Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]=[C:9]2[C:15]([OH:17])=O)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:51]([Si:55]([CH3:74])([CH3:73])[O:56][CH2:57][CH2:58][N:59]1[C:63]([CH3:64])=[CH:62][C:61]([C:65]2[CH:66]=[CH:67][C:68]([CH3:72])=[C:69]([NH2:71])[CH:70]=2)=[N:60]1)([CH3:54])([CH3:53])[CH3:52]>CN1C(=O)CCC1.O>[C:51]([Si:55]([CH3:74])([CH3:73])[O:56][CH2:57][CH2:58][N:59]1[C:63]([CH3:64])=[CH:62][C:61]([C:65]2[CH:66]=[CH:67][C:68]([CH3:72])=[C:69]([NH:71][C:15]([C:9]3[C@H:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH2:13][C:12](=[O:14])[NH:11][CH:10]=3)=[O:17])[CH:70]=2)=[N:60]1)([CH3:53])([CH3:52])[CH3:54]
Reactant: Cc1ccc(-c2cc(C)n(CCO[Si](C)(C)C(C)(C)C)n2)cc1N
Reactant: O=C1C[C@@H](c2ccc(F)cc2)C(C(=O)O)=CN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1ccc(-c2cc(C)n(CCO[Si](C)(C)C(C)(C)C)n2)cc1NC(=O)C1=CNC(=O)C[C@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.6 %

Procedure:
A solution of (S)-4-(4-fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid (138 mg), N,N-Diisopropylethylamine (155 mg) and HATU (152 mg) in NMP (1 ml) was stirred at room temperature for 10 minutes. A solution of 5-{1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-pyrazol-3-yl}-2-methyl-phenylamine (94 mg) in NMP (1 ml) was added, and the reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by “flash chromatography” (0 to 5% MeOH in CH2Cl2) to give 62.2 mg of (S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid (5-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-pyrazol-3-yl}-2-methyl-phenyl)-amide as an amorphous solid.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][N:7]([CH2:13][C:14]1[CH:15]=[C:16]2[C:23]([CH3:24])=[N:22][N:21]([CH3:25])[C:17]2=[N:18][C:19]=1[Cl:20])[C:8]1[N:9]=[N:10][NH:11][N:12]=1.[H-].[Na+].[CH3:37]I.O>CN(C=O)C>[F:32][C:29]([F:30])([F:31])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:33])([F:1])[F:34])[CH:28]=1)[CH2:6][N:7]([CH2:13][C:14]1[CH:15]=[C:16]2[C:23]([CH3:24])=[N:22][N:21]([CH3:25])[C:17]2=[N:18][C:19]=1[Cl:20])[C:8]1[N:9]=[N:10][N:11]([CH3:37])[N:12]=1
Reactant: Cc1nn(C)c2nc(Cl)c(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nn[nH]n3)cc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(C)c2nc(Cl)c(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)cc12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 121.4 %

Procedure:
A mixture of (3,5-bis-trifluoromethyl-benzyl)-(6-chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-ylmethyl)-(2H-tetrazol-5-yl)-amine (8.5 g, 10 mmol) and sodium hydride (0.81 g, 30 mmol) in DMF (150 mL) was stirred at 0° C. for 20 minutes. Thereafter, methyl iodide (3.5 g, 20 mmol) was added and the resulting mixture was stirred at 0-10° C. for 30 minutes. Water (100 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by column chromatography over 230-400 mesh silica gel. Elution of the column with 10% acetone in hexanes gave the pure product as a colorless solid (6.3 g, yield: 75%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:34]=[CH:35][C:36]=1[O:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1)[CH2:24][NH:25][CH:26]1[CH2:32][CH2:31][CH2:30][CH2:29][NH:28][C:27]1=[O:33]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:25]([CH2:24][C:23]2[CH:34]=[CH:35][C:36]([O:37][CH2:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=3)=[C:21]([O:20][CH3:19])[CH:22]=2)[CH:26]2[CH2:32][CH2:31][CH2:30][CH2:29][NH:28][C:27]2=[O:33])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: COc1cc(CNC2CCCCNC2=O)ccc1OCCc1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(CN(C2CCCCNC2=O)S(=O)(=O)c2ccc(F)cc2)ccc1OCCc1ccccn1
Reaction time: 48 h

Procedure:
4-fluorobenzenesulfonyl chloride (0.22 mmol) is added to a room temperature solution of triethylamine (0.9 mmol) and 3-[3-Methoxy-4-(2-pyridin-2-yl-ethoxy)-benzylamino]-azepan-2-one (3) (0.22 mmol) in methylene chloride (0.2 M). After stirring for 48 hours, the reaction mixture is concentrated and the resulting residue is purified by reverse phase HPLC, to afford the desired product (4).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:5]2=[N:6][CH:7]=1.Cl.[NH2:23][C@H:24]([CH3:29])[C:25]([CH3:28])([OH:27])[CH3:26].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:27][C:25]([CH3:28])([CH3:26])[C@H:24]([NH:23][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([Br:1])[N:3]=2)[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=1)=[O:13])[CH3:29]
Reactant: C[C@@H](N)C(C)(C)O
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(Br)cnc21
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(C)(C)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
In a flask were combined 2-bromo-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3.25 g, 8.74 mmol), (R)-3-amino-2-methyl-butan-2-ol hydrochloride (3.05 g, 21.9 mmol), EDC (3.85 g, 20.1 mmol) and HOBt (2.72 g, 20.1 mmol). Then added DMF (50 mL) followed by i-Pr2NEt (4.87 mL, 28.0 mmol). The mixture was stirred at room temperature overnight then concentrated under reduced pressure. The residue purified by SiO2 chromatography (20-100% EtOAc/hexane) to afford 2.40 g (60%) of 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-hydroxy-1,2-dimethyl-propyl)-amide as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[Cl:19][C:20]1[C:21]2[CH:29]=[C:28]([N:30]([CH3:32])[CH3:31])[N:27]=[CH:26][C:22]=2[N:23]=[CH:24][N:25]=1>>[ClH:19].[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:20]3[C:21]4[CH:29]=[C:28]([N:30]([CH3:32])[CH3:31])[N:27]=[CH:26][C:22]=4[N:23]=[CH:24][N:25]=3)=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: Nc1ccc2c(cnn2Cc2ccccc2F)c1
Reactant: CN(C)c1cc2c(Cl)ncnc2cn1
Product: CN(C)c1cc2c(Nc3ccc4c(cnn4Cc4ccccc4F)c3)ncnc2cn1
Product: Cl

Procedure:
Prepared according to Procedure A from 1-(2-Fluoro-benzyl)-1H-indazol-5-ylamine and 4-chloro-6-(N,N-dimethylamino)-pyrido[3,4-d]pyrimidine; δH [2H6]DMSO 11.45(1H,s), 8.90(1H,s), 8.63(1H,s), 8.24(1H,s), 8.13(1H,s), 7.87(1H,d), 7.70(1H,d), 7.62(1H,s), 7.36(1H,m), 7.20 (3H,m), 5.75(2H,s), 3.22(6H,s); m/z (M+) 413.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]2[C:10](=[O:12])[NH:9][C:8]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:7][C:6]=2[N:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:4]=1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([C:38](O)=[O:39])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>ClCCl>[CH3:2][C:3]1[C:11]2[C:10](=[O:12])[NH:9][C:8]([CH:13]3[CH2:14][CH2:15][N:16]([C:38]([CH:35]4[CH2:36][CH2:37][N:32]([C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH2:33][CH2:34]4)=[O:39])[CH2:17][CH2:18]3)=[N:7][C:6]=2[N:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: Cc1nn(-c2ccccc2)c2nc(C3CCNCC3)[nH]c(=O)c12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nn(-c2ccccc2)c2nc(C3CCN(C(=O)C4CCN(C(=O)OC(C)(C)C)CC4)CC3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 3-methyl-1-phenyl-6-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one hydrochloride (500 mg, 1.45 mmol, 1.00 equiv) in dichloromethane (50 mL) at room temperature. To the resulting mixture was then added 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (332 mg, 1.45 mmol, 1.00 equiv), in portions at room temperature, followed by BOP (767 mg, 1.74 mmol, 1.20 equiv), in portions at room temperature. To the resulting mixture was added DIPEA (280 mg, 2.17 mmol, 1.50 equiv), in portions at room temperature. The resulting solution was stirred for 4 h at room temperature. The resulting mixture was washed with water (1×50 mL). The resulting solution was extracted with DCM (3×50 mL), the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (50:1) to yield tert-butyl 4-(4-(3-methyl-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)piperidine-1-carbonyl)piperidine-1-carboxylate as a white solid.
Reaction SMILES: [Cl-].ClC1N(C)CC[NH+]1C.[NH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.C(N(CC)CC)C.[CH3:24][O:25][C:26]1[C:27](=[O:50])[C:28]([CH3:49])=[C:29]([CH2:35][C:36]2[CH:44]=[CH:43][C:39]([C:40](O)=[O:41])=[C:38]([O:45][C:46](=[O:48])[CH3:47])[CH:37]=2)[C:30](=[O:34])[C:31]=1[O:32][CH3:33]>C(Cl)(Cl)Cl.C(Cl)Cl>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([NH:10][C:40](=[O:41])[C:39]2[CH:43]=[CH:44][C:36]([CH2:35][C:29]3[C:30](=[O:34])[C:31]([O:32][CH3:33])=[C:26]([O:25][CH3:24])[C:27](=[O:50])[C:28]=3[CH3:49])=[CH:37][C:38]=2[O:45][C:46](=[O:48])[CH3:47])[CH:12]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)O)c(OC(C)=O)c2)=C(C)C1=O
Reactant: Nc1cccnc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)Nc3cccnc3)c(OC(C)=O)c2)=C(C)C1=O
Yield: 17.8 %

Procedure:
2-Chloro-1,3-dimethylimidazolinium chloride (39 mg, 0.23 mmol), 3-aminopyridine (21 mg, 0.23 mmol) and triethylamine (23 mg, 0.23 mmol) were added to a methylene chloride solution (5 ml) of 4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (57 mg, 0.152 mmol) in a nitrogen atmosphere and the resulting solution was stirred all the night through. The reaction solution was diluted with chloroform, then washed with water and dried, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography (benzene:acetone=3:1) to obtain the titled compound (12 mg, 0.027 mmol, 18%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1)(=[O:7])=[O:6].Br[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]3[O:36][N:35]=[C:34]([CH:37]([CH3:39])[CH3:38])[N:33]=3)[CH2:28][CH2:27]2)=[CH:20][N:19]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]3[CH2:31][CH2:30][N:29]([C:32]4[O:36][N:35]=[C:34]([CH:37]([CH3:39])[CH3:38])[N:33]=4)[CH2:28][CH2:27]3)=[CH:20][N:19]=2)=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: CC(C)c1noc(N2CCC(COc3ccc(Br)nc3)CC2)n1
Reactant: O=S(=O)(NCCO)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)c1noc(N2CCC(COc3ccc(-c4ccc(S(=O)(=O)NCCO)cc4)nc3)CC2)n1
Yield: 15 %

Procedure:
The title compound (30 mg, 15%) was prepared as an off-white solid from (4-{[(2-hydroxyethyl)amino]sulfonyl}phenyl)boronic acid (98 mg, 0.4 mmol), 2-bromo-5-[({1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]pyridine (153 mg, 0.4 mmol), Pd(PPh3)4 (100 mg, 0.14 mmol), 2M Na2CO3 (2 mL) and DME (4 mL) in a manner similar to Example 21, Step 3. 1H NMR (400 MHz, CDCl3): δ 8.39 (s, 1H), 8.07 (d, 2H, J=8.2 Hz), 7.93 (d, 2H, J=8.2 Hz), 7.72 (d, 1H, J=8.6 Hz), 7.30 (d, 1H, J=6.5 Hz), 5.07 (t, 1H, J=5.8 Hz), 4.28-4.18 (m, 2H), 3.94 (d, 2H, J=6.0 Hz), 3.73-3.65 (m, 2H), 3.17-3.04 (m, 4H), 2.96-2.80 (m, 1H), 2.06-1.92 (m, 3H), 1.57-1.40 (m, 2H), 1.28 (d, 6H, J=6.9 Hz); LRMS (ESI), m/z 502 (M+H).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[C:6](=[O:33])(SCC)[O:7][CH2:8][O:9][C:10](=[O:29])[C:11]1[CH:16]=[C:15]([S:17]([NH2:20])(=[O:19])=[O:18])[C:14]([Cl:21])=[CH:13][C:12]=1[NH:22][CH2:23][C:24]1[O:25][CH:26]=[CH:27][CH:28]=1>ClCCl>[C:6]([Cl:4])(=[O:33])[O:7][CH2:8][O:9][C:10](=[O:29])[C:11]1[CH:16]=[C:15]([S:17]([NH2:20])(=[O:19])=[O:18])[C:14]([Cl:21])=[CH:13][C:12]=1[NH:22][CH2:23][C:24]1[O:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCSC(=O)OCOC(=O)c1cc(S(N)(=O)=O)c(Cl)cc1NCc1ccco1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: NS(=O)(=O)c1cc(C(=O)OCOC(=O)Cl)c(NCc2ccco2)cc1Cl
Reaction time: 0.25 h

Procedure:
Freshly distilled sulfuryl chloride (0.050 mole) in dichloromethane (25 mL) is added to O-(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxymethyl) S-ethyl carbonothioate (1005) (0.050 mole) in dichloromethane (25 mL) at 0-5° C. with stirring during 15 minutes followed by stirring at ambient temperature for 45 minutes. The volatiles are removed by evaporation at ambient temperature and then at 20 millibar for 16 hours. The crude product is dissolved in ethyl acetate and applied to a column of silica gel. The column may be eluted with hexanes/ethyl acetate, and the fractions that contain pure product may be combined and spin evaporated in vacuo to give 5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxymethyl carbonochloridate (1010). See eg., Folkmann, et al., Synthesis, 1159 (1990), Method G.
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl.[CH3:17][N:18]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](Cl)=[O:26])[CH3:19]>C1(C)C=CC=CC=1>[CH3:17][N:18]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:1]1=[O:8])=[O:26])[CH3:19]
Reactant: O=C1CCCCCN1
Reactant: CN(C)CCCCCC(=O)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN(C)CCCCCC(=O)C1CCCCNC1=O
Temperature: 101 °C
Yield: 83.9 %

Procedure:
To a 1000 mL three-necked round-bottomed flask equipped with a reflux condenser, internal thermometer, argon inlet, and mechanical stirrer, are added ε-caprolactam (48.04 g, 0.42 mol), toluene (340 mL), and triethylamine (189.00 g, 1.87 mol). The mixture is heated to reflux (ca. 101° C.) for 15 min. While at that temperature, acid chloride 3 (100.00 g, 0.47 mol) is added as a solid over 30 min. The reaction is maintained at reflux for an additional 1.75 h before the heat is removed. At room temperature, the mixture is filtered and the salts washed with toluene. The dark filtrate is washed with saturated sodium bicarbonate solution (3×250 mL), water (100 mL), and dried over MgSO4. The mixture is filtered and concentrated by rotary evaporation at about 50° C. (water aspirator) and then by Kugelrohr distillation at 60° C. for 1 h to give 89.64 g (83%) of 4 as an oil.
Reaction SMILES: IC.[C:3](=O)([O-])[O-].[K+].[K+].[C:9]([O:13][C:14]([N:16]([CH3:26])[C@H:17]([C:22]([NH:24][CH3:25])=[O:23])[C:18](=[O:21])[O:19][CH3:20])=[O:15])([CH3:12])([CH3:11])[CH3:10]>C(#N)C>[C:9]([O:13][C:14]([N:16]([CH3:26])[C@:17]([CH3:3])([C:22]([NH:24][CH3:25])=[O:23])[C:18](=[O:21])[O:19][CH3:20])=[O:15])([CH3:11])([CH3:10])[CH3:12]
Reactant: CNC(=O)[C@H](C(=O)OC)N(C)C(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CNC(=O)[C@](C)(C(=O)OC)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.2 %

Procedure:
Iodomethane (1.4 mL) and potassium carbonate (1.6 g) were added to an acetonitrile (5.0 mL) solution of N2-(t-butoxycarbonyl)-N,N2,O-trimethyl-3-oxoserinamide (Intermediate 4-2, 2.0 g), and the mixture was stirred for 20 hours at room temperature under closed conditions. Iodomethane (2.8 mL) was added, and the mixture was stirred for 3 days at room temperature under closed conditions. Further, iodomethane (2.8 mL) was added, and the mixture was stirred for 1 day at room temperature under closed conditions, and then stirred for 9 hours at 50° C. After the reaction mixture was stirred for 14 hours at room temperature, potassium carbonate was filtered out. Then, the system was washed with ethyl acetate, and the reaction mixture was concentrated. The resulting residue was purified by OH type silica gel column chromatography (gradient elution with hexane/ethyl acetate=70/30→100/0) to obtain N2-(t-butoxycarbonyl)-N,N2,O,2-tetramethyl-3-oxoserinamide (Intermediate 8-2, yellow oil) (1.5 g, 78%).
Reaction SMILES: [I:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=1.I[CH:16]([CH3:18])[CH3:17].C([O-])([O-])=O.[K+].[K+].CCCCCC>CN(C=O)C.CCOC(C)=O>[I:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=2)=[CH:4][N:5]([CH:16]([CH3:18])[CH3:17])[N:6]=1
Reactant: CSc1nccc(-c2cn[nH]c2I)n1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CSc1nccc(-c2cn(C(C)C)nc2I)n1
Yield: 47.2 %

Procedure:
A mixture of 4-(5-iodo-1H-pyrazol-4-yl)-2-(methylthio)pyrimidine (A) (31.8 g, 0.1 mol), 2-iodo-propane (85 g, 50 mL, 0.5 mol) and K2CO3 (16.5 g, 0.12 mol) in DMF (500 mL) was heated at 40˜50° C. overnight. When TLC (hexane: EtOAc=15:1) showed the reaction was complete, DMF was evaporated under reduced pressure. The residue was taken up with EtOAc (400 mL). The mixture was washed with saturated aqueous NaCl, dried over Na2SO4 and concentrated to give crude product, which was purified via prep. HPLC to give pure 4-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)-2-(methylthio)pyrimidine B-1-1 (17 g, 47.2%) as a yellow oil.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[C:8]([O:11][C:12]3[CH:21]=[CH:20][N:19]=[C:18]4[C:13]=3[C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[C:16](=[O:22])[NH:17]4)[CH:9]=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1.[N:27]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1)=[C:28]=[O:29]>>[F:37][C:36]([F:38])([F:39])[C:32]1[CH:31]=[C:30]([NH:27][C:28]([N:4]2[C:5]3[CH:10]=[CH:9][C:8]([O:11][C:12]4[CH:21]=[CH:20][N:19]=[C:18]5[C:13]=4[C:14]4[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=4[C:16](=[O:22])[NH:17]5)=[CH:7][C:6]=3[O:1][CH2:2][CH2:3]2)=[O:29])[CH:35]=[CH:34][CH:33]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: O=c1[nH]c2nccc(Oc3ccc4c(c3)OCCN4)c2c2ccccc12
Product: O=C(Nc1cccc(C(F)(F)F)c1)N1CCOc2cc(Oc3ccnc4[nH]c(=O)c5ccccc5c34)ccc21
Yield: 22.8 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 221 using 218 (50 mg, 0.14 mmol) and 1-isocyanato-3-trifluoromethyl-benzene (41 mg, 0.22 mmol) to provide 224 (17 mg, 22% yield) as a tan solid. LC-MS (M+H=533, obsd.=533).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH:12][C:13]3[N:18]=[CH:17][C:16]([S:19][CH2:20][CH:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)=[C:15]([O:34][C:35]4[CH:44]=[CH:43][CH:42]=[C:41]5[C:36]=4[CH:37]=[CH:38][CH:39]=[N:40]5)[CH:14]=3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O.C(Cl)[Cl:53]>>[ClH:53].[ClH:53].[C:1]1([C:7]2[N:8]=[C:9]([NH:12][C:13]3[CH:14]=[C:15]([O:34][C:35]4[CH:44]=[CH:43][CH:42]=[C:41]5[C:36]=4[CH:37]=[CH:38][CH:39]=[N:40]5)[C:16]([S:19][CH2:20][CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[CH:17][N:18]=3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CSc2cnc(Nc3nc(-c4ccccc4)cs3)cc2Oc2cccc3ncccc23)CC1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: c1ccc(-c2csc(Nc3cc(Oc4cccc5ncccc45)c(SCC4CCNCC4)cn3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.3 %

Procedure:
A flask was charged with tert-butyl 4-((6-(4-phenylthiazol-2-ylamino)-4-(quinolin-5-yloxy)pyridin-3-ylthio)methyl)piperidine-1-carboxylate (prepared according to the method of Example 202) (0.150 g, 0.240 mmol) and 4 mL DCM. TFA (4 mL) was added and the reaction was stirred at ambient temperature for 2 hours and then concentrated. The crude material was purified on a SCX ion exchange column using DCM, methanol and ammoniated methanol as eluent. The isolated material was treated with 2M HCl (2 mL) in ether and dried to give the title compound (0.057 g, 39.3% yield) as light yellow solid. 1H NMR (DMSO-d6) δ 11.14 (s, 1H), 9.06 (dd, 1H), 8.67 (m, 1H), 8.43 (s, 1H), 8.34 (d, 1H), 8.09 (d, 1H), 7.91 (t, 1H), 7.71 (s, 1H), 7.70 (s, 1H), 7.67 (dd, 1H), 7.50 (d, 1H), 7.43 (s, 1H), 7.31 (t, 2H), 7.28 (m, 1H) 6.58 (s, 1H), 3.25 (m, 2H), 2.95 (d, 2H), 2.86 (m, 2H), 2.01 (m, 2H), 1.80 (m, 1H), 1.40 (m, 2H).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].[OH:26][S:27]([O-:29])=[O:28].[Na+]>CC#N>[S:27](=[O:26])([OH:29])[OH:28].[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: O=S([O-])O
Reactant: Clc1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: O=Cc1ccc(Oc2nc3ccccc3s2)cc1
Product: O=S(O)O
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 2-chlorobenzothiazole (33.7 g, 199 mmol) in CH3CN (500 mL) was added 4-hydroxy benzaldehyde (24.3 g, 199 mmol) and K2CO3 (28 g, 199 mmol). The heterogeneous mixture was heated at reflux for 72 h and then cooled to rt. The solids were removed by filtration and washed with CH3CN (100 mL). To the filtrate was added an aqueous solution of NaHSO3 (26 g, 199 mmol, 66 mL water). After stirring for 3.5 h, the mixture was filtered and the wet cake was dried under vacuum overnight to afford the bisulfite complex (66 g, 92%) as a white powder. 1H NMR (500 MHz, DMSO-d6): 7.93 (d, J=8.0 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.60-7.55 (m, 2H), 7.44-7.39 (m, 1H), 7.35-7.29 (m, 3H), 6.03 (d, J=5.2 Hz, 1H), 5.04 (d, J=5.2 Hz, 1H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH2:14][C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:18]=[CH:17][C:16]=1[OH:29].O1CCOCC1>N1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:14][C:15]2[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:18]=[CH:17][C:16]=2[OH:29])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCCCCCCCc1ccc(O)c(N)c1
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CCCCCCCCc1ccc(O)c(NC(=O)c2ccc(OC(C)=O)cc2)c1
Temperature: 0 °C
Yield: 70.8 %

Procedure:
In a 100 ml round-bottom flask, the resultant 4-acetoxybenzoic chloride, 3.10 g (15.1 m mole) of 2-amino-4-octylphenol and 40 ml of dioxane were placed and heated to keep inner temperature 85 to 88.5° C. To the mixture, 5.5 ml of pyridine was added dropwise under stirring, followed by heating and stirring for 20 minutes at 85 to 88.5° C. After the reaction, the reaction mixture was cooled with ice and poured into ca. 200 ml of ice water to precipitate a crystal. The crystal was filtered, washed and recrystallized from methanol to obtain 4.10 g of 2-(4-acetoxybenzoylamino)-4-octylphenol (Yield: 70.8%). ##STR79##