Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@@H:4]1[CH2:7][C@H:6]([C:8]([OH:10])=[O:9])[C:5]1([CH3:12])[CH3:11])(=[O:3])[CH3:2].C1COCC1.C1CCC(N=C=NC2CCCCC2)CC1.[C:33](O)([CH3:36])([CH3:35])[CH3:34]>CCOC(C)=O>[C:1]([C@@H:4]1[CH2:7][C@H:6]([C:8]([O:10][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:9])[C:5]1([CH3:12])[CH3:11])(=[O:3])[CH3:2]
Reactant: CC(=O)[C@@H]1C[C@H](C(=O)O)C1(C)C
Reactant: CC(C)(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)[C@@H]1C[C@H](C(=O)OC(C)(C)C)C1(C)C
Temperature: 25 °C
Reaction time: 36 h
Yield: 70 %

Procedure:
To a stirred ice cooled solution of (1S,3R)-3-acetyl-2,2-dimethylcyclobutanecarboxylic acid (16.0 g, 94.117 mmol) in THF (160 ml) DMAP (1.148 g, 9.409 mmol) and DCC (23.265 g, 112.93 mmol) were added, followed by t-butyl alcohol (27.63 ml, 282.34 mmol) was added drop wise. The reaction mixture was stirred at room temperature for 36 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc and filtered through a celite bed and washed with EtOAc. The filtrate was as such concentrated and purified by silica gel column (100-200 mesh, elution 10% EtOAc in hexane) to afford the title compound as a solid. Wt: 15.0 g: Yield: 70%; 1H NMR (300 MHz, CDCl3): δ 2.86-2.74 (m, 1H), 2.70-2.50 (m, 2H), 2.04 (s, 3H), 1.89-1.78 (m, 1H), 1.42, 1.40 (2s, 12H), 0.91 (s, 3H); Mass: [M+Na]+ 249 (100%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[NH:7][C:8]1[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=1[C:10]([NH:12][CH2:13][CH3:14])=[O:11])([O-:3])=[O:2].[O:22]1CCC[CH2:23]1.[H-].[Na+].C(Cl)(=O)OCC>O>[N+:1]([C:4]1[CH:5]=[C:6]([N:7]2[C:8]3[C:9](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:10](=[O:11])[N:12]([CH2:13][CH3:14])[C:23]2=[O:22])[CH:19]=[CH:20][CH:21]=1)([O-:3])=[O:2]
Reactant: C1CCOC1
Reactant: CCNC(=O)c1ccccc1Nc1cccc([N+](=O)[O-])c1
Agent: CCOC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCn1c(=O)c2ccccc2n(-c2cccc([N+](=O)[O-])c2)c1=O
Reaction time: 0.5 h

Procedure:
To a solution of 2.9 g of 2-(m-nitroanilino)-N-ethylbenzamide and 25 ml of tetrahydrofuran was added 1.0 g of 50 % sodium hydride, and stirring was performed for 30 minutes at room temperature. To this was added dropwise under cooling 5.4 g of ethyl chlorocarbonate, and the mixture was allowed to stand for one hour at room temperature and then refluxed for 10 hours. After the reaction was complete, the solvent was evaporated from the reaction mixture under reduced pressure, and to the residue obtained was added water to prepicpitate a crude product. This product was recrystallized from methanol to give 2.5 g of 1-(m-nitrophenyl)-3-ethylquinazoline-2,4(1H, 3H)-dione as colorless prisms, melting at 193°-194° C.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[N:4]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[CH:3]=1.C([Mg]Cl)(C)C.[C:27]([O:31][C:32](=[O:52])[N:33]([C:43]1[CH:48]=[CH:47][C:46]([CH:49]=[O:50])=[C:45]([F:51])[N:44]=1)[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)([CH3:30])([CH3:29])[CH3:28]>O1CCCC1>[C:27]([O:31][C:32](=[O:52])[N:33]([C:43]1[CH:48]=[CH:47][C:46]([CH:49]([OH:50])[C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([CH3:11])[CH:9]=3)[N:4]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[CH:3]=2)=[C:45]([F:51])[N:44]=1)[CH2:34][C:35]1[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C=O)c(F)n2)cc1
Reactant: Cc1cnc2c(c1)c(I)cn2[Si](C(C)C)(C(C)C)C(C)C
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C(O)c3cn([Si](C(C)C)(C(C)C)C(C)C)c4ncc(C)cc34)c(F)n2)cc1
Temperature: 0 °C
Yield: 73.8 %

Procedure:
To 3-iodo-5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (8, 40 g, 97.0 mmol) in 400 mL of tetrahydrofuran under an atmosphere of nitrogen at −20° C., isopropylmagnesium chloride (54.8 mL, 2 M in tetrahydrofuran, 110 mmol) is added and the reaction allowed to warm to 0° C. over 30 minutes. The reaction is cooled to −40° C. and (6-fluoro-5-formyl-pyridin-2-yl)-(4-methoxy-benzyl)-carbamic acid tert-butyl ester (47, 15.81 g, 43.9 mmol) in tetrahydrofuran is added. The reaction is allowed to warm to 0° C. over an hour, then quenched with brine and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with 0-40% ethyl acetate in hexane. Appropriate fractions are combined and the solvents removed under vacuum to provide the desired compound (48, 21 g, 32.4 mmol, 73.8% yield).
Reaction SMILES: C(OC([N:8]1[CH2:12]C[CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH2:9]1)=O)(C)(C)C.NCCN1C[CH2:38][O:37][CH2:36][CH2:35]1>>[N:8]1([CH2:9][CH2:10][NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH2:35][CH2:36][O:37][CH2:38][CH2:12]1
Reactant: NCCN1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: O=C(NCCN1CCOCC1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 4-(2-aminoethyl)morpholine instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 372 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.50 (1H, br. s.) 10.03 (1H, s) 8.00 (2H, d, J=5.47 Hz) 7.77 (1H, d, J=5.37 Hz) 7.41 (1H, d, J=5.37 Hz) 7.29 (1H, dd, J=3.42, 2.44 Hz) 6.72 (1H, d, J=5.47 Hz) 6.44 (1H, dd, J=3.47, 1.90 Hz) 3.39-3.46 (4H, m) 3.33-3.39 (2H, m) 2.41 (2H, t, J=6.64 Hz) 2.33 (4H, br. s.)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][C:12]1[CH:34]=[CH:33][C:15]([C:16]([N:18]2[CH2:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[S:21][C:20]3[CH:29]=[CH:30][CH:31]=[CH:32][C:19]2=3)=[O:17])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:25]1[C:23]2[CH2:24][N:18]([C:16]([C:15]3[CH:14]=[CH:13][C:12]([NH:11][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=4[Cl:1])=[CH:34][CH:33]=3)=[O:17])[C:19]3[CH:32]=[CH:31][CH:30]=[CH:29][C:20]=3[S:21][C:22]=2[CH:28]=[CH:27][CH:26]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Sc3ccccc32)cc1
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Sc3ccccc32)cc1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.3 %

Procedure:
To a solution of 385 mg of 2-chloro-benzoyl chloride in 6 ml of methylene chloride at 0° C. is added 0.6 g of 10-(4-aminobenzoyl)-10,11-dihydrodibenz[b,f][1,4]thiazepine followed by 0.375 ml of triethylamine. The reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is washed with 20 ml of water, 1N HCl, 1N Na2CO3, water and dried over MgSO4. The filtrate is evaporated in vacuo to give 0.7 g of yellowish solid which is purified by silica gel chromatography on thick layer plates by elution with 1:1 ethyl acetate-hexane to give 0.3 g of the desired product, m.p. 116°-119° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:10])=[C:4]([C:17]#[N:18])[CH:3]=1.N.[H][H]>CO.[Ni]>[NH2:18][CH2:17][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[NH:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:10]
Reactant: [H][H]
Reactant: N#Cc1cc(Br)ccc1NC(=O)c1ccccn1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1cc(Br)ccc1NC(=O)c1ccccn1
Yield: 95.7 %

Procedure:
2-2 (3 g, 0.0099 moles) was immediately taken up in a solution of 2.0M ammonia in methanol. To this solution was added catalytic Raney nickel. The reaction was stirred with a hydrogen balloon attached until complete by TLC. Upon completion, the reaction was filtered and the solvent was removed yielding 2.9 grams of 2-3. Analytical LCMS: (CH3CN/H2O/1% TFA, 4 min gradient), 95% pure, M+1 peak m/e 306.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:26])=[C:4]([CH2:8][N:9]2[C:14]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[S:17][C:13]=3[C:12](=[O:24])[NH:11][C:10]2=[S:25])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>CN(C)C=O>[Cl:1][C:2]1[C:3]([CH3:26])=[C:4]([CH2:8][N:9]2[C:14]3[N:15]=[C:16]([N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[S:17][C:13]=3[C:12](=[O:24])[N:11]=[C:10]2[S:25][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1Cn1c(=S)[nH]c(=O)c2sc(N3CCOCC3)nc21
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(Cl)cccc1Cn1c(SCC(=O)OC(C)(C)C)nc(=O)c2sc(N3CCOCC3)nc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.8 %

Procedure:
To a solution of 4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)-5-thioxo-5,6-dihydro[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (Example 107) (150 mg, 0.367 mmol) in N,N-Dimethylformamide (DMF) (2 mL) in a 20 mL Scintillation vial stirred at rt was added sodium hydride (27.8 mg, 1.100 mmol). After stirring at rt for 10 minutes, 1,1-dimethylethyl bromoacetate (0.108 mL, 0.734 mmol) was added and the reaction mixture was capped. Upon addition a precipitate immediately formed and the reaction mixture became a thick almost solid suspension. A portion of the solid was checked by LC/MS and it indicated that the reaction had gone about 80%. The reaction mixture was quenched with saturated NH4Cl solution and diluted with 15 mL water. The yellow-orange solid was isolated by filtration, washed with water and dried in a vacuum oven at 65 C for two hours providing 182 mg of solid that was used without further purification in the next step LC/MS (ES) m/z=524 (M+H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])[S:8]1(=[O:25])=[O:24].[CH2:26]([NH2:28])[CH3:27]>CO>[F:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[N:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:28][CH2:26][CH3:27])[S:8]1(=[O:25])=[O:24]
Reactant: O=S1(=O)N(CCOCCBr)c2ccccc2N1c1c(F)cccc1F
Reactant: CCN
Solvent: CO
Product: CCNCCOCCN1c2ccccc2N(c2c(F)cccc2F)S1(=O)=O

Procedure:
In an analogous manner to general procedure V, 1-[2-(2-bromoethoxy)ethyl]-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.1 g, 0.23 mmol) was treated with 30-40% ethylamine in methanol to give 2-{2-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethoxy}-N-ethylethanamine which was treated with 1N hydrochloric acid in ether to give its hydrochloride salt as a white solid (0.67 g, 67%). HRMS: calcd for C18H21F2N3O3S+H+, 398.13444; found (ESI, [M+H]+Obs'd), 398.1341.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[NH2:33])[C:27]([OH:29])=[O:28]>CC(O)C.Cl>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:33][C:32]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=4[O:23][CH3:22])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cl
Solvent: CC(C)O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Yield: 69.6 %

Procedure:
A mixture of 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (98g, 0.31 mol), 3-methoxy-4-aminobenzoic acid (57 g, 0.341 mol) in i-PrOH (1.05 L) and conc. HCl (30 mL) was heated to reflux for a day. The mixture was cooled to room temperature and the solid was filtered, washed with isopropanol and dried to give 96.5 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][C@H:11](OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:10][CH:11]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:12][CH2:13][CH3:14]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCC[C@H](C)OS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCC(C)Oc1ccc(C=O)cc1

Procedure:
40 g of 4-hydroxybenzaldehyde, 80 of (S)-1-methylbutyl-p-toluene sulfonate and 46 g of potassium carbonate were refluxed in acetone for 12 hours, insoluble matters were removed from the reaction solution while the reaction solution was hot, and the solvent used was distilled out. The residue was purified by column chromatography to obtain 4-(1-methylbutyloxy)benzaldehyde (30).
Reaction SMILES: [OH:1][C@H:2]([C:14]1[CH:15]=[CH:16][C:17]([O:32]CC2C=CC=CC=2)=[C:18]([N:20](CC2C=CC=CC=2)[S:21]([CH3:24])(=[O:23])=[O:22])[CH:19]=1)[CH2:3][NH:4][C@@H](C1C=CC=CC=1)CO>[Pd].CCO.CC(O)=O.[OH-].[Pd+2].[OH-]>[NH2:4][CH2:3][C@@H:2]([C:14]1[CH:15]=[CH:16][C:17]([OH:32])=[C:18]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:19]=1)[OH:1]
Reactant: CS(=O)(=O)N(Cc1ccccc1)c1cc([C@@H](O)CN[C@H](CO)c2ccccc2)ccc1OCc1ccccc1
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reaction time: 19 h

Procedure:
To an evacuated flask containing palladium hydroxide (70.8 mg) and palladium on carbon [50% water by weight] (70.8 mg) was added a solution of N-{5-((1R)-1-hydroxy-2-{[(1S)-2-hydroxy-1-phenylethyl]amino}ethyl)-2-[(phenylmethyl)oxy]phenyl}-N-(phenylmethyl)methanesulfonamide (354 mg) in EtOH (15 ml) and AcOH (3 ml). The mixture was hydrogenated for 19 h. The catalysts were filtered off and the filtrate concentrated in vacuo. The mixture was purified by column chromatography (Oasis cartridge, 0 to 50% MeOH in water) to afford the title compound. LCMS RT=0.35 min
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].Cl.[CH2:10]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH:19]([C:24](OCC)=[O:25])[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[OH:2][C:1]1[CH:8]=[CH:7][C:6]2[C:20]3[CH2:21][CH2:22][N:17]([CH2:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH2:18][C:19]=3[C:24](=[O:25])[O:5][C:4]=2[CH:3]=1
Reactant: Oc1cccc(O)c1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCC1=O
Agent: Cl
Product: O=c1oc2cc(O)ccc2c2c1CN(Cc1ccccc1)CC2

Procedure:
Prepared by the method described for Example 1 from resorcinol (22 g, 0.2 moles) and 1-benzyl-3-carbethoxy-4-piperidone hydrochloride (59.6 g, 0.2 moles). The product (55 g) is converted to 1,2,3,4-tetrahydro-3-(phenylmethyl)-8-[(1-phenyl-1H-tetrazol-5-yl)oxy]-5H-[1]benzopyrano [3,4-c]pyridin-5-one without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([OH:10])=[O:9])[N:6]=1.[C:12]1([CH:18]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:19][C:20]([C:22]([O:25][NH2:26])([CH3:24])[CH3:23])=[O:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CO>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:26]/[O:25][C:22]([C:20]([O:19][CH:18]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:21])([CH3:24])[CH3:23])/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: Nc1nc(C(=O)C(=O)O)cs1
Reactant: CC(C)(ON)C(=O)OC(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(O/N=C(\C(=O)O)c1csc(N)n1)C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 5 h
Yield: 92.9 %

Procedure:
135 g of (2-amino-4-thiazolyl)glyoxylic acid are added whilst cooling with ice to a solution of 245 g of O-(1-diphenylmethoxycarbonyl-1-methylethyl)-hydroxylamine in 400 ml of dimethylformamide. The solution is stirred for 5 hours without cooling, and is then added to 4 l of methanol. In order to complete precipitation, stirring continues for 5 hours at 10°, and the product is then filtered off by suction and dried. 320 g (93%) of the title compound are obtained as colourless crystals.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[CH:5]([CH2:7][OH:8])[NH2:6].[F:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:12]=1[C:13](Cl)=[O:14]>N1C=CC=CC=1>[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH:6][C:13](=[O:14])[C:12]1[C:11]([F:10])=[CH:19][CH:18]=[CH:17][C:16]=1[F:20]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: COC(=O)C(N)CO
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)[C@H](CO)NC(=O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 39.8 %

Procedure:
To a mixture of 39.0 g (251 mmol.) of D,L-serine methyl ester hydrochloride and 800 ml of pyridine, there was added dropwise 37 ml (324 mmol.) of 2,6-difluorobenzoylchloride with stirring at room temperature for 5 hours. Then the reaction mixture was further stirred at the same temperature for 2 hours. After the reaction was completed, the resultant mixture was concentrated under reduced pressure. To the residue, there was added 500 ml of chloroform. The mixture was washed with water, extracted with chloroform, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 25.88 g of N-(2,6-difluorobenzoyl)serine methyl ester as a colorless oily substance (nD22.9 1.5038).
Reaction SMILES: [F:1][C:2]1[CH:11]2[CH:6]([CH2:7][CH2:8][C:9](=[O:12])[NH:10]2)[CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Br:20])C(=O)C1>>[Br:20][C:4]1[CH:3]=[C:2]([F:1])[CH:11]2[CH:6]([CH2:7][CH2:8][C:9](=[O:12])[NH:10]2)[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CCC2C=CC=C(F)C2N1
Product: O=C1CCC2C=C(Br)C=C(F)C2N1

Procedure:
This intermediate was obtained according to general procedure I from 8-fluoro-3,4,4a,8a-tetrahydro-1H-quinolin-2-one (515 mg, 3.12 mmol) and NBS (583 mg, 3.27 mmol) after flash chromatography on silica gel (hexanes/ethyl acetate, 5/1, Rf=0.32) as white solid (647 mg, 2.65 mmol, 85%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][C@@H:17]4[CH2:22][N:21]([C:23]5[N:28]=[CH:27][C:26]([C:29]6[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][OH:37])[CH2:31][CH:30]=6)=[CH:25][N:24]=5)[CH2:20][CH2:19][O:18]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1>CO.C(Cl)Cl.[Pt]=O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][C@@H:17]4[CH2:22][N:21]([C:23]5[N:24]=[CH:25][C:26]([CH:29]6[CH2:30][CH2:31][N:32]([CH2:35][CH2:36][OH:37])[CH2:33][CH2:34]6)=[CH:27][N:28]=5)[CH2:20][CH2:19][O:18]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(C6=CCN(CCO)CC6)cn5)CCO4)c3n2)cn1
Agent: O=[Pt]
Solvent: ClCCl
Solvent: CO
Product: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(C6CCN(CCO)CC6)cn5)CCO4)c3n2)cn1
Yield: 13.8 %

Procedure:
(S)-2-(4-(2-(2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)-5,6-dihydropyridin-1(2H)-yl)ethanol 54 mg (0.11 mmol) was dissolved in methanol 3 ml and methylene chloride 2 ml, and an excess of platinum oxide was added. The mixture was degassed, and a hydrogen balloon was connected, followed by reaction at room temperature for 1 day. After the reaction, the platinum oxide was removed using a celite filter, and separation by PLC (methylene chloride:methanol=5:1) gave a yellow solid 7.7 mg (14%).
Reaction SMILES: Cl[C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:5]=[CH:4][N:3]=1.[OH-:21].[Na+].O>CS(C)=O>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:7]2[C:2](=[O:21])[NH:3][CH:4]=[CH:5][N:6]=2)[CH2:9][CH2:10]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Reactant: [OH-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc[nH]c2=O)CC1
Reaction time: 3 h
Yield: 68 %

Procedure:
2-Chloro-3-(4-tert-butoxycarbonyl-1-piperazinyl)pyrazine* (60 g, 0.20 mol) was added to a mixture of NaOH (100 g, 2.50 mol), water (100 mL) and DMSO (100 g) at 100° C. After being stirred for 3 h, the mixture was allowed to cool and partitioned between toluene (100 g) and water (200 mL). Water (300 mL), crushed ice (200 g), EtOAc (600 g) and sodium chloride (100 g) were added to the aqueous layer. The layers were separated and the aqueous layer was extracted with an additional portion of EtOAc (600 g). The combined organic layers were concentrated in vacuo to furnish 38 g (68%) of the title product. 1H and 13C NMR data support the stated structure. HPLC purity: 100%. HRMS m/z calcd for C13H20N4O3 (M)+ 280.1535, found 280.1530. *Prepared according to the procedure described in WO 00/76984, Example 52, Step 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:27])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[Cl:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:4]1[C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15](=[O:17])[N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)=[O:27]
Reactant: O=C(O)CN1CCN(c2ncc(Cl)cc2NC(=O)c2cccc(Cl)c2)CC1
Reactant: C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Cl)cnc1N1CCN(CC(=O)N2CCCCC2)CC1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.6 %

Procedure:
A mixture of 0.011 g (0.027 mmol) of {4-[5-chloro-3-(3-chloro-benzoylamino)-pyridin-2-yl]-piperazin-1-yl}-acetic acid in N,N-dimethylformamide (1 mL), 0.011 g (0.13 mmol) of piperdine, 0.011 g (0.10 mmol) of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, and 0.011 mL (0.081 mmol) of triethylamine is stirred at room temperature for 4 hours. The mixture is concentrated under reduced pressure and the residue is diluted with water causing a solid to precipitate from solution. The material is collected by filtration, washed with water and dried on the filter pad to provide 0.0060 g (47%) of the title compound (282) as a colorless solid. [M+H]+=476.2.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>CN(C)C=O.C(OCC)(=O)C>[C:24]([Si:21]([CH3:23])([CH3:22])[O:20][CH2:19][CH2:18][O:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[CH:7]=[O:8])([CH3:27])([CH3:26])[CH3:25]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(Cl)cc1C=O
Temperature: 60 °C
Yield: 99.2 %

Procedure:
To a solution of 5-chlorosalicylaldehyde (5 g, 32 mmol) (Aldrich) in N,N-dimethylformamide (40 mL) was added potassium carbonate (20 g, 145 mmol), and (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (10 g, 42 mmol, Aldrich). The reaction mixture was heated at 60° C. for 18 h. The crude was cooled to room temperature, diluted with ethyl acetate, washed with water, brine. The organic layer was separated, concentrated, and the residue was purified by chromatography (EtOAc:Hexanes=1:8, then 1:4) to give 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-benzaldehyde as a white solid (Yield 10 g, 99%).