Azzindani/Open_Reaction_Data huggingface dataset:
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]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22]O>>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][O: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]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1F
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccccc2F)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (2-fluorophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.31 (2H, s), 5.81 (1H, d, J=1.6 Hz), 7.09-7.20 (2H, m), 7.36-7.41 (2H, m), 7.48-7.51 (1H, m), 7.58 (1H, d, J=2.0 Hz), 8.03 (1H, s), 8.70 (1H, d, J=5.2 Hz). [M+H] Calc'd for C16H11FN4O, 295; Found, 295.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:41][CH3:42])=[C:28]([O:31][CH2:32][CH2:33][CH2:34][N:35]5[CH2:40][CH2:39]CC[CH2:36]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:43][CH2:44][CH2:45][N:46]1CCNC[CH2:47]1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:41][CH3:42])=[C:28]([O:31][CH2:32][CH2:33][CH2:34][N:35]5[CH2:36][CH2:47][N:46]([CH2:45][CH2:44][OH:43])[CH2:39][CH2:40]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCN1CCCCC1
Reactant: OCCN1CCNCC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCN1CCN(CCO)CC1
Yield: 7.6 %

Procedure:
The title compound was prepared as described in Example 57B by using 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-chloropropoxy)-7-methoxyquinazolin-4-ylthio)phenyl)urea from Example 57B (200 mg, 0.37 mmol) and 1-(2-hydroxyethyl)piperazine (136 μL, 1.11 mmol) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-(4-(2-hydroxyethyl)piperazin-1-yl)propoxy)-7-methoxyquinazolin-4-ylthio)phenyl)urea (17.86 mg, 7%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 9.62 (bs, 1H), 9.05 (bs, 1H), 8.69 (s, 1H), 7.85 (s, 1H), 7.65-7.36 (m, 5H), 6.49 (s, 1H), 4.21 (bs, 2H), 3.99 (s, 3H), 3.70-3.19 (m, 6H), 2.50-2.29 (m, 8H), 1.98 (bs, 2H), 1.27 (s, 9H); LC-MS (ESI) m/z 636 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:9][CH3:10])[C:4]1[CH:8]=[CH:7][S:6][CH:5]=1.C([Li])CCC.CN(C)[CH:18]=[O:19]>CCOCC>[CH3:1][O:2][CH:3]([O:9][CH3:10])[C:4]1[CH:8]=[CH:7][S:6][C:5]=1[CH:18]=[O:19]
Reactant: CN(C)C=O
Reactant: COC(OC)c1ccsc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: COC(OC)c1ccsc1C=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2a (423 g., 2.68 moles) in anhydrous ether (1 L) was added dropwise in 1 hour a freshly prepared solution of n-butyllithium (27 moles) in ether keeping a gentle reflux under dry N2. Reflux being continued for 0.5 hour, a solution of DMF (dimethylformamide) (432 g., 6 moles) in anhydrous ether (0.8 L) was added dropwise to the mixture over a period of 0.75 hour with vigorous stirring. After the complete addition the mixture was stirred overnight, poured onto crushed ice (1 Kg.) with stirring and allowed to rise to room temperature. The organic layer was separated and the water layer was saturated with NaCl and extracted thoroughly with ether (2×200 ml.). The ether extracts were combined, dried over MgSO4 and concentrated. The residue was distilled under reduced pressure and the pale yellow oil was collected at 100°-125° C., 0.7 mmHg. Yield, 277 g. (56%).
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][NH2:11]>>[CH3:10][NH:11][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CN
Reactant: N#Cc1cccnc1Cl
Product: CNc1ncccc1C#N
Temperature: 25 °C

Procedure:
A solution of 2-chloronicotinonitrile (97.82 g, 706 mmol) in 40% aqueous methylamine (706 ml) was heated to reflux for 1.5 hour. The excess methylamine was evaporated off and the resulting solids filtered and washed with water (250 mL). The crude product was dissolved in boiling water (1.4 l) and treated with charcoal and filtered through Celite. The aqueous filtrate was cooled to room temperature. After 10 hours the crystalline solid was collected, washed with water and dried to leave 71.10 g of 2-(methylamino)-nicotinonitrile (mp. 86-88 degrees C.). A sample was further purified by sublimation (100 degrees C. at 0.025 mm) mp. (87-88 degrees C.).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[C:27](O)(=[O:31])[CH:28]([CH3:30])[CH3:29]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: CC(C)C(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CC(C)C(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (78 mg, 79%), MS (ISP) m/z=399.4 [(M+H)+], mp 212° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and isobutyric acid.
Reaction SMILES: [N:1](=[C:3]([C:9]([CH3:11])=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])O.[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][NH2:16]>C(#N)C>[CH2:7]([O:6][C:4]([C:3]1[N:1]=[C:15]([C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[Cl:12])[NH:16][C:9]=1[CH3:11])=[O:5])[CH3:8]
Reactant: NCc1ccccc1Cl
Reactant: CCOC(=O)C(=NO)C(C)=O
Solvent: CC#N
Product: CCOC(=O)c1nc(-c2ccccc2Cl)[nH]c1C
Temperature: 25 °C

Procedure:
To a solution of 8.5 g of ethyl 2-oximinoacetoacetate in acetonitrile (100 ml) was added 7.5 ml of 2-chlorobenzylamine. The reaction mixture was then refluxed for 4 hours under argon atmosphere. After such time the reaction mixture was then concentrated in vacuo and the residue was triturated with warm ethylacetate for 10 minutes. After allowing to cool down to room temperature the solid was filtered and dried in vacuo to yield 11.3 g of a white powder, MS (ISP) 265.1 (M+H)+.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[OH:9])C=C.C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18].O>CC1OCCC1>[C:17]([O:9][CH:5]1[CH2:6][CH:7]1[CH2:8][CH:4]=[CH2:1])(=[O:19])[CH3:18]
Reactant: C=CCC1CCCC1O
Reactant: CC(=O)Cl
Solvent: O
Solvent: CC1CCCO1
Solvent: CCN(CC)CC
Product: C=CCC1CC1OC(C)=O
Temperature: 0 °C

Procedure:
Into a reaction vessel was added 2-allylcyclopentanol M (1 equivalent) in MeTHF (10 volumes). The vessel was purged with nitrogen and the solution was then cooled to 0° C. Triethylamine (3.0 equivalents) was then slowly added to the solution over about 30 minutes. The mixture was allowed to stir for about 30 minutes after which acetyl chloride (2.5 equivalents) was added maintaining the internal temperature about below 20° C. The reaction was then allowed to stir for at least 12 hours at about 21° C. After the allotted time, water (6 volumes) was slowly charged to the reactor and the phases were separated. The organic layer was then washed with 2M hydrochloric acid (6 volumes), 10 wt. % sodium bicarbonate (6 volumes) and then brine (6 volumes). The organic layer is concentrated under reduced pressure at about 0° C. to obtain crude racemic 2-allylcyclopropyl acetate N. 1H NMR (400 MHz, CDCl3): δ 5.85-5.73 (m, 1H), 5.10-5.04 (m, 1H), 5.00-4.97 (m, 1H), 3.85-3.82 (m, 1H), 2.13-2.07 (m, 1H), 1.99 (s, 3H), 2.01-1.89 (m, 1H), 1.14-1.03 (m, 1H), 0.87-0.76 (m, 1H), 0.64-0.57 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:3]2[S:23](=[O:24])[CH2:22][CH2:21][C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=1.FC(F)(F)C(O)=O.[NH2:32][C@H:33]([CH2:36][C:37]1[CH:41]=[CH:40][O:39][CH:38]=1)[CH2:34][OH:35]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]3[N:7]=[C:2]([NH:32][C@H:33]([CH2:36][C:37]4[CH:41]=[CH:40][O:39][CH:38]=4)[CH2:34][OH:35])[C:3]4[S:23](=[O:24])[CH2:22][CH2:21][C:4]=4[N:5]=3)[CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: N[C@@H](CO)Cc1ccoc1
Reactant: O=S1CCc2nc(N3CCN(c4ccc(Cl)cc4)CC3)nc(Cl)c21
Solvent: O=C(O)C(F)(F)F
Product: O=S1CCc2nc(N3CCN(c4ccc(Cl)cc4)CC3)nc(N[C@@H](CO)Cc3ccoc3)c21

Procedure:
Starting from 4-chloro-2-[4-(4-chloro-phenyl)-piperazin-1-yl]-6,7-dihydro-thieno[3,2-d]pyrimidine 5-oxide (cf Example 124, 3.1.3) and (R)-2-amino-3-furan-3-yl-propan-1-ol trifluoroacetate, the two diastereomers of (R)-2-{2-[4-(4-chloro-phenyl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-4-ylamino}-3-furan-3-yl-propan-1-ol are prepared as described in Example 124 (cf 3.1.4). The diastereomers are separated by preparative HPLC (method B). Analytical HPLC-MS (method D): Diastereomer 1: RT=1.23 min (Example 206); Diastereomer 2: RT=1.24 min (Example 207).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][CH:3]=1.Br[CH2:8][CH2:9][CH2:10]Br.O1CCOCC1>C(N(CC)CC)C>[N:5]1[N:6]2[CH2:8][CH2:9][CH2:10][NH:1][C:2]2=[CH:3][CH:4]=1
Reactant: Nc1ccn[nH]1
Reactant: BrCCCBr
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: c1cc2n(n1)CCCN2
Temperature: 25 °C

Procedure:
5-Aminopyrazole (10 g) and 1,3-dibromopropane (13.4 ml) were added to 1,4-dioxane (20 ml) under stirring at ambient temperature. Triethylamine (40.1 ml) was added thereto. The mixture was refluxed under stirring for 4 hours. The reaction mixture was cooled to 0°-5° C. in an ice-bath and stirred for 30 minutes. An insoluble material was filtered off, and the filtrate was evaporated under reduced pressure to give 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (5.1 g).
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:6]([CH3:7])[O:5][C:4]([C:8]2[NH:12][C:11]([C:13]3[CH:14]=[C:15]([OH:25])[CH:16]=[C:17]([O:19][C@@H:20]([CH3:24])[CH2:21][O:22][CH3:23])[CH:18]=3)=[CH:10][CH:9]=2)=[N:3]1.Cl[C:27]1[CH:32]=[N:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][N:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C(#N)C>[CH3:1][C@@H:2]1[C@H:6]([CH3:7])[O:5][C:4]([C:8]2[NH:12][C:11]([C:13]3[CH:14]=[C:15]([CH:16]=[C:17]([O:19][C@@H:20]([CH3:24])[CH2:21][O:22][CH3:23])[CH:18]=3)[O:25][C:27]3[CH:32]=[N:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][N:28]=3)=[CH:10][CH:9]=2)=[N:3]1
Reactant: CS(=O)(=O)c1cnc(Cl)cn1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=N[C@H](C)[C@H](C)O3)[nH]2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: COC[C@H](C)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C3=N[C@H](C)[C@H](C)O3)[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
3-{5-[(4R,5S)-4,5-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[(2S)-1-methoxypropan-2-yl]oxy}phenol (420 mg, 1.22 mmol) synthesized in Example (109c) was dissolved in acetonitrile (20 mL), and 2-chloro-5-(methylsulfonyl)pyrazine (345 mg, 1.46 mmol) synthesized in Example (97c) and cesium carbonate (1.02 g, 3.13 mmol) were added at room temperature, followed by stirring at room temperature overnight under nitrogen atmosphere. To this reaction solution, water (30 mL) was added, and extraction was carried out with methylene chloride (40 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=2%-3%) to afford the desired compound (513 mg, yield 84%) as a white solid.
Reaction SMILES: [Li]CCCC.[Si:6]([O:13][CH2:14][CH2:15][CH:16]([C:24]1[S:28][C:27](Cl)=[N:26][C:25]=1[Cl:30])[O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]>C1COCC1>[Si:6]([O:13][CH2:14][CH2:15][CH:16]([C:24]1[S:28][CH:27]=[N:26][C:25]=1[Cl:30])[O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)([C:9]([CH3:12])([CH3:10])[CH3:11])([CH3:7])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)OCCC(OC1CCCCO1)c1sc(Cl)nc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCC(OC1CCCCO1)c1scnc1Cl
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
At −78° C., a soln. of n-BuLi in hexanes (2.2 M, 9.6 mL, 21.0 mmol) was added to a soln. of 5-(3-((tert-butyldimethylsilyl)oxy)-1-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-2,4-dichlorothiazole (6.89 g, 16.2 mmol) in THF (125 mL). The mixture was stirred at −78° C. for 45 min, then, quenched by the addition of aq. sat. NaHCO3 and extracted with EtOAc. The comb. org. layers were washed with brine, dried over MgSO4, and conc. in vacuo. Purification by means of CC (2-20% EtOAc/Hept) provided the product as a yellow oil as an isomeric mixture.
Reaction SMILES: Cl[C:2]1[N:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:3]=1[C:4]([NH:6][C:7](=[NH:19])[CH2:8][O:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=[O:5].CC([O-])(C)C.[K+]>>[Cl:24][C:21]1[CH:22]=[N:23][C:2]2[N:19]=[C:7]([CH2:8][O:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[NH:6][C:4](=[O:5])[C:3]=2[CH:20]=1
Reactant: N=C(COCCc1ccc(F)cc1)NC(=O)c1cc(Cl)cnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: O=c1[nH]c(COCCc2ccc(F)cc2)nc2ncc(Cl)cc12

Procedure:
In analogy to the procedure described in example 78.4, 2,5-dichloro-N-{2-[2-(4-fluoro-phenyl)-ethoxy]-1-imino-ethyl}-nicotinamide was treated with KOtBu to obtain 6-chloro-2-[2-(4-fluoro-phenyl)-ethoxymethyl]-3H-pyrido[2,3-d]pyrimidin-4-one as yellow crystals. MS: m/e=334.4 [M+H+].
Reaction SMILES: [B-].[B-].C1CCOCC1.C1CCOCC1.[Ca+2].[C:16]([O:20][C:21](=[O:41])[NH:22][C@@H:23]1[C:28](=[O:29])[C@H:27]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[C:33]([F:40])[CH:32]=2)[CH2:26][S:25][CH2:24]1)([CH3:19])([CH3:18])[CH3:17].OS([O-])(=O)=O.[K+]>C1COCC1>[C:16]([O:20][C:21](=[O:41])[NH:22][C@@H:23]1[C@H:28]([OH:29])[C@H:27]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[C:33]([F:40])[CH:32]=2)[CH2:26][S:25][CH2:24]1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N[C@H]1CSC[C@@H](Cc2ccc([N+](=O)[O-])c(F)c2)C1=O
Agent: O=S(=O)([O-])O
Agent: [B-]
Agent: [Ca+2]
Solvent: C1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CSC[C@@H](Cc2ccc([N+](=O)[O-])c(F)c2)[C@H]1O
Temperature: -40 °C
Reaction time: 1 h

Procedure:
To a solution of calcium borohydride bis-THF complex (1.14 g, 4.6 mmol) in anhydrous THF (100 mL) was added under argon a solution of [(3R*,5S*)-5-(3-fluoro-4-nitro-benzyl)-4-oxo-tetrahydro-thiopyran-3-yl]-carbamic acid tert-butyl ester (1.77 g, 4.6 mmol) in THF (50 mL) at −70° C. The reaction mixture was slowly warmed to −40° C. and stirred for 1 h at −40° C. The reaction mixture was poured onto a cold aq. KHSO4 solution and the product was extracted with EtOAc. Combined extracts were washed with NaHCO3 solution and brine, dried over MgSO4 and evaporated. The mixture of diastereoisomers was separated by flash-chromatography on silica gel (toluene-EtOAc 6:1 to 3:1) to yield the undesired [(3R*,4S*,5S*)-diastereoisomer and the desired [(3R*,4R*,5S*)-diastereoisomer after crystallization from EtOH as a white crystalline solid: TLC (toluene-EtOAc 3:1) Rf=0.20; HPLC RtA=1.94 min; ESIMS [M+H-isobutylene]+=331; 1H NMR (600 MHz, DMSO-d6): δ 8.09 (t, 1H), 7.41 (d, 1H), 7.27 (d, 1H), 6.67 (d, 1H), 4.94 (d, 1H), 3.42 (m, 1H), 3.27 (dd, 1H), 2.91 (m, 1H), 2.55 (m, 2H), 2.39 (dd, 1H), 2.24 (m, 2H), 1.93 (m, 1H), 1.37 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([CH3:20])([CH3:19])[NH:5][C:6](=[O:18])[C:7]([CH3:17])([CH3:16])[NH:8]C(OC(C)(C)C)=O.[C:22]([OH:28])([C:24]([F:27])([F:26])[F:25])=[O:23]>C(Cl)Cl>[F:25][C:24]([F:27])([F:26])[C:22]([OH:28])=[O:23].[CH3:1][O:2][C:3](=[O:21])[C:4]([CH3:20])([CH3:19])[NH:5][C:6](=[O:18])[C:7]([CH3:17])([CH3:16])[NH2:8]
Reactant: COC(=O)C(C)(C)NC(=O)C(C)(C)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(C)(C)NC(=O)C(C)(C)N
Reaction time: 8 h
Yield: 90 %

Procedure:
N-tert-butoxycarbonyl α,α-dimethylglycyl α,α-dimethylglycine methyl ester 3 (10.79 g, 35.69 mmol) was dissolved in 50% (v/v) TFA in CH2Cl2 (100 mL). The reaction mixture was stirred for 2 h 30 min at room temperature before the solvent and bulk of excess TFA were evaporated at 50° C. over 1 h 30 min. The residue was left standing overnight, dissolved in CH2Cl2 (100 mL) and the bulk of solvent evaporated. More CH2Cl2 (2×100 mL) was added and evaporated. The residue was washed with Et2O (3×60 mL) and the Et2O decanted off. The residue was dissolved in CH2Cl2 (30 mL). Upon standing a solid precipitated and was collected by filtration. The residue was washed with Et2O (3×60 mL) under suction and dried under vacuum affording the title compound as a white solid (10.17 g, 90%), with spectral characteristics in accordance with literature data5,6; 1H NMR (300 MHz, DMSO-d6) δ 8.45 (s, 1H, NH), 8.20 (br s, 3H, NH3+), 3.57 (s, 3H, OCH3), 1.47 (s, 6H, CH3), 1.39 (s, 6H, CH3); 13C NMR (75 MHz, DMSO-d6) δ 174.1, 171.4, 158.3 (q, JCF=33 Hz), 116.7 (q, JCF=295 Hz), 56.4, 55.9, 52.1, 24.8, 23.3; HRMS (m/z): M+ calcd. for C9H19N2O3, 203.1395. found, 203.1396; Anal. Calcd. for C11H19F3N2O5: C, 41.77; H, 6.06; N, 8.86. Found: C, 41.8; H, 6.1; N, 8.7.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:22]=[CH:21][C:14]3[N:15]([CH3:20])[C:16](=[S:19])[CH2:17][S:18][C:13]=3[CH:12]=2)[CH2:6]1)=O.[NH3:23]>CO>[CH3:20][N:15]1[C:14]2[CH:21]=[CH:22][C:11]([N:7]3[CH2:6][CH:5]([C:3]([NH2:23])=[O:2])[O:9][C:8]3=[O:10])=[CH:12][C:13]=2[S:18][CH2:17][C:16]1=[S:19]
Reactant: COC(=O)[C@H]1CN(c2ccc3c(c2)SCC(=S)N3C)C(=O)O1
Reactant: N
Solvent: CO
Product: CN1C(=S)CSc2cc(N3CC(C(N)=O)OC3=O)ccc21
Temperature: 40 °C
Yield: 26 %

Procedure:
To a stirred suspension of (5R)-3-(3,4-dihydro-4-methyl-3-thioxo-2H-1,4-benzothiazin-7-yl)-2-oxo-5-oxazolidinecarboxylic acid methyl ester (Step 1, 100 mg, 0.2955 mmol) in MeOH (3 mL) is added 2.0 M ammonia in MeOH (1.0 mL). This mixture is heated at 40° C. for 24 h at which time the reaction is concentrated under reduced pressure. The residue is washed with MeOH (4 mL) and purified by column chromatography (2% MeOH/CH2Cl2) to give the title compound as a white solid (25 mg, 26%), 1H NMR (300 MHz, DMSO) δ 7.87 (br s, 1H), 7.64 (d, 2H), 7.51 (s, 2H), 5.03 (dd, 1H), 4.28 (t, 1H), 4.02 (dd, 1H), 3.85 (s, 2H), 3.32 (s, 3H); MS for C13H13N3O3S2 m/z 324.5 (M+H)+.
Reaction SMILES: C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(OC(=O)[C:22]1[CH:27]=[C:26]([C:28]2[CH:33]=[C:32]([S:34][CH2:35][CH2:36][CH2:37][C:38](=[O:50])[NH:39][CH2:40][CH2:41][NH:42][C:43](OC(C)(C)C)=[O:44])[N:31]=[C:30]([NH2:51])[N:29]=2)[C:25]([CH3:52])=[CH:24][C:23]=1[CH3:53])(C)(C)C.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[NH2:51][C:30]1[N:31]=[C:32]2[CH:33]=[C:28]([C:26]3[CH:27]=[C:22]([C:43](=[O:44])[NH:42][CH2:41][CH2:40][NH:39][C:38](=[O:50])[CH2:37][CH2:36][CH2:35][S:34]2)[C:23]([CH3:53])=[CH:24][C:25]=3[CH3:52])[N:29]=1
Reactant: Cc1cc(C)c(-c2cc(SCCCC(=O)NCCNC(=O)OC(C)(C)C)nc(N)n2)cc1C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c2cc1C(=O)NCCNC(=O)CCCSc1cc-2nc(N)n1
Reaction time: 8 h
Yield: 20 %

Procedure:
Anisole (0.060 ml, 0.55 mmol) and trifluoroacetic acid (1.2 ml) were added to a dichloromethane (3.7 ml) solution of 5-{2-amino-6-[3-(2-tert-butoxycarbonylaminoethylcarbamoyl)propylsulfanyl]pyrimidin-4-yl}-2,4-dimethylbenzoic acid tert-butyl ester (124 mg, 0.22 mmol) obtained in Step 2 above. The mixture was stirred for 8 hours while gradually warming from 0° C. to room temperature. The reaction solution was concentrated under reduced pressure, and then benzene (1.5 ml) was added to the residue. The resulting solution was concentrated under reduced pressure. This treatment was repeated three times, and then the obtained pale yellow oily material was dissolved in N,N-dimethylformamide (111 ml). N-Hydroxybenzotriazole (150 mg, 1.11 mmol), diisopropylethylamine (0.39 ml, 2.2 mmol), and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (426 mg, 2.2 mmol) were sequentially added to the solution. The resulting mixture was reacted at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate (100 ml), and then sequentially washed twice with water (50 ml), and with a saturated aqueous sodium bicarbonate solution (50 ml), water (50 ml), and a saturated aqueous sodium chloride solution (50 ml). The washed ethyl acetate solution was dried over anhydrous sodium sulfate (10 g). After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography with diol-silica gel (developing solvent: ethyl acetate to ethyl acetate:methanol=15:1) and amino-silica gel (developing solvent: ethyl acetate to ethyl acetate:methanol=15:1) to yield 4-amino-18,20-dimethyl-7-thia-3,5,12,15-tetraazatricyclo[15.3.1.12,6]docosa-1(20),2(22),3,5,17(21),18-hexaene-11,16-dione (Compound 4) (17 mg) as a white solid material.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:13][CH2:14][N:15]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH2:16][CH2:17]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(N2CCN(C3CCN(C(=O)OC(C)(C)C)CC3)CC2)ccc1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(N2CCN(C3CCNCC3)CC2)ccc1[N+](=O)[O-]
Yield: 92.6 %

Procedure:
A solution of 1,1-dimethylethyl 4-{4-[3-(methyloxy)-4-nitrophenyl]-1-piperazinyl}-1-piperidinecarboxylate (5.67 g, 13.5 mmol) and DCM (110 mL) was cooled with an ice/H2O bath. TFA (30.0 mL, 389 mmol) was added dropwise via addition funnel. Upon completion, by TLC, the reaction mixture was quenched with 1N NaOH (300 mL), extracted with DCM, dried (MgSO4) and concentrated to provide the title compound of step D (4.01 g, 12.5 mmol, 93%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20-1.31 (m, 2H), 1.68 (d, J=9.9 Hz, 2H), 2.22-2.32 (m, 2H), 2.34-2.45 (m, 2H), 2.54-2.61 (m, 4H), 2.95 (d, J=12.1 Hz, 2H), 3.36-3.43 (m, 4H), 3.88 (s, 3H), 6.50 (d, J=2.6 Hz, 1H), 6.57 (dd, J=9.4, 2.4 Hz, 1H), 7.86 (d, J=9.5 Hz, 1H).