Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22](Cl)=[N:21][CH:20]=[N:19][C:18]=2[CH:17]=[CH:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:45]=[CH:44][C:29]([O:30][C:31]2[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:33][CH:32]=2)=[C:28]([Cl:46])[CH:27]=1>C(O)(C)C>[C:1]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22]([NH:25][C:26]3[CH:45]=[CH:44][C:29]([O:30][C:31]4[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:33][CH:32]=4)=[C:28]([Cl:46])[CH:27]=3)=[N:21][CH:20]=[N:19][C:18]=2[CH:17]=[CH:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccc(N)cc2Cl)cc1
Reactant: O=C(OCCOCCn1ccc2ncnc(Cl)c21)c1ccccc1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)c1ccc(Oc2ccc(Nc3ncnc4ccn(CCOCCOC(=O)c5ccccc5)c34)cc2Cl)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
A mixture of 2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate (1.46 g), tert-butyl 4-(4-amino-2-chlorophenoxy)benzoate (1.35 g) and isopropyl alcohol (30 mL) was stirred at 80° C. overnight. The reaction mixture was concentrated under reduced pressure, water and saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography (eluent, ethyl acetate). The object fraction was concentrated under reduced pressure and the residue was crystallized from ethyl acetate-diethyl ether to give the title compound (1.54 g) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.[CH2:18]([N:25]1[CH2:29][CH2:28][C@H:27](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC(C)([O-])C.[K+].O>C1COCC1>[CH2:18]([N:25]1[CH2:29][CH2:28][C@@H:27]([C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]#[N:11])[CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CCN(Cc3ccccc3)C2)cc1
Reactant: COc1cccc(C(C#N)c2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(C(C#N)(c2ccccc2)[C@@H]2CCN(Cc3ccccc3)C2)c1
Temperature: 80 °C
Yield: 77.3 %

Procedure:
To a stirred solution of (3-methoxyphenyl)phenylacetonitrile (5.2 g, 23 mmol; prepared as described in Preparation 6) in THF (100 mL) was added toluene-4-sulfonic acid (S)-1-benzylpyrrolidin-3-yl ester (7.2 g, 22 mmol), followed by the addition of potassium t-butoxide (4.0 g, 36 mmol). The mixture was heated to 80° C. for 1 hour, then allowed to cool and H2O (10 mL) was added. The mixture was filtered through a pad of Celite®. The mixture was washed with a saturated aqueous NaCl solution (100 mL) and the organic phase was separated, dried over MgSO4, and filtered. The solvent was removed under reduced pressure. The crude material was purified via silica gel chromatography to afford the title compound (6.2 g, 17 mmol). MS m/z: {M+H+] calcd for C26H26N2O, 382.5; found 383.4.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.C(N(CC)CC)C.[CH3:35][C:36]([CH3:38])=O>ClC(Cl)C>[CH:36]([NH:23][CH2:22][C:16]1([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:11][CH:12]=2)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1)([CH3:38])[CH3:35]
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: CC(C)=O
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CC(C)NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
To a solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (400 mg, 1.256 mmol) in dichloroethane (10 mL) under nitrogen atmosphere was added acetic acid (180.5 mg, 2.76 mmol), triethylamine (306.4 mg, 2.76 mmol) and acetone (80.2 mg, 1.38 mmol). The mixture was stirred for 1 h at ambient temperature and NaHB(OAc)3 (601 mg, 2.76 mmol) was added. After stirring overnight, the reaction mixture was filtered over celite, concentrated in vacuo and purified by column chromatography on silica gel eluting with DCM:MeOH:NH3 (89:10:1) to give the title compound as an oil (282 mg, 60%). 1H NMR (400 MHz, CDCl3) δ 7.13 (d, 2H), 6.82 (d, 2H), 3.96 (t, 2H), 3.68 (m, 2H), 3.49 (m, 2H), 2.61 (s, 2H), 2.56 (t, 2H), 2.46 (m, 5H), 2.04 (m, 2H), 1.94 (m, 2H), 1.84 (m, 2H), 1.72 (m, 4H), 1.19 (s, 1H), 0.83 (d, 6H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](I)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][N:16]=1.[NH2:24][C:25]1[S:26][CH:27]=[C:28]([CH3:30])[N:29]=1>>[Cl:14][C:15]1[N:16]=[CH:17][C:18]([C:5]2[CH:4]=[N:3][C:2]([NH:24][C:25]3[S:26][CH:27]=[C:28]([CH3:30])[N:29]=3)=[C:11]3[C:6]=2[CH:7]=[CH:8][C:9]([CH3:12])=[N:10]3)=[CH:19][CH:20]=1
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: Cc1ccc2c(I)cnc(Cl)c2n1
Reactant: Cc1csc(N)n1
Product: Cc1csc(Nc2ncc(-c3ccc(Cl)nc3)c3ccc(C)nc23)n1

Procedure:
The title compound, MS: m/e=368.1 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 8-chloro-5-iodo-2-methyl-[1,7]naphthyridine (Example I), 2-chloro-5-pyridineboronic acid and 2-amino-4-methylthiazole.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][CH2:6][C:7](O)=[O:8])[CH3:2].C(OCCCl)=O.[NH2:17][NH:18][C:19]([NH2:21])=[S:20].Cl>O1CCCC1.O.C(N(CC)CC)C>[NH2:21][C:19]([NH:18][NH:17][C:7](=[O:8])[CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:10])=[S:20]
Reactant: NNC(N)=S
Reactant: CCOC(=O)CCC(=O)O
Agent: Cl
Agent: O=COCCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CCC(=O)NNC(N)=S
Reaction time: 0.5 h

Procedure:
To a solution of succinic acid monoethyl ester (22.0 g) and triethylamine (16.8 g) in tetrahydrofuran (150 ml) was added dropwise chloroethyl formate (18.0 g) at −20° C. After stirring for 30 min., pulverized thiosemicarbazide (13.7 g) was added and the mixture was stirred at room temperature for 7 hrs. Water was added to the reaction mixture, acidified with 2N hydrochloric acid and extracted with chloroform. The aqueous layer was separated and sodium chloride was added. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residual crystals were recrystallized from dichloromethane-ethanol to give ethyl 4-[2-(aminocarbothioyl)hydrazino]-4-oxobutanoate as colorless prism crystals (8.23 g, 25%). melting point: 143–144° C.
Reaction SMILES: [SH:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][CH2:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[S:1][CH2:9][CH2:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21]
Reactant: Sc1ncccn1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCSc1ncccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.4 %

Procedure:
A mixture of 2-mercaptopyrimidine (7.3 g), N-(2-bromoethyl)phthalimide (16.5 g), potassium carbonate (10.8 g) and N,N-dimethylformamide (DMF) (85 ml) was stirred at room temperature for 3 hours. The reaction mixture was poured into water and the crystals separated were collected by filtration to obtain N-[2-(2-pyrimidinylthio)ethyl]-phthalimide (17.3 g, 93%). The resultant was recrystallized from ethanol-isopropyl ether to obtain pale yellow prisms, m.p. 149°-150° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[CH:6][CH:7]=1.C1([Mg]Cl)CCCCC1.[NH2:17][C:18]1[N:22]([C:23]2[CH:24]=[C:25]([CH:32]=[CH:33][C:34]=2[CH3:35])[C:26]([NH:28][CH:29]2[CH2:31][CH2:30]2)=[O:27])[CH:21]=[N:20][C:19]=1[C:36]#N.Cl.C([O-])([O-])=[O:40].[K+].[K+]>C1COCC1>[NH2:17][C:18]1[N:22]([C:23]2[CH:24]=[C:25]([CH:32]=[CH:33][C:34]=2[CH3:35])[C:26]([NH:28][CH:29]2[CH2:31][CH2:30]2)=[O:27])[CH:21]=[N:20][C:19]=1[C:36](=[O:40])[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: Brc1cccc(I)c1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc(C#N)c1N
Agent: Cl
Agent: Cl[Mg]C1CCCCC1
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc(C(=O)c2cccc(Br)c2)c1N
Reaction time: 0.33 h
Yield: 54 %

Procedure:
To a solution of 3-bromo-1-iodobenzene (2.82 g) in THF (20 mL) at −40° C. under N2 was added cyclohexylmagnesium chloride (2M in THF, 6 mL). The solution was kept at −40° C. to 0° C. for 20 min. then 3-(5-amino-4-cyano-imidazol-1-yl)-N-cyclopropyl-4-methyl-benzamide (0.18 g) was added and the reaction was kept at rt for 1 h. Then HCl (4 M, 20 mL) was added and the mixture was kept at rt for two days. The mixture was neutralized with K2CO3 solution and extracted with EtOAc (2×100 mL) and the combined organics dried over Na2SO4, and concentrated. Purification of the crude product by column chromatography (EtOAc) gave the desired product (0.15 g, 54%). HPLC (4 minute 10-90 gradient) tR 1.85 min; MS m/z 438.10, 441.07 [M+H]+.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:34])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH:14][C:15]([C:17]2[C:18]([S:23][CH2:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[N:19][CH:20]=[CH:21][CH:22]=2)=[O:16])[CH:8]=1.CO.C1COCC1>O>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][CH2:25][CH2:24][S:23][C:18]2[C:17]([C:15]([NH:14][CH2:13][C:9]3[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=3)[C:6]([OH:34])=[O:5])=[O:16])=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:28][CH:29]=1
Reactant: COC(=O)c1cccc(CNC(=O)c2cccnc2SCCCc2ccc(F)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(CNC(=O)c2cccnc2SCCCc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.8 %

Procedure:
A solution of 120 mg (2.92 mmol) of lithium hydroxide monohydrate in water (4 ml) was added to a solution of 320 mg (0.73 mmol) of 3-[[[2-[3-(4-fluorophenyl)-propylsulfanyl]-pyridine-3-carbonyl]amino]-methyl]-benzoic acid methyl ester (exemplary compound 129) in a MeOH/THF mixture (2:1 vv, 9 ml), and the mixture was stirred for 16 h at RT. Concentration in vacuo was then carried out. The residue was taken up in water and washed with EA. The aqueous phase was then adjusted to pH ˜2 with 2M hydrochloric acid at 0° C. The resulting precipitate was filtered off, taken up in toluene and concentrated in vacuo. The residue was washed with an ether/pentane mixture (1:4 vv), yielding 170 mg (0.4 mmol, 55%) of 3-[[[2-[3-(4-fluorophenyl)-propylsulfanyl]-pyridine-3-carbonyl]amino]-methyl]-benzoic acid. MS: m/z 425.1 [m+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:5]=1[O:6][C:7](=[CH:10]OC)[C:8]#[N:9])([CH3:3])[CH3:2].[S:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:28]([NH2:30])=[NH:29])[CH2:23][CH2:22]1>>[CH:1]([C:4]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:5]=1[O:6][C:7]1[C:8]([NH2:9])=[N:29][C:28]([NH:27][CH:24]2[CH2:25][CH2:26][S:21][CH2:22][CH2:23]2)=[N:30][CH:10]=1)([CH3:2])[CH3:3]
Reactant: COC=C(C#N)Oc1cc(OC)c(OC)cc1C(C)C
Reactant: N=C(N)NC1CCSCC1
Product: COc1cc(Oc2cnc(NC3CCSCC3)nc2N)c(C(C)C)cc1OC

Procedure:
5-(2-Isopropyl-4,5-dimethoxy-phenoxy)-N2-(tetrahydro-thiopyran-4-yl)-pyrimidine-2,4-diamine was prepared according to the procedure of example 5, using 2-(2-isopropyl-4,5-dimethoxy-phenoxy)-3-methoxy-acrylonitrile (prepared using the procedure of Example 4) together with N-(tetrahydro-thiopyran-4-yl)-guanidine from Preparation 1.
Reaction SMILES: C(OC([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:22])[C:17]=2Br)[CH:12]1[C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[OH:30])=O)C1C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>CN(C=O)C>[CH2:42]([O:41][C:39](=[O:40])[CH2:38][O:30][C:24]1[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:23]=1[CH:12]1[C:13]2[C:18](=[CH:17][C:16]([F:22])=[CH:15][CH:14]=2)[CH2:19][CH2:20][NH:11]1)[CH3:43]
Reactant: CCOC(=O)CBr
Reactant: O=C(OCc1ccccc1)N1CCc2c(ccc(F)c2Br)C1c1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(F)cc1C1NCCc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (±)-5-bromo-6-fluoro-1-(5-fluoro-2-hydroxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (50 mg, 0.11 mmol, 1.0 eq.) and Cs2CO3 (104 mg, 0.32 mmol, 3.0 eq.) in DMF (1 mL), ethyl bromoacetate (18 μL, 0.16 mmol, 1.5 eq.) was added. The resulting solution was stirred at r.t. for 18 hours. The solvent was evaporated and the mixture was poured into water and extracted with DCM (3×). The combined extracts were washed with water and dried over MgSO4. To a solution under N2 of the residue in EtOH (4 mL), palladium on activated carbon (10 wt. %, 10 mg) was added. The flask was evacuated and backfilled with H2 (3×). The black suspension was stirred at r.t. under an H2-atmosphere for 18 hours. The suspension was filtered through Celite, the Celite rinsed with EtOH, and the filtrate was concentrated in vacuo. The residue was purified by prep. HPLC (column: Waters X-bridge, 19×50 mm, 10 um, UV/MS, basic conditions) to give the title amine.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH:20][CH2:21][CH:22]([O:40][C@@H:41]1[O:46][C@H:45]([CH2:47][OH:48])[C@@H:44]([O:49][C@H:50]2[O:55][C@@H:54]([CH2:56][OH:57])[C@@H:53]([O:58][C@H:59]3[O:64][C@@H:63]([CH2:65][OH:66])[C@@H:62]([OH:67])[C@@H:61]([O:68][C@H:69]4[O:74][C@@H:73]([CH2:75][OH:76])[C@@H:72]([OH:77])[C@@H:71]([O:78][C@]5(C(O)=O)O[C@@H](C(O)C(O[C@]6(C(O)=O)O[C@@H](C(O)C(O)CO)[C@H](N)[C@@H](O)C6)O)[C@H](N)[C@@H](O)C5)[C@@H:70]4[OH:112])[C@@H:60]3[NH:113][C:114]([CH3:116])=[O:115])[C@@H:52]([O:117][C@:118]3([C:132]([OH:134])=[O:133])[O:123][C@@H:122]([CH:124]([OH:129])[CH:125]([OH:128])[CH2:126][OH:127])[C@H:121]([NH2:130])[C@@H:120]([OH:131])[CH2:119]3)[C@@H:51]2[OH:135])[C@H:43]([OH:136])[C@H:42]1[OH:137])C(O)/C=C/CCCCCCCCCCCCC)=O.[C:138]([O-:141])(=O)[CH3:139].[OH2:142]>C(Cl)(Cl)Cl>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH:20][C@H:21]([C@H:138]([OH:141])/[CH:139]=[CH:14]/[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[CH2:22][O:40][C@@H:41]1[O:46][C@H:45]([CH2:47][OH:48])[C@@H:44]([O:49][C@@H:50]2[O:55][C@H:54]([CH2:56][OH:57])[C@H:53]([O:58][C@@H:59]3[O:64][C@H:63]([CH2:65][OH:66])[C@H:62]([OH:67])[C@H:61]([O:68][C@@H:69]4[O:74][C@H:73]([CH2:75][OH:76])[C@H:72]([OH:77])[C@H:71]([OH:78])[C@H:70]4[OH:112])[C@H:60]3[NH:113][C:114]([CH3:116])=[O:115])[C@H:52]([O:117][C@@:118]3([C:132]([OH:134])=[O:133])[O:123][C@@H:122]([C@H:124]([OH:129])[C@H:125]([OH:128])[CH2:126][OH:127])[C@H:121]([NH:130][C:22]([CH3:21])=[O:40])[C@@H:120]([OH:131])[CH2:119]3)[C@H:51]2[OH:135])[C@H:43]([OH:136])[C@H:42]1[OH:137])=[O:142]
Reactant: CC(=O)[O-]
Reactant: CCCCCCCCCCCCC/C=C/C(O)C(CNC(=O)CCCCCCCCCCCCCCCCC)O[C@@H]1O[C@H](CO)[C@@H](O[C@H]2O[C@@H](CO)[C@@H](O[C@H]3O[C@@H](CO)[C@@H](O)[C@@H](O[C@H]4O[C@@H](CO)[C@@H](O)[C@@H](O[C@@]5(C(=O)O)C[C@H](O)[C@@H](N)[C@H](C(O)C(O)O[C@@]6(C(=O)O)C[C@H](O)[C@@H](N)[C@H](C(O)C(O)CO)O6)O5)[C@@H]4O)[C@@H]3NC(C)=O)[C@@H](O[C@@]3(C(=O)O)C[C@H](O)[C@@H](N)[C@H](C(O)C(O)CO)O3)[C@@H]2O)[C@H](O)[C@H]1O
Reactant: O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCC/C=C/[C@@H](O)[C@H](CO[C@@H]1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O[C@@H]3O[C@H](CO)[C@H](O)[C@H](O[C@@H]4O[C@H](CO)[C@H](O)[C@H](O)[C@H]4O)[C@H]3NC(C)=O)[C@H](O[C@]3(C(=O)O)C[C@H](O)[C@@H](NC(C)=O)[C@H]([C@H](O)[C@H](O)CO)O3)[C@H]2O)[C@H](O)[C@H]1O)NC(=O)CCCCCCCCCCCCCCCCC

Procedure:
A 1 ml quantity of 0.4% ganglioside GTlb solution, 1 ml of 40 mM acetate buffer (pH 4.0) and 1 ml of distilled water were mixed together, and to the mixture was added 1 ml of aqueous solution of Isozyme S (5 U/ml). The mixture was allowed to react at 37° C. for 1 hour, and 1/10 part by volume of chloroform was added thereto to stop the enzyme reaction. Ganglioside GMl was extracted from the reaction solution with use of a mixture of chloroform and methanol (2:1) and then lyophilized, giving 2.4 mg of ganglioside GMl as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]2[S:18][C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[N:16][C:15]=2[CH3:29])=[CH:8][C:7]=1[CH3:30].N1C=CC=CC=1.Cl[C:39]([O:41][CH3:42])=[O:40].O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([C:39]([O:41][CH3:42])=[O:40])[CH2:13][C:14]2[S:18][C:17]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:23][CH:24]=3)=[N:16][C:15]=2[CH3:29])=[CH:8][C:7]=1[CH3:30]
Reactant: COC(=O)Cl
Reactant: COC(=O)CCc1ccc(NCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)CCc1ccc(N(Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)C(=O)OC)cc1C
Temperature: 25 °C
Yield: 102.3 %

Procedure:
To a 0° C. solution of 3-(2-Methyl-4-{[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-phenyl)-propionic acid methyl ester (0.05 g, 0.11 mmol) and pyridine (0.027 mL, 0.33 mmol) in anhydrous CH2Cl2 (3 mL) is added methyl chloroformate (0.026 mL, 0.34 mmol) dropwise. The mixture is allowed to warm to RT overnight. Water is added, and the mixture is extracted with CH2Cl2. The combined organics are dried with MgSO4 and concentrated to yield the title compound (57 mg, quant.)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=1.[Cl:17][C:18]([Cl:24])([Cl:23])[C:19](=N)OC.O>C(O)(=O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:19]([C:18]([Cl:24])([Cl:23])[Cl:17])[N:9]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=3)[C:3]=2[CH:4]=1
Reactant: Nc1nccc(Nc2cc(Br)ccc2N)n1
Reactant: COC(=N)C(Cl)(Cl)Cl
Solvent: CC(=O)O
Solvent: O
Product: Nc1nccc(-n2c(C(Cl)(Cl)Cl)nc3ccc(Br)cc32)n1
Temperature: 45 °C
Reaction time: 7 h

Procedure:
To a solution of 4-N-(2-amino-5-bromophenyl)pyrimidine-2,4-diamine (3.0 g, 10.71 mmol) in acetic acid (10 mL) was added methyl 2,2,2-trichloroethanimidoate (1.4 mL, 11.25 mmol). The reaction was stirred at 45° C. for 7 hr. Water (15 mL) was then added. The precipitate was collected by filtration and dried under vacuum to give the title product (3.94 g as the acetic acid salt); 1H NMR (500 MHz, DMSO) delta 1.90 (3H, s), 7.01 (1H, d, J=5.0 Hz), 7.21 (2H, s), 7.75-7.46 (2H, m), 8.09-7.75 (1H, m), 8.58 (1H, d, J=5.0 Hz); LC-MS: m/z=+406/408/410/412 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[NH2:5].C(N(C(C)C)CC)(C)C.[Si:24](Cl)([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C@H:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][Si:24]([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:11][CH:12]=1)[NH2:5]
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](N)Cc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Yield: 87.7 %

Procedure:
To a solution of L-tyrosine methyl ester (Sigma Chemical Company) (10.0 g, 51.3 mmol) and diisopropylethylamine (25.9 g, 200.0 mmol) in CH2Cl2 (400 mL) was added t-butyldiphenylsilyl chloride (TBDPS-Cl; 35.2 g, 128.2 mmol) at 23° C. The resultant mixture was stirred at 23° C. for 14 hours. The crude reaction mixture was dried over (MgSO4) and concentrated in vacuo. The resultant residue was purified by silica gel flash column chromatography. The polarity of the eluting solvent mixture was adjusted according to the Rf value of the product. The eluted fractions were combined, dried over MgSO4, concentrated and dried to give 19.5 g (87.8% yield) of O-(tert-butyldiphenylsilyl)-L-tyrosine methyl ester as a colorless syrup. Rf (hexanes/ethyl acetate (AcOEt)/methanol (MeOH) 20:20:1)=0.38.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C(N(CC)C(C)C)(C)C.[Cl:29][CH2:30][C:31](Cl)=[O:32]>C1COCC1>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][N:14]2[C:31](=[O:32])[CH2:30][Cl:29])=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCN2)no1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCN2C(=O)CCl)no1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-Piperidine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl) amide; hydrochloride (611 mg; 2.123 mmol) in THF (15 mL) is added N,N-diisopropylethylamine (0.74 mL; 4.246 mmol), followed by alpha-chloroacetyl chloride (0.17 mL; 2.134 mmol). The reaction mixture is stirred at room temperature for 18 hours.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][NH2:7])([O-:3])=[O:2].[C:12]([O-])([O-])=O.[K+].[K+].C[CH:19](Br)[C:20]#[N:21]>C(#N)C>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]([NH:7][CH2:19][C:20]#[N:21])[CH3:12])([O-:3])=[O:2]
Reactant: CC(Br)C#N
Reactant: O=C([O-])[O-]
Reactant: NCc1ccccc1[N+](=O)[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(NCC#N)c1ccccc1[N+](=O)[O-]
Temperature: 65 °C

Procedure:
2-Nitrobenzylamine (513 mg, 3.37 mmol) was added to an acetonitrile (40 mL) containing K2CO3 (932 mg, 6.74 mmol) and 2-bromopropanitrile (677 mg, 5.06 mmol) under a nitrogen atmosphere. The reaction mixture was heated to 65° C. for 14 hours. The product (18) was used without purification or concentration in the next step.
Reaction SMILES: [CH2:1]1[CH2:11]CN2[C:4](=[N:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][CH2:2]1.[CH3:12][N:13]([CH:15]=[O:16])[CH3:14]>CC(=O)OCC.O>[CH2:11]=[C:1]1[C:2]2=[CH:3][CH:4]=[N:5][C:6]3[CH:7]=[CH:8][C:15](=[O:16])[N:13]([C:14]=32)[CH2:12]1
Reactant: CN(C)C=O
Reactant: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CCOC(C)=O
Product: C=C1Cn2c(=O)ccc3nccc1c32
Yield: 72 %

Procedure:
A solution of intermediate BD.v (1.03 g) in DMF (10 mL) was stirred at rt in the presence of DBU (1.12 mL) for 2 h. The reaction mixture was diluted with EA and water. The aq. layer was extracted with EA (2×100 mL) and DCM/MeOH (3×50 mL; 9:1). The combined org. layers were sequentially washed with water and brine and dried over MgSO4. The solvent was evaporated under reduced pressure, affording a yellow solid (490 mg; 72% yield).