Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[F:18])[CH:5]=[CH:4][N:3]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH2:32][C:33](O)=[O:34])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[F:18][C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:33]([CH2:32][CH:29]2[CH2:28][CH2:27][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:31][CH2:30]2)=[O:34])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)Nc2cc(Oc3ccc([N+](=O)[O-])cc3F)ccn2)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 43.1 %

Procedure:
2-Amino-4-(2-fluoro-4-nitrophenoxy)pyridine (400 mg) was dissolved in dimethylformamide (4.0 ml) under nitrogen atmosphere. To the solution were added 2-[1-(tert-butoxycarbonyl)piperidin-4-yl]acetic acid (487 mg), triethylamine (0.335 ml) and BOP reagent (1.06 g) at room temperature, followed by stirring at 60° C. for 3 hours. The reaction mixture was partitioned between ethyl acetate and water. The separated organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was purified by silica gel column chromatography (eluent; ethyl acetate:heptane=1:2 to 1:1) to provide the titled compound (328 mg, 43%) as pale yellow powder.
Reaction SMILES: [CH3:1][C:2]([N:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)([CH3:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[F:18][C:19]([F:35])([F:34])[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:1][C:2]([N:11]1[CH2:16][CH2:15][CH:14]([NH:33][CH2:32][C:29]2[CH:28]=[CH:27][C:26]([C:23]3[CH:24]=[CH:25][C:20]([C:19]([F:18])([F:34])[F:35])=[CH:21][CH:22]=3)=[CH:31][CH:30]=2)[CH2:13][CH2:12]1)([CH3:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: NCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)CC1
Temperature: 25 °C
Yield: 57.5 %

Procedure:
A mixture of 1,1-dimethylethyl 2-methyl-2-(4-oxo-1-piperidinyl)propanoate (Int. A6) (370 mg, 1.2 equiv), {[4′-(trifluoromethyl)-4-biphenylyl]methyl}amine (Int. A1) (397 mg, 1 equiv), sodium triacetoxyborohydride (400 mg, 1.5 equiv), DCM (10 ml) and acetic acid (0.076 ml, 1 equiv) was combined and stirred at room temperature until LCMS confirmed disappearance of the amine starting material (approx. 18 hours). Aqueous sodium carbonate was added and then extracted with DCM. The organics were dried over sodium sulfate and concentrated to give a solid (420 mg) that was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9](N)=[O:10])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.O.C(=O)([O-])[OH:14].[Na+]>Cl>[NH2:1][C:2]1[C:3]([C:9]([OH:10])=[O:14])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: O=C([O-])O
Reactant: NC(=O)c1ncc(Br)cc1N
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Nc1cc(Br)cnc1C(=O)O
Temperature: 100 °C
Reaction time: 20 h
Yield: 55 %

Procedure:
3-Amino-5-bromopyridine-2-carboxamide (216 mg, 1.0 mmol) was dissolved in concentrated hydrochloric acid (3 μL), and stirred at 100° C. for 20 hours. After cooled to 0° C., water (10 mL) was added to it and controlled to have a pH of 7 with sodium hydrogencarbonate solution added thereto. The resulting gray solid was taken out through filtration and dried to obtain the intended compound (119 mg, 55%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:41]([NH2:43])=[S:42].C(N(C(C)C)CC)(C)C>ClCCl>[CH:41]([NH:43][C:14]([CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1)=[O:16])=[S:42]
Reactant: NC=S
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NC=S)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (747 mg, 3.26 mmol), HATU (1549 mg, 4.07 mmol) and the product from step A (166 mg, 2.72 mmol) were mixed in anhydrous dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 30 min. N,N-diisopropyl-N-ethylamine (1.423 mL, 8.15 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. The solution was concentrated and the crude was purified on SiO2 (10 to 60% ethyl acetate/hexanes) to afford the title compound. HPLC/MS: 170.1 (M−102), Rt=2.91 (LC4).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1([CH2:21][CH3:22])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH:8](N)[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][CH3:19].[OH2:24].C=O>C1COCC1>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1([CH2:21][CH3:22])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH:8]([OH:24])[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][CH3:19]
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3N
Reactant: O
Agent: C=O
Solvent: C1CCOC1
Product: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3O
Yield: 80.5 %

Procedure:
To a solution of 4-amino-1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid methyl ester (prepared in Example 1) (1.5 g, 0.0047 mol) in THF (5 mL) was added water (5 mL) and paraformaldehyde (0.5 g). The mixture was heated at reflux for 1 hour, then concentrated in vacuo and the residue extracted with ether. The ether extracts were washed with saturated NaHCO3 solution, brine, and dried and concentrated in vacuo. Elution from a silica gel column with a 7:3 hexane:ethyl acetate mixture gave the product (1.2 g, 80.5%), m.p. 117°-118° C. (ether/hexane). Analytical HPLC showed that the product consisted of two diastereomers in a ratio of 19:1.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]2[N:14]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34]OS(C)(=O)=O)[CH:28]=3)[C:15](=[O:26])[N:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[CH2:17][C:11]2=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:40]([NH:42][CH2:43][CH3:44])[CH3:41]>C(O)C>[NH:1]([C:8]1[N:13]=[C:12]2[N:14]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34][N:42]([CH2:43][CH3:44])[CH2:40][CH3:41])[CH:28]=3)[C:15](=[O:26])[N:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[CH2:17][C:11]2=[CH:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCNCC
Reactant: CS(=O)(=O)OCCc1cccc(N2C(=O)N(c3ccc(Cl)cc3Cl)Cc3cnc(Nc4ccccc4)nc32)c1
Solvent: CCO
Product: CCN(CC)CCc1cccc(N2C(=O)N(c3ccc(Cl)cc3Cl)Cc3cnc(Nc4ccccc4)nc32)c1
Yield: 28 %

Procedure:
A solution of 58 mg (0.1 mmol) of 7-anilino-3-(2,4-dichlorophenyl)-3,4-dihydro-1-[3-(2-methanesulfonyloxyethyl)phenyl]-pyrimido[4,5-d]pyrimidin-2(1H)-one (prepared in Example 74) and 0.5 ml of diethylamine in 2 ml of ethanol was heated at 50° C. for 3 hours. The reaction mixture was evaporated and the crude material purified by flash chromatography on silica gel, eluting with 5% methanol in dichloromethane. Product containing fractions were combined and evaporated to give 16 mg (28%) of 7-anilino-3-(2,4-dichlorophenyl)-1-[3-[2-(diethylamino) ethyl]phenyl]-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one as an off-white solid of melting point 186° C. [Mass spectrum (ESI) MH+ =561].
Reaction SMILES: C1(COC([N:11]2[CH2:16][CH:15]3[CH2:17][CH:12]2[CH2:13][N:14]3[CH2:18][CH:19]([OH:31])[C:20]2[CH:29]=[CH:28][C:23]3[C:24](=[O:27])[O:25][CH2:26][C:22]=3[C:21]=2[CH3:30])=O)C=CC=CC=1>CCOC(C)=O.[Pd]>[CH:15]12[CH2:17][CH:12]([NH:11][CH2:16]1)[CH2:13][N:14]2[CH2:18][CH:19]([C:20]1[CH:29]=[CH:28][C:23]2[C:24](=[O:27])[O:25][CH2:26][C:22]=2[C:21]=1[CH3:30])[OH:31]
Reactant: Cc1c(C(O)CN2CC3CC2CN3C(=O)OCc2ccccc2)ccc2c1COC2=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1c(C(O)CN2CC3CC2CN3)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of isomers A of phenylmethyl-5-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (340 mg, 0.804 mmol) in 50 mL of EtOAc was added 100 mg of Pd/C under Ar, and the mixture was stirred at ambient temperature under H2 atmosphere overnight. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by prep-TLC (MeOH/DCM=1:15) to give isomers A of 5-[2-(2,5-diazabicyclo[2.2.1]hept-2-yl)-1-hydroxyethyl]-4-methyl-2-benzofuran-1(3H)-one. MS m/z 289 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH2:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])=[N+:6]([O-:8])[CH:7]=1.ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9]([CH2:10][C:11]2[C:12]([Cl:18])=[CH:13][CH:14]=[CH:15][C:16]=2[Cl:17])=[O:27])=[N+:6]([O-:8])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: [O-][n+]1cc(Cl)ccc1SCc1c(Cl)cccc1Cl
Solvent: ClC(Cl)Cl
Product: O=S(Cc1c(Cl)cccc1Cl)c1ccc(Cl)c[n+]1[O-]
Reaction time: 0.17 h
Yield: 95.2 %

Procedure:
3.2 g of 5-chloro-2-(2,6-dichlorobenzylthio)pyridine-N-oxide was dissolved in 50 ml of chloroform, and a solution of 2.5 g of metachloroperbenzoic acid (content: 70%) dissolved in 30 ml of chloroform was added dropwise thereto at 5° to 10° C. over 10 minutes. The mixture was stirred at 5° to 10° C. for an additional 2 hours. The resulting mixture was washed twice with potassium carbonate solution and dried over magnesium sulfate. The chloroform was evaporated and the residue was recyrstallized from 1:1 benzene-hexane to obtain 3.2 g of 5-chloro-2-(2,6-dichlorobenzylsulfinyl)pyridine-N-oxide (Compound (1)). Yield, 95%. M.P., 176.5°-177.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20](C(C)=C)[C:19]3=[O:30])[CH2:11][CH2:10]2)=[C:4]([N+:31]([O-:33])=[O:32])[CH:3]=1.CC1C=CC=CC=1.Cl>CC(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[NH:20][C:19]3=[O:30])[CH2:13][CH2:14]2)=[C:4]([N+:31]([O-:33])=[O:32])[CH:3]=1
Reactant: C=C(C)n1c(=O)n(CCCN2CCC(Nc3ccc(Cl)cc3[N+](=O)[O-])CC2)c2ccccc21
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: O=c1[nH]c2ccccc2n1CCCN1CCC(Nc2ccc(Cl)cc2[N+](=O)[O-])CC1
Yield: 75.5 %

Procedure:
A solution of 98.5 parts of 1-[3-{4-[(4-chloro-2-nitrophenyl)amino]-1-piperidinyl}propyl]-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one in 360 parts of methylbenzene is acidified with 2-propanol, previously saturated with gaseous hydrogen chloride. After boiling for a while, an oil precipitates. The supernatant phase is decanted and the residual oil is suspended in water. The suspension is alkalized with a concentrated ammonium hydroxide solution. The product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and dried, yielding 68 parts (75.5%) of 1-[3-{4-[(4-chloro-2-nitrophenyl)amino]-1-piperidinyl}-propyl]-1,3-dihydro-2H-benzimidazol-2-one.
Reaction SMILES: Br[C:2]([C:5](=[O:7])[CH3:6])=[CH:3]O.[NH2:8][C:9]([NH2:11])=[O:10]>CC(C)=O>[C:5]([C:2]1[O:10][C:9]([NH2:11])=[N:8][CH:3]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)C(Br)=CO
Reactant: NC(N)=O
Solvent: CC(C)=O
Product: CC(=O)c1cnc(N)o1
Reaction time: 1 h
Yield: 49.9 %

Procedure:
A mixture of 132.3 g (0.80 mole) of 2-bromo-1-hydroxy-3-oxo-1-butene, 120.1 g (2.0 mole) of urea, and 1.85 l of acetone was heated at reflux with overhead stirring for one hour. The mixture was concentrated and the oil residue was taken up into 600 ml of water, then made basic with concentrated ammonium hydroxide. After sitting at room temperature for 0.5 hour, a precipitate formed. This was collected, and dried in vacuo to give 61.1 g of crude product. The filtrate was again concentrated and the oil residue taken up in 50 ml of water and again made basic with concentrated ammonium hydroxide. After sitting overnight a second crop of crude product, amounting to 17.6 g was isolated. Both crops were combined and recrystallized from methanol to give 50.3 g (50%) of 5-acetyl-2-amino-oxazole, m.p. 214°-215° C.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[C:4]([CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[CH:3]=1.[NH4+].[Cl-].[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C=O)C>[C:17]1([CH:15]([C:4]2[CH:3]=[C:2]([OH:1])[N:6]([C:7]3[CH:12]=[C:11]([C:13]4[NH:27][N:26]=[N:25][N:14]=4)[CH:10]=[CH:9][N:8]=3)[N:5]=2)[CH3:16])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(c1ccccc1)c1cc(O)n(-c2cc(C#N)ccn2)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(c1ccccc1)c1cc(O)n(-c2cc(-c3nnn[nH]3)ccn2)n1
Temperature: 110 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
To a suspension of 2-[5-hydroxy-3-(1-phenylethyl)pyrazol-1-yl]pyridine-4-carbonitrile (150 mg, 0.5 mmol), NH4Cl (278 mg, 5.2 mmol) in DMF (5 mL) was added NaN3 (338 mg, 5.2 mmol) at r.t. The reaction mixture was stirred at 110° C. for 2 h in a microwave oven. The reaction mixture was then filtered and purified by pre-HPLC to give the title compound (100 mg, 58%) as a brown solid. 1H NMR (400 MHz, CD3OD): δ 1.64 (3H, d, J=7.2 Hz), 4.07-4.12 (1H, m), 7.17-7.19 (1H, m), 7.20-7.35 (4H, m), 7.83 (1H, dd, J=1.2, 5.2 Hz), 8.43 (1H, d, J=5.2 Hz), 8.74 (1H, s). [M+H] Calc'd for C17H15N7O, 334; Found, 334.
Reaction SMILES: [CH2:1]([Sn:9](=[O:18])[CH2:10][CH2:11][CH2:12][CH2:13]CCCC)[CH2:2][CH2:3][CH2:4]CCCC.[CH3:19][CH:20]([CH3:24])[CH2:21][CH2:22][OH:23]>>[CH2:10]([Sn:9]([CH2:1][CH2:2][CH2:3][CH3:4])([O:18][CH2:22][CH2:21][CH:20]([CH3:24])[CH3:19])[O:18][Sn:9]([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:1][CH2:2][CH2:3][CH3:4])[O:23][CH2:22][CH2:21][CH:20]([CH3:24])[CH3:19])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCC[Sn](=O)CCCCCCCC
Reactant: CC(C)CCO
Product: CCCC[Sn](CCCC)(OCCC(C)C)O[Sn](CCCC)(CCCC)OCCC(C)C
Temperature: 25 °C
Yield: 99 %

Procedure:
972 g (2.7 mol) of di-n-octyl tin oxide (Sankyo Organic Chemicals Co., Ltd., Japan) and 2100 g (23.9 mol) of 3-methyl-1-butanol were placed in a 5000 mL volumetric pear-shaped flask. The flask was connected to an evaporator to which was connected an oil bath equipped with a temperature controller, a vacuum pump and a vacuum controller. The purge valve outlet of the evaporator was connected to a line containing nitrogen gas flowing at normal pressure. After closing the purge valve of the evaporator to reduce pressure inside the system, the purge valve was opened gradually to allow nitrogen to flow into the system and return to normal pressure. The oil bath temperature was set to about 145° C., the flask was immersed in the oil bath and rotation of the evaporator was started. After heating for about 40 minutes in the presence of atmospheric pressure nitrogen with the purge valve of the evaporator left open, distillation of 3-methyl-1-butanol containing water began. After maintaining in this state for 7 hours, the purge valve was closed, pressure inside the system was gradually reduced, and excess 3-methyl-1-butanol was distilled with the pressure inside the system at from 74 to 35 kPa. After the fraction no longer appeared, the flask was taken out of the oil bath. After allowing the flask to cool to the vicinity of room temperature (25° C.), the purge valve was opened gradually and the pressure inside the system was returned to atmospheric pressure. 1176 g of reaction liquid were obtained in the flask. Based on the results of 119Sn-, 1H- and 13C-NMR analyses, 1,1,3,3-tetra-n-butyl-1,3-bis(3-methylbutyloxy) distannoxane was confirmed to have been obtained at a yield of 99% based on the di-n-octyl tin oxide. The same procedure was then repeated 12 times to obtain a total of 14120 g of 1,1,3,3-tetra-n-octyl-1,3-bis(3-methylbutyloxy) distannoxane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14]O)=[C:12]([CH:16]([CH3:18])[CH3:17])[O:11][N:10]=1.P(Br)(Br)[Br:20]>C1COCC1.CCOC(C)=O>[Br:20][CH2:14][C:13]1[C:9]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])=[N:10][O:11][C:12]=1[CH:16]([CH3:18])[CH3:17]
Reactant: BrP(Br)Br
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CBr

Procedure:
To a solution of [3-(2,6-dichloro-phenyl)-5-isopropyl-isoxazol-4-yl]-methanol (1.14 g, 4 mmol) in THF (20 mL) is added PBr3 (0.76 mL, 8 mmol). The reaction mixture is stirred at reflux for 30 minutes. The reaction mixture is diluted with EtOAc and is washed with 0.2 N HCl. The organic layer is separated, dried (MgSO4), filtered, and concentrated to give the title compound as an oil.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:28][C:13]3=[N:14][CH:15]=[C:16]([O:18][CH:19]4[CH2:24][CH2:23][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]4)[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH2:33][CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37]>>[C:39]([Si:36]([CH3:38])([CH3:37])[O:35][CH2:34][CH2:33][N:28]1[C:13]2=[N:14][CH:15]=[C:16]([O:18][CH:19]3[CH2:20][CH2:21][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:23][CH2:24]3)[CH:17]=[C:12]2[CH:11]=[C:10]1[C:8]([N:5]1[CH2:6][CH2:7][C:2]([F:1])([F:29])[CH2:3][CH2:4]1)=[O:9])([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)N1CCC(Oc2cnc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2cnc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3CCO[Si](C)(C)C(C)(C)C)CC1
Yield: 29 %

Procedure:
The title compound was synthesized in analogy to example 18 from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]methanone (example 13), sodium hydride and (2-bromoethoxy)-tert-butyldimethylsilane, to give the desired product as a light yellow solid (29%).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.[NH2:42][CH:43]1[CH2:48][CH2:47][O:46][C:44]1=[O:45]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH2:35][C:36]([NH:42][CH:43]3[CH2:48][CH2:47][O:46][C:44]3=[O:45])=[O:37])=[CH:31][CH:32]=2)=[CH:39][CH:40]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)O)cc2)cc1
Reactant: NC1CCOC1=O
Agent: Br
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)NC3CCOC3=O)cc2)cc1

Procedure:
The product from Example 100 (56 mg, 0.1 mmole) and α-Amino-γ-butyrolactone hydrobromide (36 mg, 0.2 mmole) were processed as in Examples 213A and 224B to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ8.95 (s, 1 H), 8.31 (d, 1 H), 7.26 (m, 6 H), 7.18 (m, 3 H), 7.04 (m, 1 H), 6.97 (m, 2 H), 6.88 (m, 4 H), 4.53 (dd, 1 H), 4.34 (t, 1 H), 4.20 (m, 1 H), 4.06 (s, 2 H), 4.02 (s, 2 H), 3.17 (s, 3 H), 2.91 (s, 3 H), 2.55 (t, 2 H), 2.39 (m, 2 H), 2.13 (t, 2 H), 1.67-1.90 (m, 2 H); MS (APCI+) m/z 642 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH2:42][CH3:43])[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH2:42][CH3:43])[CH:37]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1N
Product: CCc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(Cl)cc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from (2-amino-5-chloro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J19) (233 mg, 0.75 mmol) and 3-[3-(2-ethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K20) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (288 mg, 67%).
Reaction SMILES: [CH3:1][C:2]([CH3:20])=[CH:3][CH2:4][C@H:5]1[O:7][C@@:6]1([C@@H:9]1[C@:14]2([O:16][CH2:15]2)[CH2:13][CH2:12][C@@H:11]([OH:17])[C@H:10]1[O:18][CH3:19])[CH3:8].[Cl:21][CH2:22][C:23]([N:25]=[C:26]=[O:27])=[O:24].O>ClCCl>[CH3:1][C:2]([CH3:20])=[CH:3][CH2:4][C@@H:5]1[O:7][C@:6]1([C@@H:9]1[C@:14]2([O:16][CH2:15]2)[CH2:13][CH2:12][C@@H:11]([O:17][C:26]([NH:25][C:23]([CH2:22][Cl:21])=[O:24])=[O:27])[C@H:10]1[O:18][CH3:19])[CH3:8]
Reactant: CO[C@@H]1[C@H](O)CC[C@]2(CO2)[C@H]1[C@@]1(C)O[C@@H]1CC=C(C)C
Reactant: O=C=NC(=O)CCl
Solvent: O
Solvent: ClCCl
Product: CO[C@@H]1[C@H](OC(=O)NC(=O)CCl)CC[C@]2(CO2)[C@H]1[C@]1(C)O[C@H]1CC=C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
To a solution of fumagillol (314 mg) in dichloromethane (5 ml) was added dropwise chloroacetyl isocyanate (160 mg) under ice cooling, followed by addition of dimethylaminopyrldine (130 mg). The mixture was stirred at 0° C. for 2 hours. To this reaction mixture was added water and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography. The eluate obtained with a mixture of n-hexane and ethyl acetate (3:1) was concentrated under reduced pressure to give colorless, powdery O-chloroacetylcarbamoylfumagillol (318 mg) (71% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[CH:4]=1.Cl[CH2:11][CH:12]=O.C(=O)([O-])O.[Na+]>O.C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]2[CH:11]=[CH:12][N:9]=[C:5]2[CH:4]=1
Reactant: O=CCCl
Reactant: COc1ccnc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccn2ccnc2c1
Yield: 45 %

Procedure:
A stirred suspension of 4-methoxypyridin-2-ylamine (4.50 g, 36.3 mmol), chloroacetaldehyde (8.54 g of a 50 wt % solution in water, 54.4 mmol) and sodium hydrogencarbonate (6.09 g, 72.6 mmol) in ethanol (70 ml) was heated under reflux for 4 h. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic layer was washed with brine, dried and evaporated to give an orange oil. Purification by silica gel chromatography eluting with 2% methanol in dichloromethane gave 7-methoxyimidazo[1,2-α]pyridine (2.40 g, 45%) as a brown oil. 1H NMR (400 MHz, CDCl3) δH 3.85 (3H, s), 6.50 (1H, d, J 7), 6.88 (1H, s), 7.41 (1H, s), 7.48 (1H, s), 7.92 (1H, d, J 7).