisely added. After agitating for 30 minutes, the reaction mixture was filtered and THF in the filtrate was distilled off under reduced pressure. The residue was extracted by benzene, and rinsed with 3N-HCl, a saturated sodium bicarbonate solution and water successively in this order. The benzene layer was dried by adding anhydrous magnesium sulfate and then benzene was distilled off under reduced pressure to obtain the desired product. The yield was 1.98 grams (87%), and the product had a melting point of 87.5° to 88.5° C. and an IR absorption peak at 1655 cm-1 (c=b 0).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:7][N:8]([CH3:16])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[I-:23].[K+]>CC(C)=O>[I:23][CH2:2][CH2:3][O:4][C:5]1[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:7][N:8]([CH3:16])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cn1nc(-c2ccccc2)c(OCCBr)c1-c1ccccc1
Reactant: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1nc(-c2ccccc2)c(OCCI)c1-c1ccccc1

Procedure:
A mixture of 4-(2-bromoethoxy)-1-methyl-3,5-diphenylpyrazole (3.57 g, 0.01 mole), potassium iodide (16.6 g, 0.1 mole) and acetone (50 ml) is stirred and refluxed for 24 hours.
Reaction SMILES: [CH2:1]([C:6]1[CH2:11][CH2:10][CH:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]2)[CH2:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C([C@H]1CC[C@H](C2CCC(=[O:40])CC2)CC1)CCCC>>[CH2:1]([C:6]1([OH:40])[CH2:11][CH2:10][CH:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[C@H]1CC[C@H](C2CCC(=O)CC2)CC1
Reactant: CCCCCC1=CCC([C@H]2CC[C@H](CCCCC)CC2)CC1
Product: CCCCCC1(O)CCC([C@H]2CC[C@H](CCCCC)CC2)CC1

Procedure:
30.4 g of 1-pentyl-4-(trans-4-pentylcyclohexyl)-cyclohexene [obtainable by reacting 4-(trans-4-pentylcyclohexyl)-cyclohexanone with pentyl-MgBr, hydrolysing the product to give 1-pentyl-4-(trans-4-pentylcyclohexyl)-cyclohexanol and dehydrating the latter], 2.7 g of liquid HCN, 0.1 g of palladium bis-[2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis-(diphenylphosphino)-butane] and 100 ml of acetonitrile are heated at 130° for 1 hour in an autoclave. The mixture is cooled, evaporated and worked up in the customary manner to give r-1-cyano-1-pentyl-cis-4-(trans-4-pentylcyclohexyl)-cyclohexane, m.p. 28°, c.p. 63°.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:6][C@H:5]([C:7](=O)C)[CH2:4][O:3]1.Cl.[NH2:12][OH:13].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[CH3:1][C:2]1([CH3:10])[O:6][C@H:5]([CH:7]=[N:12][OH:13])[CH2:4][O:3]1
Reactant: CC(=O)[C@@H]1COC(C)(C)O1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)OC[C@@H](C=NO)O1
Reaction time: 0.33 h
Yield: 97.5 %

Procedure:
To a solution of (S)-1-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanone (10.5 g, 72.8 mmol) in 150 (mL) THF: 60 mL was added hydroxylamine hydrochloride (5.06 g, 72.8 mmol), and the reaction was stirred for 20 minutes. Na2CO3 (3.78 g, 35.7 mmol) was added and the reaction was stirred overnight. The reaction was extracted with ethyl acetate, washed with water and brine, dried over MgSO4, filtered and concentrated to afford (R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde oxime (10.3 g, 71.0 mmol, 97.4% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][C:17](F)=[CH:18][C:19]=3[C:11]=2[C:10](C)(C)[CH2:9][N:8]([C:23](=[O:31])[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH:7]=1)=[O:5])[CH3:2].C([O:34]C(C1C2NC3C=CC(N)=CC=3C=2C(C)(C)CN(C(=O)C2C=CC(F)=CC=2)C=1)=O)C.[H+].[B-](F)(F)(F)F.O>CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[C:15]([OH:34])=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][N:8]([C:23](=[O:31])[C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)(C)c2c1[nH]c1ccc(F)cc21
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)(C)c2c1[nH]c1ccc(N)cc21
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1c(O)cccc21
Temperature: 10 °C
Reaction time: 0.33 h

Procedure:
For the preparation of 9-fluoro-3-(4-fluoro-benzoyl)-1,1-dimethyl-1,2,3,6-tetrahydro-azepino[4,5-b]indole-5-carboxylic acid ethyl ester, to a stirred solution of 9-amino-3-(4-fluoro-benzoyl)-1,1-dimethyl-1,2,3,6-tetrahydro-azepino[4,5-b]indole-5-carboxylic acid ethyl ester (Example 41C) (0.024 g, 0.055 mmol) in 1.0 mL of MeCN was added 11 μL of 48% HBF4 water solution at ±10° C. under N2 for 10 minutes. 9 μL of tBuONO (90%, 0.066 mmol) was added to the reaction mixture and stirred at ±10° C. for 20 minutes. The reaction mixture was warmed to room temperature for 1 hour and monitored by LC-MS. The solvents were removed in vacuo, and the residue was washed with Et2O/hexane (1:1) once and benzene twice. After having dried in high vacuo for several hours, a brown solid was obtained. The solid in 1.5 mL of xylenes was heated at 145° C. reflux under N2 for 1 hour and then concentrated. The crude product was purified by flash chromatograph on silica gel, eluting with EtOAc-hexane (0-30%) to yield the title compound (0.012 g) as a light yellow solid. 1H-NMR (CDCl3): δ10.68 (1H, s), 7.83 (1H, s), 7.62 (2H, m), 7.44 (1H, dd), 7.29 (1H, m), 7.13 (2H, m), 6.93 (1H, m), 4.23 (2H, q), 1.56 (6H, s), 1.22 (3H, t). MS (ESI): 425 (MH+).
Reaction SMILES: [CH2:1]([C@:8]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:28])[C:9](=O)[CH2:10][NH:11][C:12](=[O:26])[C:13]1[CH:18]=[C:17]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])[N:16]=[C:15]([Cl:25])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1(C)C=CC=CC=1>[Cl:25][C:15]1[CH:14]=[C:13]([C:12]2[O:26][C:9]([C@@:8]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])([CH3:28])[CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][N:11]=2)[CH:18]=[C:17]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:21])=[O:22])[N:16]=1
Reactant: CN(c1cc(C(=O)NCC(=O)[C@@](C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(Cl)n1)S(C)(=O)=O
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: Cc1ccccc1
Product: CN(c1cc(-c2ncc([C@@](C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)cc(Cl)n1)S(C)(=O)=O

Procedure:
To a solution of tert-butyl (1R)-1-benzyl-3-({2-chloro-6-[methyl(methylsulfonyl)amino]isonicotinoyl}amino)-1-methyl-2-oxopropylcarbamate (0.190 g, 0.35 mmol) in 2 mL toluene was added Burgess reagent (0.504 g, 2.12 mmol). The reaction was microwaved at 130° C. for 30 min. The clear yellow, top layer of the reaction mixture was concentrated in vacuo and purified by normal phase chromatography (0->50% EtOAc/hexanes) to give tert-butyl (1R)-1-(2-{2-chloro-6-[methyl(methylsulfonyl)amino]pyridin-4-yl}-1,3-oxazol-5-yl)-1-methyl-2-phenylethylcarbamate. NMR (CDCl3, 400 MHz) 7.86 (s, 1H); 7.69 (s, 1H); 7.28 (m, 3H); 7.04 (m, 3H); 3.45 (s, 3H); 3.13 (m, 4H); 1.60 (s, 3H); 1.42 (s, 9H); LC/MS [M+H]+=521.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1.[O:15]=[C:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1>C1COCC1>[Cl:14][C:9]1[CH:8]=[C:7]([C:16]2([OH:15])[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:20][CH2:21]2)[CH:12]=[CH:11][C:10]=1[Cl:13]
Reactant: Clc1ccc(Br)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)c(Cl)c2)CC1
Reaction time: 0.33 h
Yield: 97.5 %

Procedure:
n-BuLi (2.5 M, 2 mL, 5.21 mmol) was added into a solution of 4-bromo-1,2-dichlorobenzene (1.07 g, 4.74 mmol) in dry THF (10 mL) at −78° C. The mixture was stirred for 20 mins and then a solution of tert-butyl 4-oxopiperidine-1-carboxylate (0.95 g, 4.74 mmol) in THF (5 mL) was added. The mixture was further stirred at −78° C. for 1 h. After this time, the reaction was quenched with NH4Cl (aq., 15 mL), extracted with ethyl acetate (50 mL×3), dried over Na2SO4 and concentrated to yield a residue. The residue was purified by flash chromatography using 10-30% ethyl acetate in hexanes as an eluent to provide tert-butyl 4-(3,4-dichlorophenyl)-4-hydroxypiperidine-1-carboxylate (1.6 g, 90% purity, 88% yield) as a colorless oil. MS found: 346.3 (M+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15]C(OC)=O)=[CH:10][C:9]=1[N:20]1[C:24](=[O:25])[C:23]2[CH2:26][CH2:27][CH2:28][CH2:29][C:22]=2[C:21]1=[O:30].Cl>CO>[F:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([OH:15])=[CH:10][C:9]=1[N:20]1[C:24](=[O:25])[C:23]2[CH2:26][CH2:27][CH2:28][CH2:29][C:22]=2[C:21]1=[O:30]
Reactant: COC(=O)Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc(O)c(Cl)cc1F
Reaction time: 5 h
Yield: 67.8 %

Procedure:
Potassium carbonate (4.6 g, 33.3 mmol) was added to a solution of N-(2-fluoro-4-chloro-5-methoxycarbonyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (11.8 g, 33.4 mmol) obtained as described above in methanol (100 ml), followed by stirring for 5 hours under refluxing. After completion of the reaction, the mixture was poured into 1N hydrochloric acid (200 ml), and the mixture was extracted with ethyl acetate (100 ml×3 times). The organic layer was washed with water, dried, and the solvent was distilled off under reduced pressure to obtain a crude product (9.4 g). The product was recrystallized from ether/hexane to obtain N-(2-fluoro-4-chloro-5-hydroxypheyl) 3,4,5,6-tetrahydrophthalimide as a white solid (6.7 g 22.7 mmol, 67.8% yield).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][S:11][C:5]2=[N:4][C:3]=1[CH:12](Br)[CH3:13].[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:15]([CH:12]([C:3]1[N:4]=[C:5]2[S:11][CH:10]=[CH:9][N:6]2[C:7](=[O:8])[C:2]=1[Br:1])[CH3:13])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(Br)c1nc2sccn2c(=O)c1Br
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(N=[N+]=[N-])c1nc2sccn2c(=O)c1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65.4 %

Procedure:
A mixture of 6-bromo-7-(1-bromoethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (3.7 g, 11 mmol) and sodium azide (1.4 g, 22 mmol) in N,N-dimethylformamide (30 mL) was stirred at room temperature for 1.5 hour. After diluted with ethyl acetate, the mixture was washed with water, dried over Na2SO4, concentrated and purified on silica gel (0-60% ethyl acetate/hexanes) to give the desired product (2.16 g). LCMS calculated for C8H7BrN5OS (M+H)+: m/z=300.0. Found: 300.0.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:21][OH:22])=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]1>C1COCC1.O=[Mn]=O>[CH:21]([C:3]1[C:2]([OH:1])=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][CH2:6][N:7]1[CH2:8][CH2:9][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:12]1)=[O:22]
Reactant: CCOC(=O)C1CCN(CCc2cccc(O)c2CO)CC1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(CCc2cccc(O)c2C=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To ethyl 1-(3-hydroxy-2-(hydroxymethyl)phenethyl)piperidine-4-carboxylate (85 mg, crude above) in THF (20.0 mL) was added MnO2 (500 mg, 5.75 mmol) at rt. The mixture was stirred at rt for 1 h, filtered, and concentrated to give ethyl 1-(2-formyl-3-hydroxyphenethyl)piperidine-4-carboxylate (80 mg, crude) as a pale brown solid, which was used for next step with purification. LRMS (M+H+) m/z 306.1.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:9][CH:10]=1)([CH3:3])[CH3:2].CS(O[CH2:24][CH:25]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH3:26])(=O)=O.[H-].[Na+]>CN(C=O)C>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:26][CH:25]([NH:27][C:28](=[O:29])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH3:24])=[CH:16][CH:17]=2)=[N:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reactant: CC(C)Oc1ccc(Oc2ccc(O)cc2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(COc1ccc(Oc2ccc(OC(C)C)cn2)cc1)NC(=O)OC(C)(C)C

Procedure:
4-(5-Isopropoxypyridin-2-yloxy)phenol (592 mg, 2.41 mmol) and 2-tert-butoxycarbonylaminopropyl methanesulfonate (734 mg, 2.89 mmol) were reacted with sodium hydride in DMF in analogy to example 2c. Yield: 414 mg (43%), M+H+: 403.19.