Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:5][C:6](=O)[CH:7]=1.[SH:14][CH2:15][CH2:16][C:17](O)=[O:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.CS(O)(=O)=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:7]2[C:17](=[O:18])[CH2:16][CH2:15][S:14][C:6]=2[CH2:5][CH2:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C1CCC(=O)C=C1C
Reactant: O=C(O)CCS
Agent: CS(=O)(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(C)C2=C(CC1)SCCC2=O
Temperature: 25 °C
Yield: 36 %

Procedure:
A mixture of ethyl 2-methyl-4-oxo-2-cyclohexenecarboxylate (2.0 kg, 91.2%, 10.98 moles), β-mercaptopropionic acid (1.165 kg, 10.98 moles), p-toluenesulfonic acid (ptsa) monchydrate (0.710 kg, 3.73 moles) and pyridine (0.304 kg, 3.84 moles) in toluene is heated to reflux temperature, heated at reflux temperatures for 7 hours using a Dean Stark trap for removal of water, allowed to cool to room temperature over a 17 hour period, cooled to 50° C., treated with trifluoroacetic anhydride (TFAA) (2.306 kg, 10.98 moles) at 50°-12° C., treated with methanesulfonic acid (0.053 kg, 0.55 moles), allowed to warm to room temperature, held at room temperature until reaction is complete by HPLC analysis and quenched with water. The phases are separated. The organic phase is washed with water and distilled to remove the toluene. The remaining pot residue is treated with isopropyl alcohol (1.89 kg), cooled to 45° C., treated with heptane (1.65 kg), and cooled to room temperature. The resultant mixture is filtered and the filtercake is washed sequentially with a 1:1 isopropanol:heptane mixture (0.735 kg) and heptane (1.37 kg). The washed filtercake is dried in vacuo to give he title product as a white crystalline solid, 0.931 kg (36% yield) 98.4% purity, identified by HPLC analysis.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8](S(C3C=CC=CC=3)(=O)=O)[C:9]([C:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]=3)=[CH:10][C:3]=12.[OH-].[Na+].O>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([C:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]=3)=[CH:10][C:3]=12
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Br)ccnc3n2S(=O)(=O)c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Br)ccnc3[nH]2)CC1

Procedure:
A mixture of Example 135C (3.00 g, 5.63 mmol) and 20% sodium hydroxide in water (2.5 mL, 5.63 mmol) in dioxane (35 mL) was heated at 90° C. for 6 hours. The solvent was evaporated. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated to about 10 mL. The solid material was filtered, washed with ethyl acetate and dried to provide the title compound. MS (ESI+) m/z 378 (M+1).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[C:9]([NH:10][C:11](=[O:22])[C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([O:19][CH3:20])=[C:14]([CH3:21])[CH:13]=2)=[C:8]([OH:23])[N:7]=[C:6]([S-:24])[N:5]=1.[Na+].I[CH3:27].Cl>O.CN1CCCC1=O>[OH:23][C:8]1[C:9]([NH:10][C:11](=[O:22])[C:12]2[CH:13]=[C:14]([CH3:21])[C:15]([O:19][CH3:20])=[C:16]([CH3:18])[CH:17]=2)=[C:4]([OH:3])[N:5]=[C:6]([S:24][CH3:27])[N:7]=1
Reactant: CI
Reactant: COc1c(C)cc(C(=O)Nc2c(O)nc([S-])nc2O)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1c(C)cc(C(=O)Nc2c(O)nc(SC)nc2O)cc1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
22.78 g of sodium hydroxide were initially charged in 735 ml of water, the mixture was cooled to 0° C., 78.21 g of sodium 4,6-dihydroxy-5-(4-methoxy-3,5-dimethylbenzoylamino)pyrimidine-2-thiolate and 365 ml of N-methyl-2-pyrrolidone were added and, after 30 min at 0° C., 14.2 ml of iodomethane were added dropwise. After 2 hours at 0° C., the reaction mixture was carefully adjusted to pH 2 using concentrated aqueous hydrochloric acid. About 200 ml of water were added, and the precipitated solid was filtered off with suction, washed with water until neutral and dried under reduced pressure. This gave 50.89 g (67%) of the title compound, which was reacted further without any further purification.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:11]([OH:12])=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1.[CH2:19]([N:21]([CH2:24]C)[CH2:22]C)C.C(=O)([O-])O.[Na+]>ClCCl.C(OCC)(=O)C>[CH3:19][N:21]([CH3:24])[C:22]1[O:12][C:11]2[C:10]3[CH:9]([CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])[CH2:8][CH2:7][C:6]=3[CH:5]=[CH:4][C:3]=2[N:2]=1
Reactant: CC(=O)NCCC1CCc2ccc(N)c(O)c21
Reactant: CCN(CC)CC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)NCCC1CCc2ccc3nc(N(C)C)oc3c21
Reaction time: 0.25 h
Yield: 7 %

Procedure:
N-[2-(6-Amino-7-hydroxy-2,3-dihydro-1H-inden-1-yl)ethyl]acetamide hydrochloride (100 mg, 0.369 mmol) was suspended in dichloromethane (3.7 mL), triethylamine (51.5 μg, 0.369 mmol) was added at room temperature, and the mixture was stirred for 15 min. Thereto was added dichloromethylenedimethyliminium chloride (59.9 mg, 0.369 mmol), and the mixture was heated under reflux for 1 hr. To the reaction solution was added saturated aqueous sodium hydrogencarbonate solution. The mixture was diluted with ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→90/10) to give the title compound (7.4 mg, yield 7%).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[C:29](Cl)(=[O:35])[O:30][CH2:31][CH2:32][O:33][CH3:34]>C(Cl)Cl>[CH3:34][O:33][CH2:32][CH2:31][O:30][C:29]([NH:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]2)[CH2:9]1)=[O:6])=[O:35]
Reactant: COCCOC(=O)Cl
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCOC(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.8 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (150 mg, 0.45 mmol) in DCM (5 ml), was added triethylamine (188 μl, 1.35 mmol) and 2-methoxyethyl carbonochloridate (63 μl, 0.54 mmol). The reaction was stirred at RT for 4 hours, and then the solvent was evaporated. The residue was taken up with EtOAc, and the organic phase was washed with water and brine, dried over Na2SO4 and evaporated to dryness, obtaining (R)-quinuclidin-3-yl 2-((2-methoxyethoxy)-carbonylamino)-2-phenylacetate (73.0 mg; 45% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:36][CH2:35][C:34]([F:38])([F:37])[CH2:33][C@@H:32]2[C:39]2[N:43]([CH3:44])[N:42]=[CH:41][CH:40]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:36][CH2:35][C:34]([F:38])([F:37])[CH2:33][C@@H:32]2[C:39]2[N:43]([CH3:44])[N:42]=[CH:41][CH:40]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:9])=[O:10])[CH:7]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@H]3CCC(F)(F)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CC(F)(F)CC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1Cl
Yield: 89.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 5-chloro-4-{[(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide (104 mg, 0.16 mmol) prepared in Example 131a, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (72.2 mg, 90%) as a colorless solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([CH3:12])[N:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([NH2:27])[CH:18]=[CH:19][C:20]=1[N:21]1[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]1>ClCCl.CO>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([NH:27][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([CH3:12])[N:3]=2)[CH:18]=[CH:19][C:20]=1[N:21]1[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]1
Reactant: Cc1cc(C(F)(F)F)cc(Cl)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(Nc2cc(C(F)(F)F)cc(C)n2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogous manner as described in example 1e) from 2-chlor-6-methyl-4-(trifluormethyl)pyridine (59 mg, 0.3 mmol) and 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (61 mg, 0.3 mmol). The reaction was heated for 16 h to reflux. Obtained as a pale-yellow solid (75 mg 69%) after column chromatography of the crude reaction product on silica gel using dichloromethane/methanol (19:1 v/v) as eluent.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5](/[CH:6]=[N:7]/[S@@:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[O:9])=[CH:4][CH:3]=1.[Li][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1>C1COCC1>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([C@@H:6]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:7][S@@:8]([C:10]([CH3:11])([CH3:12])[CH3:13])=[O:9])=[CH:4][CH:3]=1
Reactant: [Li]c1ccccc1
Reactant: CC(C)(C)[S@@](=O)/N=C/c1ccc(Br)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)N[C@H](c1ccccc1)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 4 h
Yield: 63 %

Procedure:
(R,E)-N-(4-bromobenzylidene)-2-methylpropane-2-sulfinamide, 18-b, (10 g, 34.84 mmol) was dissolved in anhydrous THF (100 ml). The mixture was then cooled to −78° C. and PhLi (34.84 ml, 69.68 mmol) was added dropwise. After addition the mixture was allowed to stir at −78° C. for additional 4 h and warmed to room temperature for another 2 h. The reaction was TLC monitored and prolonged the time if necessary. The mixture was quenched with saturated NH4Cl followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/ethyl acetate=2/1) to provide the product, 23-a, (8 g, 63%). HPLC indicated that the diastereomer ratio is 80:20 and recrystallization once in hexane/ethyl acetate can increase it to above 95:5 with around 40% material lost in the mother liquid.
Reaction SMILES: O[Li].O.[O:4]=[C:5]1[C:14]2[C:9](=[C:10]([C:15]([O:17]C)=[O:16])[CH:11]=[CH:12][CH:13]=2)[O:8][C:7]([C:19]2[C:20]([C:25]([F:28])([F:27])[F:26])=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:6]1.O>O.C1COCC1.CO>[O:4]=[C:5]1[C:14]2[C:9](=[C:10]([C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)[O:8][C:7]([C:19]2[C:20]([C:25]([F:28])([F:27])[F:26])=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:6]1
Reactant: COC(=O)c1cccc2c(=O)cc(-c3cccnc3C(F)(F)F)oc12
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cccc2c(=O)cc(-c3cccnc3C(F)(F)F)oc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 111.9 %

Procedure:
LiOH.H2O (28 mg, 0.64 mmol) was added to a solution of methyl 4-oxo-2-(2-(trifluoromethyl)pyridin-3-yl)-4H-chromene-8-carboxylate 40 (120 mg, 0.32 mmol) in H2O/THF/MeOH (5 mL, 1:2:2). The reaction mixture was stirred at ambient temperature for 12 h, poured into H2O and the pH adjusted to 3. The mixture was extracted with ethyl acetate, dried (MgSO4) and concentrated to give 41 (120 mg) which was with no further purification.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].C(=O)([O-])O.[Cs+].Cl[CH2:16][CH2:17][O:18][C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20]>CN1C(=O)CCC1>[C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O:6][CH2:16][CH2:17][O:18][C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])=[O:5]
Reactant: COC(=O)/C=C/C(=O)O
Reactant: CC(C)OC(=O)OCCCl
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COC(=O)/C=C/C(=O)OCCOC(=O)OC(C)C
Yield: 90.9 %

Procedure:
Following general procedure A, methyl hydrogen fumarate (0.39 g, 3.0 mmol) in NMP (8 mL) was reacted with CsHCO3 (0.69 g, 3.6 mmol) and methylethyl (chloroethoxy)formate (0.70 g, 4.2 mmol) to afford 0.71 g (91% yield) of the title compound (40) after isolation and purification. 1H NMR (CDCl3, 400 MHz): δ 6.89 (d, J=15.6 Hz, 1H), 6.84 (q, J=5.2 Hz, 1H, superimposed), 6.82 (d, J=15.6 Hz, 1H, superimposed), 4.90 (heptet, J=6.2 Hz, 3H), 3.81 (s, 3H), 1.57 (d, J=5.2 Hz, 3H), 1.32 (d, J=6.2 Hz, 3H), 1.31 (d, J=6.2 Hz, 3H). MS (ESI): m/z 261.02 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:43]([N:50]1[CH2:55][CH2:54][O:53][CH:52]([C:56]2[CH:61]=[CH:60][C:59]([CH2:62]O)=[CH:58][CH:57]=2)[CH2:51]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C1COCC1>[CH2:43]([N:50]1[CH2:55][CH2:54][O:53][CH:52]([C:56]2[CH:57]=[CH:58][C:59]([CH2:62][O:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])=[CH:60][CH:61]=2)[CH2:51]1)[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: Oc1c(Cl)cccc1Cl
Reactant: OCc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1cccc(Cl)c1OCc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 144 %

Procedure:
To a solution of 2,6-dichlorophenol (0.68 g; 4.19 mmol) in THF (20 mL) was added DIAD (1.13 mL; 5.72 mmol), and triphenylphosphine (1.50 g; 5.72 mmol), at RT, followed, after 30 minutes, by [4-(4-benzyl-morpholin-2-yl)-phenyl]-methanol (1.08 g; 3.81 mmol). Subsequently, the resulting mixture was stirred at RT for 1 hour, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O:hexanes 1:1) to afford 4-benzyl-2-[4-(2,6-dichloro-phenoxymethyl)-phenyl]-morpholine (2.35 g) which was used as such in the next step.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:28])[C@@H:6]([NH2:27])[CH2:7][NH:8][C:9]([C@@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:12]1)=[O:10])[CH3:3].C(N(CC)CC)C.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.O>ClCCl>[CH2:2]([O:4][C:5](=[O:28])[C@@H:6]([NH:27][C:36](=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:7][NH:8][C:9]([C@@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH2:12]1)=[O:10])[CH3:3]
Reactant: CCOC(=O)[C@@H](N)CNC(=O)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)[C@H](CNC(=O)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1)NC(=O)c1ccccc1
Temperature: 0 °C

Procedure:
A solution of N-[(R)-(1-benzyloxycarbonyl-3-piperidyl)carbonyl]-2(S)-amino-β-alanine ethyl ester hydrochloride (300 mg) in dichloromethane (3 ml) was added triethylamine (222 μl) and benzoyl chloride (93 μl) under stirring at 0° C. After stirring at ambient temperature for 1 hour, the mixture was poured into water and extracted with dichloromethane. The extract was washed with water, saturated aqueous NaHCO3 solution, water and brine, and dried over MgSO4, and evaporated in vacuo. The residue was recrystallized from diethyl ether to give N-[(R)-(1-benzyloxycarbonyl-3-piperidyl)carbonyl]-2(S)-benzoylamino-β-alanine ethyl ester (349 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:10])[CH2:8][NH2:9].Br[C:12]([CH3:19])([CH3:18])[C:13]([O:15]CC)=O>C1(C)C=CC=CC=1>[CH3:19][C:12]1([CH3:18])[NH:10][CH2:7][CH2:8][NH:9][C:13]1=[O:15]
Reactant: NCCN
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC1(C)NCCNC1=O

Procedure:
Potassium carbonate (390 grams) and ethylene diamine (1001 grams) are stirred with toluene (1.50 l). A solution of ethyl 2-bromoisobutyrate (500 grams) in toluene (750 ml) is added. The suspension is heated to reflux over night, and filtered. The filter cake is washed with toluene (500 ml). The combined filtrates (volume 4.01) are heated on a water bath and distilled at 0.3 atm. using a Claisen apparatus; first 1200 ml distillate is collected at 35° C. (the temperature in the mixture is 75° C.). More toluene is added (600 ml), and another 1200 ml distillate is collected at 76° C. (the temperature in the mixture is 80° C.). Toluene (750 ml) is added again, and 1100 ml of distillate is collected at 66° C. (temperature in the mixture 71° C.). The mixture is stirred on an ice bath and inoculated, whereby the product precipitates. The product is isolated by filtration, washed with toluene, and dried over night in a vacuum oven at 50° C. Yield 171 g (52%) of 3,3-dimethylpiperazin-2-one. NMR consistent with structure.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([CH:9]=[O:10])C.[S:11]1[C:15]([NH:16][C:17](=[O:32])[CH2:18][N:19]2[C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:21]([C:28]([F:31])([F:30])[F:29])=[N:20]2)=[CH:14][C:13]2[CH2:33][CH2:34][CH2:35][CH2:36][C:12]1=2.C([O-])(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[CH:9]([C:14]1[C:13]2[CH2:33][CH2:34][CH2:35][CH2:36][C:12]=2[S:11][C:15]=1[NH:16][C:17](=[O:32])[CH2:18][N:19]1[C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[C:21]([C:28]([F:31])([F:29])[F:30])=[N:20]1)=[O:10]
Reactant: O=C(Cn1nc(C(F)(F)F)c2c1CCCC2)Nc1cc2c(s1)CCCC2
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c(NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)sc2c1CCCC2
Temperature: 25 °C
Yield: 86.4 %

Procedure:
Phosphorus oxychloride (399 μl, 4.28 mmol) was added dropwise to a stirred solution of DMF (332 μl, 4.28 mmol) in 1,2-dichloroethane (3 mL). A suspension of N-(4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)-2-(3-trifluoromethyl-4,5,6,7-tetrahydroindazol-1-yl)-acetamide (1.64 g, 4.28 mmol) in 1,2-dichloroethane (80 mL) was added portionwise with stirring, and the mixture stirred at RT for 15 min. The resulting yellow solution was refluxed for 20 min. After cooling to RT, the mixture was added to a solution of sodium acetate (13.6 g, 166 mmol, in 130 mL of water) and the solution heated at 50° C. for 20 min. After cooling to RT, the solution was diluted with DCM (100 mL), and the phases separated. The aqueous layer was extracted with DCM (100 mL) and the combined organics washed with saturated sodium bicarbonate solution (100 mL), dried over sodium sulphate and concentrated in vacuo to afford the title compound as a yellow solid (1.52 g, 3.70 mmol, 86%).
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]([CH3:26])[CH3:25])[N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[OH-].[Li+].Cl>C1COCC1.O>[CH3:26][N:24]([CH3:25])[C:20]1[N:19]=[C:18]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([OH:27])=[O:3])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)[CH:23]=[CH:22][N:21]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ccnc(N(C)C)n3)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Oc2ccnc(N(C)C)n2)cc2c1C(CC(=O)O)OB2O
Reaction time: 2 h

Procedure:
A solution of [6-(2-dimethylamino-pyrimidin-4-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.094 g, 0.25 mmol) in THF (5 mL) was treated with lithium hydroxide (0.029 g, 1.27 mmol) in water (0.5 mL) at 0° C. The solution was stirred at 0° C. to room temperature for 2 hours, then acidified with 2N HCl to pH 2, and concentrated. The residue was purified by silica gel flash column chromatography (AcOH:acetone:hexanes; trace:1:2; then MeOH:CH2Cl2; 5:95) to give [6-(2-dimethylamino-pyrimidin-4-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid as a white solid after lyophilization (0.02 g, 23%). 1H NMR (400 MHz, DMSO-d6) δ 8.18 (d, J=5.47 Hz, 1H), 7.24 (s, 1H), 7.07 (s, 1H), 6.01 (d, J=5.47 Hz, 1H), 5.50-5.45 (m, 1H), 3.02 (dd, J=15.63, 2.40 Hz, 1H), 2.96 (s, 6H), 2.28 (s, 3H), 2.11 (dd, J=15.63, 9.38 Hz, 1H). MS (ESI) m/z: 344 [M+1].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=O)[C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:46]([C:50]1[CH:70]=[CH:69][C:53]([CH2:54][NH:55][CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([O:64][C:65]([F:68])([F:67])[F:66])[CH:59]=2)=[CH:52][CH:51]=1)([CH3:49])([CH3:48])[CH3:47]>CN(C=O)C.O>[C:46]([C:50]1[CH:70]=[CH:69][C:53]([CH2:54][N:55]([CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([O:64][C:65]([F:68])([F:67])[F:66])[CH:59]=2)[C:12]([C:9]2[C:10]([F:11])=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:14])=[CH:52][CH:51]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(OC(F)(F)F)c2)cc1
Reactant: O=C(O)c1c(F)c(Cl)cc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CCc2cccc(OC(F)(F)F)c2)C(=O)c2c(F)c(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 25.3 %

Procedure:
To a solution of 200 mg (0.94 mmol) 5-chloro-6-fluoro-1H-indole-7-carboxylic acid and 300 mg of TBTU (0.94 mmol) in 15 ml DMF, were added 0.8 ml (4.68 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 329 mg (0.94 mmol) (4-tert-butyl-benzyl)-[2-(3-trifluoromethoxy-phenyl)-ethyl]-amine in 1 ml DMF was added. After stirring for 17 h at rt, the reaction mixture was diluted with 160 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (90 g silica gel; diethylether/heptane 1:1) to give 130 mg off-white foam (23%). MS (ISP) 547.4 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[CH3:30][O:31][CH2:32][C:33](Cl)=[O:34]>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([C:33](=[O:34])[CH2:32][O:31][CH3:30])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Reactant: COCC(=O)Cl
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)COC)C3)cc1

Procedure:
Compound dt was prepared according to the procedure described in Example 5 by reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with 2-methoxyacetyl chloride. LC-MS: m/z=+469 (M+H)−.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].[C:14]1([S:20][CH3:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O>[CH3:21][S:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:9]1[C:10](=[O:11])[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:7]1=[O:8]
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: CSc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CSc1ccccc1C1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 13.3 %

Procedure:
Ninhydrin (0.10 g, 0.56 mmols) and thioanisole (0.07 mL, 0.56 mmols) were dissolved in trifluoroacetic acid (3 mL) and was stirred for 90 min at room temperature. The reaction mixture was neutralization with an aqueous sodium bicarbonate solution and was extracted with ethylacetate and was purified by silica gel column chromatography to afford the title compound (20 mg, 13%).