Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[CH2:21]([O:23][C:24](=[O:34])[CH2:25][CH:26]1[CH2:30][CH2:29][C:28](=O)[C:27]1([CH3:33])[CH3:32])[CH3:22].[B][B][B][B][B][B][B][B][B][B]>>[CH2:21]([O:23][C:24](=[O:34])[CH2:25][CH:26]1[CH2:30][CH2:29][CH:28]([NH:19][C:17]2[CH:16]=[CH:15][C:14]([F:20])=[C:13]([C@:4]3([CH3:12])[C:5]([CH3:10])([CH3:11])[C:6](=[O:9])[N:7]([CH3:8])[C:2]([NH2:1])=[N:3]3)[CH:18]=2)[C:27]1([CH3:33])[CH3:32])[CH3:22]
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Reactant: CCOC(=O)CC1CCC(=O)C1(C)C
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: CCOC(=O)CC1CCC(Nc2ccc(F)c([C@@]3(C)N=C(N)N(C)C(=O)C3(C)C)c2)C1(C)C

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and rac-(2,2-dimethyl-3-oxo-cyclopentyl)-acetic acid ethyl ester (prepared according to Bunce, R. A. et al., J. Org. Chem. 1995, 60(9), 2748) using decaborane yielded a mixture of isomers of the title compound as a white foam. MS (ESI): m/z=461.3 [M+H]+.
Reaction SMILES: [CH2:1]([Sn](CCCC)(CCCC)C=C)[CH2:2]CC.Br[C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH:24]=1)[C:22]#[N:23].[Cl-].[NH4+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]([C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH:24]=1)[C:22]#[N:23])=[CH2:2]
Reactant: N#Cc1cncc(Br)c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=Cc1cncc(C#N)c1
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 70.3 %

Procedure:
Add bis(triphenylphosphine)palladium (II) dichloride (0.460 g, 0.66 mmol) and tributyl-vinyl-stannane (7.2 mL, 24.6 mmol) to a solution of 5-bromonicotinonitrile (3.0 g, 16.4 mmol) in toluene (50 mL) and stir at 110° C. for 150 min. Add an aqueous saturated solution of ammonium chloride and ethyl acetate and separate the layers. Wash the organic layer twice with an aqueous saturated solution of potassium fluoride and once with water. Dry (sodium sulfate), filter, and concentrate. Purify the residue by silica gel chromatography, eluting with 3:1 hexane:ethyl acetate, to give the title compound (1.5 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5].[CH2:12]([O:14][P:15]([CH2:20]O)(=[O:19])[O:16][CH2:17][CH3:18])[CH3:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH2:12]([O:14][P:15]([CH2:20][O:10][C:8]1[CH:9]=[C:2]([Cl:1])[C:3]([CH:4]=[O:5])=[C:6]([Cl:11])[CH:7]=1)(=[O:19])[O:16][CH2:17][CH3:18])[CH3:13]
Reactant: O=Cc1c(Cl)cc(O)cc1Cl
Reactant: CCOP(=O)(CO)OCC
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOP(=O)(COc1cc(Cl)c(C=O)c(Cl)c1)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,6-dichloro-4-hydroxy-benzaldehyde (190 mg, 1.0 mmol) and hydroxymethyl-phosphonic acid diethyl ester (278 mg, 1.0 mmol) in THF (8 mL) was added PPh3-resin (553 mg, 2.13 mmol/g) and DEAD (0.54 ml of 40% solution, 1.2 mmol). The suspension was stirred at ambient temperature overnight then the reaction mixture was filtered and partioned between water and EtOAc. The aqueous layer was extracted with EtOAc and the combined organic layers were dried with MgSO4, filtered and concentrated. Purification by flash chromatography using heptane/EtOAc (1:3) gave (3,5-dichloro-4-formylphenoxymethyl)-phosphonic acid diethyl ester as a colorless oil.
Reaction SMILES: [CH2:1]([C:6]1[C:7]([F:13])=[C:8]([F:12])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3]CC.[C:14](=[O:16])=[O:15]>>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:14]([OH:16])=[O:15])=[C:8]([F:12])[C:7]=1[F:13])[CH2:2][CH3:3]
Reactant: CCCCCc1cccc(F)c1F
Reactant: O=C=O
Product: CCCc1ccc(C(=O)O)c(F)c1F
Temperature: -20 °C

Procedure:
3-Propyl-1,2-difluorobenzene (obtainable according to Example 2) is metalated as described in 1c). 20 g of dry ice are added slowly at -70° C. The mixture is subsequently warmed to -20° C. Customary working up gives colourless crystals, m.p. 148° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=O)[CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)=[CH:18][C:17]=1[CH3:34].Cl.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[CH:18][C:17]=1[CH3:34]
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)COc4ccc(C)cc4)cc3C)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(NCCOc4ccc(C)cc4)cc3C)c2cc1OC
Temperature: 0 °C
Yield: 79.9 %

Procedure:
N1-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-methylphenyl}-2-(4-methylphenoxy)acetamide (200 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A 1 M solution (1.3 ml) of a borane-tetrahydrofuran complex in tetrahydrofuran was then added to the solution, and the mixture was stirred with heating under reflux for 2 hr. The reaction solution was cooled to 0° C. and was adjusted to pH=1 by the addition of 1 N hydrochloric acid, followed by stirring with heating under reflux for 30 min. The reaction solution was cooled to 0° C., was adjusted to pH=12 by the addition of a 1 N aqueous sodium hydroxide solution, and was extracted with chloroform. After the concentration of the extract, the residue was purified on a column using chloroform/methanol to give the title compound (155 mg, yield 80%).
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:27][OH:28])[C@@H:10]([NH:20][S@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([Cl:19])[CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)C.C(Cl)Cl>[Si:1]([O:8][C@H:9]([CH:27]=[O:28])[C@@H:10]([NH:20][S@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([Cl:19])[CH:13]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[S@](=O)N[C@@H](Cc1cc(F)cc(Cl)c1)[C@@H](CO)O[Si](C)(C)C(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)N[C@@H](Cc1cc(F)cc(Cl)c1)[C@@H](C=O)O[Si](C)(C)C(C)(C)C
Reaction time: 2 h
Yield: 803.6 %

Procedure:
To a 250 ml rbf was added (S)—N-((2S,3S)-3-(tert-butyldimethylsilyloxy)-1-(3-chloro-5-fluorophenyl)-4-hydroxybutan-2-yl)-2-methylpropane-2-sulfinamide (160.00 mg) and DCM (10 ml) followed by SODIUM BICARBONATE (148.7 mg, 5 eq) and Dess-MartinPeriodinane (195.1 mg, 1.30 eq). The reaction was allowed to stir for 2 h and then quenched with sodium bicarbonate (sat, 100 mL) and added SODIUM THIOSULFATE (391.7 mg, 2477 μmol) along with diethyl ether (100 ml). The quenched reaction was allowed to stir for 2 h and then the aq. layer was extracted with ether (3×75 mL). The combined organics were washed with brine and dried with magnesium sulfate, filtered and concentrated to give 1280 mg of a solid/oil mixture, which was purified on a silica gel column (20% EtOAc in hexanes) to give the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:9]=2[N:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[NH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:9]=2[N:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)[NH:4][CH:3]=1
Reactant: Cc1c[nH]c2ncc(-c3ccccc3)c(N3CCN(C(=O)OC(C)(C)C)CC3)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c[nH]c2ncc(-c3ccccc3)c(N3CCNCC3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 120.4 %

Procedure:
tert-Butyl 4-(3-methyl-5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (0.390 g, 0.994 mmol) was placed in DCM (10 mL) at room temperature. TFA (1 mL) was added, and the reaction was stirred at room temperature for 1 hour. The reaction was then concentrated to dryness, dissolved in minimal DCM, and added dropwise to a stirring solution of 1M HCl in ether. The solid product was filtered, washed with ether, and dried to give 3-methyl-5-phenyl-4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine (0.350 g, 96.4% yield), which was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@@H:10]([NH:14][C:15](=[O:51])[CH2:16][NH:17][C:18](=[O:50])[CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C@@H:27]3[C@@H:30]([S:31][CH2:32][C:33]([C:35]4[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=4)=[O:34])[C:29](=[O:42])[N:28]3[C:43]3[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=3)=[CH:23][CH:22]=2)[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1)#[N:2].[BH4-].[Na+]>CO.C(O)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@@H:10]([NH:14][C:15](=[O:51])[CH2:16][NH:17][C:18](=[O:50])[CH2:19][O:20][C:21]2[CH:22]=[CH:23][C:24]([C@@H:27]3[C@@H:30]([S:31][CH2:32][CH:33]([C:35]4[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=4)[OH:34])[C:29](=[O:42])[N:28]3[C:43]3[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=3)=[CH:25][CH:26]=2)[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C[C@@H](NC(=O)CNC(=O)COc2ccc([C@@H]3[C@@H](SCC(=O)c4ccc(F)cc4)C(=O)N3c3ccc(F)cc3)cc2)C(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: N#Cc1ccc(C[C@@H](NC(=O)CNC(=O)COc2ccc([C@@H]3[C@@H](SCC(O)c4ccc(F)cc4)C(=O)N3c3ccc(F)cc3)cc2)C(=O)O)cc1
Yield: 83.3 %

Procedure:
(2R)-3-(4-cyanophenyl)-2-{[({[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}amino}acetyl]amino)propanoic acid (0.006 g, 0.0084 mmole) was dissolved in methanol (1.5 ml). NaBH4 (0.0035 g, 0.092 mmole) was added and when the reaction was complete according to LC-MS a few drops of acetic acid was added. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC on a Kromasil C8-column using a stepwise gradient of 33.5%, 43% and then 55.5% MeCN in 0.1M ammonium acetate buffer as eluent. After freeze-drying, 0.005 g (83%) of the desired product was obtained.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][CH:16]=1.I[CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>O1CCCC1.CN1CCCN(C)C1=O>[CH:27]1([CH2:26][CH:21]([C:18]2[CH:17]=[CH:16][C:15]([S:14][CH3:13])=[CH:20][CH:19]=2)[C:22]([OH:24])=[O:23])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: ICC1CCCC1
Reactant: CSc1ccc(CC(=O)O)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CSc1ccc(C(CC2CCCC2)C(=O)O)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 34.6 %

Procedure:
A solution of diisopropylamine (3.2 mL, 23.16 mmol) in dry tetrahydrofuran (10.3 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3.4 mL) was cooled to −78° C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (2.3 mL, 23.16 mmol). The resulting reaction mixture was stirred at −78° C. for 30 min and then treated dropwise with a solution of 4-(methylthio)phenylacetic acid (2.01 g 11.03 mmol) in dry tetrahydrofuran (10.3 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3.4 mL). The reaction mixture was allowed to stir at −78° C. for 1 h, at which time, a solution of iodomethylcyclopentane (2.55 g, 12.13 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was stirred at −78° C. for 30 min and then allowed to warm to 25° C. where it was stirred for 24 h. The reaction mixture was quenched with water and then concentrated in vacuo to remove tetrahydrofuran. The remaining aqueous phase was acidified to pH=2 with a 10% aqueous hydrochloric acid solution and then extracted with ethyl acetate (200 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)propionic acid (1.01 g, 35%) as a cream solid: mp 91-93° C.; EI-HRMS m/e calcd for C15H20S (M+) 264.1184, found 264.1177.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl.[I-].[K+].[I:13]([O-])(=O)=O.[K+]>CO.O>[CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[C:7]=1[I:13]
Reactant: [O-][I+2]([O-])[O-]
Reactant: Cc1cc(C)cc(O)c1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1cc(O)cc(C)c1I
Temperature: 25 °C
Reaction time: 20 h

Procedure:
3,5-dimethyl-4-iodophenol was prepared as follows: To a solution of 59.1 g (484 mmol) of 3,5-dimethylphenol in 1 l of methanol was added 395 ml of 36% hydrochloric acid, with occasional cooling to maintain the temperature at 20°-30° C. To the resulting solution was then added a solution of 54.3 g (327 mmol) potassium iodide and 33.5 g (157 mmol) potassium iodate in 500 ml water over a 5 minute period. The solution became red and cloudy and a tan precipitate formed. After stirring at room temperature for 20 hours, the reaction mixture was cooled in ice and the precipitate collected and washed with ice cold 2/1 (v:v) water/methanol. The resulting tan solid was recrystallized several times from hot methanol and water to yield 36.4 g (15% yield) of white needles, mp 131°-132° C., which were identified as 3,5-dimethyl-4-iodophenol. 1H NMR analysis indicated the following: (δ, CDCls) 8.03 (br s, lH), 6.52 (s, 2H) and 2.35 (s, 6H). Mass spectrum analysis indicated the following: (m/e) 248 (m+, 100%), 121, 91 and 77.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:8]([NH2:10])=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6].[OH-].[Na+].C([O:15][C:16](=O)[CH2:17][CH2:18][CH:19]=O)C>O>[CH2:4]([CH:3]1[N:2]2[C:16](=[O:15])[CH2:17][CH2:18][CH:19]2[NH:10][C:8]1=[O:9])[CH:5]([CH3:7])[CH3:6]
Reactant: CCOC(=O)CCC=O
Reactant: CC(C)CC(N)C(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)CC1C(=O)NC2CCC(=O)N21
Yield: 74.7 %

Procedure:
To a solution of DL-leucinamide hydrochloride (1.5 g, 9 mmol) in water (40 ml), adjusted to pH 9.5 with 10% sodium hydroxide, ethyl-4-oxobutanoate (1g, 7.5 mmol) was added. The mixture was placed in a microwave oven and refluxed for 1 hour. Water was then evaporated under vacuum and the residue was chromatographated over silica gel (CH2Cl2/MeOH/NH4OH 98/2/0.1) to afford 1.1 g of the title compound.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14]1>CO>[CH2:19]([N:16]1[CH2:17][CH2:18][CH:13]([N:12]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])[CH2:14][CH2:15]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CO
Product: O=C1c2ccccc2C(=O)N1C1CCN(Cc2ccccc2)CC1
Temperature: 150 °C

Procedure:
16.8 Grams of phthalic anhydride and 21.6 grams of 4-amino-1-benzyl-piperidine were stirred together while they were being heated in an oil bath at 150° C. for 30 minutes. On cooling, the resulting glassy solid was heated with 400 milliliters of methanol to give 26.5 grams of 1-benzyl-4-phthalimidopiperidine. Melting point: 154°-7° C.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[C:13]([O:20][CH3:21])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].Cl>C1COCC1.O>[C:23]([C:7]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[C:13]([O:20][CH3:21])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1cc(C(=O)O)c(Br)c(OC)c1OC
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)c(C(=O)OCc2ccccc2)c(OC)c1OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
tert-Butyllithium (1.7M solution in pentane, 15 mmol) is added to a solution of 2-bromo-3,4,5-trimethoxybenzoic acid 5 (5 mmol) in 50 mL of THF, while maintaining the temperature of the mixture below −95° C. After the addition is completed, the mixture is allowed to warm to −78° C. After 30 minutes, benzyl chloroformate (5 mmol) is added in one portion, and the mixture is allowed to warm to 0° C. Water (50 mL) is added, and then the pH of the mixture is carefully adjusted to 3 using 0.1 M HCl. The mixture is extracted with ethyl acetate (5×100 mL). The organic phases are dried over anhydrous Na2SO4 and concentrated in vacuo. The mixture is purified by flash chromatography to give the product as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[Cl:15][CH2:16][CH2:17]O.Cl>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([O:10][CH2:17][CH2:16][Cl:15])=[O:9])=[CH:13][CH:14]=1
Reactant: OCCCl
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)O
Agent: Cl
Product: CC(C)(Oc1ccc(Cl)cc1)C(=O)OCCCl

Procedure:
107.3 g (0.5 mole) of p-chlorophenoxy-2-methylpropionic acid are dissolved in 241.5 g (3 moles) of 2-chloroethanol. The solution is saturated with HCl gas. The excess of solvent is distilled under 11 Torr. The ester is distilled under 0.02 Torr, at a temperature of 97°-98°.
Reaction SMILES: FC1C=CC([C:8]2[CH:13]=[C:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](C)=[C:19](C4C=CC(F)=CC=4)[CH:18]=3)(=[O:16])=[O:15])[CH:11]=[CH:10][C:9]=2[CH3:31])=CC=1.[O:32]1[C:36]2([CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[O:35][CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+].O>CN1C(=O)N(C)CCC1>[C:9]1([CH3:31])[CH:10]=[CH:11][C:12]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([N:39]3[CH2:40][CH2:41][C:36]4([O:35][CH2:34][CH2:33][O:32]4)[CH2:37][CH2:38]3)=[CH:19][CH:18]=2)(=[O:15])=[O:16])=[CH:13][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)c2ccc(C)c(-c3ccc(F)cc3)c2)cc1-c1ccc(F)cc1
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCN(C)C1=O
Product: Cc1ccc(S(=O)(=O)c2ccc(N3CCC4(CC3)OCCO4)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.4 %

Procedure:
To a solution of 4-fluorophenyl-4-tolylsulfone (1.25 g, 5 mmol) in N,N′-dimethylpropyleneurea (5 ml) was added 1,4-dioxa-8-aza-spiro[4.5]decane (0.88 g, 6 mmol), and potassium carbonate (0.83 g, 6 mmol). The mixture was stirred at room temperature for 4 h and then heated at 70° C. for 18 h. An additional 0.22 g of 1,4-dioxa-8-aza-spiro[4.5]decane was added, and the reaction was continued for 1 day. The mixture was cooled to room temperature, and treated with water. The resulting suspension was filtered, and the precipitate washed with water and methanol, and dried in vacuo to give 1.80 g of a white solid; m.p. 164-165° C.; MS (ES) m/z 373.9 (MH+); HRMS (EI) Calcd. for C20H23NO4S (M+): 373.1348, Found: 373.1342.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3]([OH:5])=O.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:43][CH:44]1[CH2:49][CH2:48][CH:47]([C:50]2[O:54][N:53]=[C:52]([C:55]3[N:60]=[C:59]([N:61]([CH3:68])[C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)[N:58]=[C:57]([NH2:69])[N:56]=3)[N:51]=2)[CH2:46][CH2:45]1>CN(C=O)C>[NH2:69][C:57]1[N:58]=[C:59]([N:61]([CH3:68])[C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[N:60]=[C:55]([C:52]2[N:51]=[C:50]([CH:47]3[CH2:48][CH2:49][CH:44]([NH:43][C:3](=[O:5])[CH:2]([CH3:6])[CH3:1])[CH2:45][CH2:46]3)[O:54][N:53]=2)[N:56]=1
Reactant: CC(C)C(=O)O
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(C3CCC(N)CC3)n2)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)NC1CCC(c2nc(-c3nc(N)nc(N(C)c4ccccc4)n3)no2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 21.4 %

Procedure:
To a solution of 2-methylpropanoic acid (0.03 g, 0.327 mmol) in DMF (5 mL) was added DIPEA (0.122 mL, 0.682 mmol) followed by (1H-benzotriazol-1-yloxy)[tris(dimethylamino)]phosphonium hexafluorophosphate (0.13 g, 0.3 mmol). The reaction mixture was stirred at room temperature for 5 min and 6-[5-(4-aminocyclohexyl)-1,2,4-oxadiazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-triazine-2,4-diamine (batch 1 from Example 422, 0.1 g, 0.273 mmol) was added. The reaction mixture was stirred at room temperature for 16 h and then concentrated, extracted with EtOAc, washed with water, dried over sodium sulfate and concentrated. The residue was purified by FCC, eluting with 0-10% MeOH in DCM. The crude product was dissolved in EtOAc, washed with saturated aq. sodium bicarbonate, dried over sodium sulfate and concentrated under vacuum to afford the title compound (0.0255 g, 21%).
Reaction SMILES: C(O[C:5]1[C:6](=[O:20])[C:7](=[O:19])[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)(C)C.[NH2:21][CH:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:23]>>[F:18][C:15]([F:16])([F:17])[C:12]1[CH:11]=[CH:10][C:9]([C:8]2[C:7](=[O:19])[C:6](=[O:20])[C:5]=2[NH:21][CH:22]([CH3:23])[C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:14][CH:13]=1
Reactant: CC(C)Oc1c(-c2ccc(C(F)(F)F)cc2)c(=O)c1=O
Reactant: CC(N)C(C)(C)C
Product: CC(Nc1c(-c2ccc(C(F)(F)F)cc2)c(=O)c1=O)C(C)(C)C

Procedure:
In a manner similar to Example 9, Step 2, 3-isopropoxy-4-(4-trifluoromethyl-phenyl)-cyclobut-3-ene-1,2-dione (0.40 g, 1.408 mmol) and 2-amino-3,3-dimethylbutane (0.28 mL, 2.11 mmol) were converted to the title compound. Recrystallization from hot ethyl acetate afforded 0.18 g (39%) of compound as a white solid: m.p. 191-193° C.; 1H NMR (DMSO-d6) δ8.97(br d,1H), 8.22(ABq,2H), 7.88(ABq,2H), 4.30(m,1H), 1.26(d,3H), 0.92(s,9H); IR (KBr) 3450, 3180, 2970, 1775, 1740, 1600, 1420, 1370, 1170, 1110, 1060, 850 cm−1; MS (m/z) 325 [M+].
Reaction SMILES: Cl.C(O[C:5](=[O:19])[C@H:6]([CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[NH:11][CH:10]=1)[NH2:7])C.[CH2:20]([NH2:22])[CH3:21]>>[CH2:20]([NH:22][C:5](=[O:19])[C@H:6]([CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[NH:11][CH:10]=1)[NH2:7])[CH3:21]
Reactant: CCOC(=O)[C@@H](N)Cc1c[nH]c2ccc(O)cc12
Reactant: CCN
Agent: Cl
Product: CCNC(=O)[C@@H](N)Cc1c[nH]c2ccc(O)cc12
Temperature: 60 °C

Procedure:
5-Hydroxytryptophan ethyl ester hydrochloride (69 mg, obtained from Sigma Chemical Co.) was dissolved in 0.5 ml of a 70% aqueous solution of ethylamine (obtained from Aldrich Chemical Co., Inc.) and heated on a steam bath at 60° C. under argon for twelve hours. The solvent was evaporated under a stream of argon. The resulting oil was dissolved in methanol/ether and acidified with gaseous HCl. Insolubles were allowed to precipitate and the solvent decanted. The hydrochloride salt of the product (40 mg) was dried under high vacuum. Mass spectroscopy (CI-NH3) showed a parent ion at 247 mass units (m+1).
Reaction SMILES: I[C:2]1[C:10]2[O:9][N:8]=[C:7]([NH2:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:12].[O:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][O:21][CH:22]2[CH2:45][CH2:44][C:25]3([C:33]4[C:28](=[CH:29][C:30](B5OC(C)(C)C(C)(C)O5)=[CH:31][CH:32]=4)[NH:27][C:26]3=[O:43])[CH2:24][CH2:23]2)[CH2:15][CH2:14]1>>[NH2:11][C:7]1[C:6]2[CH:5]=[CH:4][C:3]([CH3:12])=[C:2]([C:30]3[CH:29]=[C:28]4[C:33]([C:25]5([CH2:24][CH2:23][CH:22]([O:21][CH2:20][CH2:19][N:16]6[CH2:15][CH2:14][O:13][CH2:18][CH2:17]6)[CH2:45][CH2:44]5)[C:26](=[O:43])[NH:27]4)=[CH:32][CH:31]=3)[C:10]=2[O:9][N:8]=1
Reactant: Cc1ccc2c(N)noc2c1I
Reactant: CC1(C)OB(c2ccc3c(c2)NC(=O)C32CCC(OCCN3CCOCC3)CC2)OC1(C)C
Product: Cc1ccc2c(N)noc2c1-c1ccc2c(c1)NC(=O)C21CCC(OCCN2CCOCC2)CC1

Procedure:
Obtained as a white solid (16%, exact isomeric form not determined) from 7-iodo-6-methyl-1,2-benzisoxazol-3-amine (preparation 24) and 4-(2-morpholinoethoxy)-6′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclohexane-1,3′-indolin]-2′-one (preparation 15) following the experimental procedure as described in example 1 followed by purification by flash chromatography (97:3 dichloromethane/methanol).