Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[S:7]1[C:15]2[CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C:10]=2[CH:9]=[C:8]1[C:23](OCC)=[O:24].C(OCC)(=O)C.CCCCCC>O1CCCC1>[OH:24][CH2:23][C:8]1[S:7][C:15]2[CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C:10]=2[CH:9]=1
Reactant: CCOC(=O)c1cc2c(s1)CCN(C(=O)OC(C)(C)C)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCc2sc(CO)cc2C1
Temperature: 0 °C
Reaction time: 0.21 h

Procedure:
Tetrahydrofuran (10 ml) was added dropwise to lithium aluminium hydride (0.46 g, 2 eq.) at 0° C. and the mixture was stirred for 10-15 min at the same temperature. Then a solution of 5-tert-butyl 2-ethyl 6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxylate (2 g, 0.006 mol) in tetrahydrofuran (10 ml) was added dropwise to the mixture at 0° C. and the resulting reaction mixture was stirred for 1-2 h at the same temperature. Progress of the reaction was monitored by TLC (30% ethyl acetate/hexane). Upon completion of the reaction the reaction mixture was poured into ice water and quenched with saturated sodium sulfate solution at 0° C. The mixture was filtered over a bed of Celite and the filtrate was extracted with ethyl acetate (2×150 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to yield the crude product as a pale yellow colored liquid. The crude product obtained was directly employed in the next step. Yield: 1.6 g (92%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7](=[O:28])[C@@H:8]([NH:20]C(OC(C)(C)C)=O)[C@H:9]([CH3:19])[CH2:10][CH2:11][NH:12][CH2:13][N:14]=[N:15][N+:16]([O-:18])=[O:17].[ClH:29]>C1COCC1.O1CCOCC1>[ClH:29].[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7](=[O:28])[C@@H:8]([NH2:20])[C@H:9]([CH3:19])[CH2:10][CH2:11][NH:12][CH2:13][N:14]=[N:15][N+:16]([O-:18])=[O:17]
Reactant: C[C@H](CCNCN=N[N+](=O)[O-])[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1nccs1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: C[C@H](CCNCN=N[N+](=O)[O-])[C@H](N)C(=O)Nc1nccs1
Reaction time: 2 h
Yield: 97 %

Procedure:
(2S,3R)-2-tert-Butoxycarbonylamino-3-methyl-5-(nitroimino-amino)methylaminopentanoic acid 1,3-thiazol-2-ylamide (101 mg, 0.243 mmol) is dissolved in 1 mL THF and 1.5 mL of 4 N HCl in dioxane is added. After 2 h, THF is added and the white precipitate is collected by filtration. The resulting oily solid is treated with methanol and concentrated in vacuo. THF is added and the mixture is concentrated in vacuo; this THF addition and concentration is repeated several times to give (2S,3R)-2-amino-3-methyl-5-(nitroimino-amino)methylaminopentanoic acid 1,3-thiazol-2-ylamide hydrochloride as a solid (83 mmol, 97%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23](=[O:35])CC3C4C(=CC=CC=4)N(C)C=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([N:43]=C=O)=[CH:39][CH:38]=1>>[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:23]([NH:22][C@@H:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C@H:16]2[NH:15][C@H:11]2[CH2:12][CH2:13][CH2:14][N:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)[CH2:10]2)=[O:35])=[CH:39][CH:38]=1
Reactant: Cn1cc(CC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c2ccccc21
Reactant: O=C=Nc1ccc(Cl)cc1
Product: N#Cc1ccc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3NC(=O)Nc3ccc(Cl)cc3)C2)cc1

Procedure:
1-(4-Chlorophenyl)-3-((1R,2R)-2-((S)-1-(4-cyanophenyl)piperidin-3-ylamino)cyclohexyl)urea was synthesized using 4-((S)-3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzonitrile (from intermediate D, Example 10) (60 mg, 0.2 mmol) and 1-chloro-4-isocyanatobenzene (30.9 mg, 0.2 mmol) according to General Procedure G to give 25 mg (27.5%) of white solid. Anal. Calcd. for C25H30ClN5O m/z 451.2, found: 452.2 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.66 (bs, 1H), 7.43 (d, J=8.8 Hz, 4H), 7.26 (d, J=8.8 Hz, 2H), 6.95 (m, 2H), 6.13 (s, 1H), 3.80 (m, 2H), 3.3 (m, 1H), 2.79 (bs, 1H), 2.4 (m, 1H), 1.91 (m, 3H), 1.64 (m, 4H), 1.48 (m, 1H), 1.23 (m, 4H).
Reaction SMILES: [C:1]1([S:7]([C:10]([CH3:22])([CH3:21])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH:16]([OH:20])[CH2:15]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:23](I)([CH3:25])[CH3:24]>>[C:1]1([S:7]([C:10]([CH3:22])([CH3:21])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH:16]([O:20][CH:23]([CH3:25])[CH3:24])[CH2:15]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(CCCN1CCCC(O)C1)S(=O)(=O)c1ccccc1
Reactant: CC(C)I
Product: CC(C)OC1CCCN(CCCC(C)(C)S(=O)(=O)c2ccccc2)C1

Procedure:
The title compound was prepared from 1-(4-benzenesulfonyl-4-methylpentyl)-3-hydroxypiperidine and i-propyl iodide.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH3:66])[C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:26]([O:60][CH3:61])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:58][CH3:59])[C@@H:36]([CH3:57])[C:37]([NH:39][C@@:40]1([C:49]([N:51]2[CH2:56][CH2:55][CH2:54][CH2:53][O:52]2)=[O:50])[CH2:42][C@@H:41]1[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH:11]([CH3:13])[CH3:12])([OH:3])=[O:2].O[N:68]1[C:72](=[O:73])[CH2:71][CH2:70][C:69]1=[O:74].Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C1C=CN=CC=1)C>[O:74]=[C:69]1[CH2:70][CH2:71][C:72](=[O:73])[N:68]1[O:2][C:1](=[O:3])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH3:66])[C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:26]([O:60][CH3:61])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:58][CH3:59])[C@@H:36]([CH3:57])[C:37]([NH:39][C@@:40]1([C:49]([N:51]2[CH2:56][CH2:55][CH2:54][CH2:53][O:52]2)=[O:50])[CH2:42][C@@H:41]1[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:19])[CH3:20])=[O:15])[CH:11]([CH3:12])[CH3:13]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCC(=O)O)C(C)C
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCC(=O)ON1C(=O)CCC1=O)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
18 mg (20 μmol) of N-(5-carboxypentyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-{[(1S,2R)-1-(1,2-oxazinan-2-ylcarbonyl)-2-phenylcyclopropyl]amino}-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Intermediate 64) were dissolved in 3.2 ml of dichloromethane and admixed with 22 mg (190 mmol) of 1-hydroxypyrrolidine-2,5-dione and then with 11 mg (60 μmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.24 mg (0.17 μmol) of DMAP. After stirring at RT for 2 h, another 22 mg (190 mmol) of 1-hydroxypyrrolidine-2,5-dione, 11 mg (60 μmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.24 mg (0.17 mol) of DMAP were added and the reaction mixture was stirred at RT for a further hour. This was followed by concentration under reduced pressure. The remaining residue was purified by means of preparative HPLC. After lyophilization, 8.2 mg (41% of theory) of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[OH:13]S(O)(=O)=O>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH2:9])=[O:13])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1nc(Cl)ccc1[N+](=O)[O-]
Product: NC(=O)c1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 73 %

Procedure:
A solution of 6-chloro-3-nitropicolinonitrile (1.00 g, 5.45 mmol) in 90% H2SO4 (15 mL) is warmed at 70° C. for 3.5 h, and then poured into ice-water. The mixture is extracted four times with EtOAc and the combined extracts worked up to give 6-chloro-3-nitropicolinamide (0.80 g, 73%). 1H NMR (DMSO) δ 8.55 (1H, d, J=8.5 Hz), 8.31, 8.04 (1H, 1H, 2 brs), 7.93 (1H, d, J=8.5 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].Cl>C(Cl)Cl.O>[OH:12][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cc(N)ccc1O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc(NS(C)(=O)=O)ccc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.5 %

Procedure:
To a solution of methyl 5-amino-2-hydroxybenzoate (9.58 g, 57.3 mmol) in DCM (150 ml), pyridine (9.27 ml, 115 mmol) was added followed by methanesulfonyl chloride (4.47 ml, 57.3 mmol). The reaction mixture was stirred at RT for 4 hours. Water (50 ml) and HCl 6M (15 ml) were added, and the resulting precipitate was collected by filtration, washed with water and dried to give methyl 2-hydroxy-5-(methylsulfonamido)benzoate (13 g, 53.0 mmol, 92% yield, MS/ESI+ 246.0 [MH]+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][C:10]([OH:18])([CH2:11]3)[CH2:9]1)[CH2:15]2)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH3:27][S:28]([O:18][C:10]12[CH2:16][CH:14]3[CH2:13][CH:12]([CH2:17][C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:19])([CH2:15]3)[CH2:9]1)[CH2:11]2)(=[O:30])=[O:29]
Reactant: CC(C)(C)OC(=O)NC12CC3CC(CC(O)(C3)C1)C2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC12CC3CC(C1)CC(OS(C)(=O)=O)(C3)C2
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 40 %

Procedure:
5.6 g (21 mmole) of tert-butyl(3-hydroxy-1-adamantyl)carbamate are dissolved in 80 ml of dichloromethane, 4.4 ml (31.5 mmole) of triethylamine are added to it. The mixture is cooled to 0° C. and 1.82 ml (23.5 mmole) of methanesulphonyl chloride is added to it dropwise. The reaction mixture is stirred at that temperature for 45 minutes, then washed consecutively with water and saturated sodium hydrogen carbonate solution. The organic phase is dried over sodium sulphate, evaporated, the residue is purified by column chromatography (n-hexane—ethyl acetate—chloroform 2:1:1) and crystallised from n-hexane, to obtain 2.9 g (40%) of product: Mp.: 100-102° C. 1H-NMR (DMSO-d6): 1.37 (s, 9H), 1.48 (s, 2H), 1.77 (q, 4H), 2.05 (t, 4H), 2.17 (d, 2H), 3.10 (s, 3H), 6.66 (s, 1H).
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]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][S:41](=[O:45])(=[O:44])[CH2:40][CH2:39]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[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]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36][N:38]5[CH2:43][CH2:42][S:41](=[O:45])(=[O:44])[CH2:40][CH2:39]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCCl
Reactant: O=S1(=O)CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCN1CCS(=O)(=O)CC1
Temperature: 60 °C
Yield: 31.2 %

Procedure:
To a solution of 1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-urea (described in Example 27B, 235 mg, 0.446 mmol) in DMF (3 mL) was added thiomorpholine 1,1-dioxide (181 mg, 1.338 mmol) followed by diisopropyl ethylamine (0.233 mL, 1.338 mmol) and tetrabutyl ammonium iodide (164 mg, 0.446 mmol). The reaction mixture was heated at 60° C. for 4 days. Formation of the product was determined by LCMS. The crude reaction mixture was purified by preparative HPLC (phenylhexyl reverse phase column eluted with gradient of solvent A=0.05% HOAc/H2O and solvent B=0.05% HOAc/CH3CN) to afford 1-(5-tert-butyl-isoxazol-3-yl)-3-(3-{7-[3-(1,1-dioxo-thiomorpholin-4-yl)-propoxy]-6-methoxy-quinazolin-4-yloxy}-phenyl)-urea as a white solid (87 mg, 31%). 1H NMR (300 MHz, DMSO-d6) δ 9.80-9.35 (brs, 2H), 8.52 (s, 1H), 7.55 (d, 2H), 7.35 (m, 3H), 7.25 (d, 1H), 6.92 (d, 1H), 6.45 (s, 1H), 4.25 (m, 2H), 3.95 (s, 3H), 3.10 (s, 4H), 2.80 (s, 4H), 2.60 (s, 2H), 1.95 (s, 1H), 1.20 (s, 9H); LC-MS (ESI) m/z 625 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:9][CH3:10])[CH2:5][C:6]([OH:8])=O)[CH3:3].C(N1C=CN=C1)(N1C=CN=C1)=O.CN(C=O)C.[N+:28]([C:31]1[C:40]2[N:41]=[CH:42][CH:43]=[CH:44][C:39]=2[C:38]2[C:33](=[N:34][C:35](=[O:46])[C:36](=[O:45])[N:37]=2)[CH:32]=1)([O-:30])=[O:29]>C1COCC1.C(N(CC)CC)C>[CH2:9]([N:4]([CH2:5][C:6]([N:41]1[CH2:42][CH2:43][C:44]2[C:31]([N+:28]([O-:30])=[O:29])=[CH:32][C:33]3[NH:34][C:35](=[O:46])[C:36](=[O:45])[NH:37][C:38]=3[C:39]=2[CH2:40]1)=[O:8])[CH2:2][CH3:3])[CH3:10]
Reactant: CCN(CC)CC(=O)O
Reactant: O=C1N=c2cc([N+](=O)[O-])c3ncccc3c2=NC1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCN(CC)CC(=O)N1CCc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1
Temperature: 80 °C
Yield: 72.9 %

Procedure:
A mixture of N,N-diethylglycine hydrochloride (96 mg, 0.57 mmol) and carbonyldiimidazole (92 mg, 0.57 mmol) in THF (5 mL) were refluxed under a nitrogen atmosphere for 15 min. With the bath temperature at 70° C., DMF (7 mL) and 6-nitro-pyridoquinoxalinedione (0.1 g, 0.38 mmol) were added, and finally triethylamine (265 μL) was added and the reaction heated for 14 h at 80° C. The solvent was removed and the residue triturated with water, collected by filtration and washed with diethyl ether. An orange brown solid (104 mg) was obtained in 73% yield, mp 285-290° C. (dec); m/e M+1 376, nmR, IR.
Reaction SMILES: [C:1]([C:4]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:5]=1[NH2:6])(=[O:3])[CH3:2].CN(C1C=CC=CN=1)C.[CH:24]1([C:27](Cl)=[O:28])[CH2:26][CH2:25]1.[OH-].[K+]>O1CCCC1.C(N(CC)CC)C>[CH:24]1([C:27]([NH:6][C:5]2[CH:7]=[C:8]([O:13][CH3:14])[C:9]([O:11][CH3:12])=[CH:10][C:4]=2[C:1](=[O:3])[CH3:2])=[O:28])[CH2:26][CH2:25]1
Reactant: COc1cc(N)c(C(C)=O)cc1OC
Reactant: O=C(Cl)C1CC1
Agent: CN(C)c1ccccn1
Agent: [K+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(NC(=O)C2CC2)c(C(C)=O)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
2-Acetyl-4,5-dimethoxyaniline (2.0 g) was dissolved in tetrahydrofuran (50 ml), and to the mixture were added triethylamine (2.2 g) and dimethylaminopyridine (400 mg), and then a solution of cyclopropylcarbonyl chloride (1.7 g) in tetrahydrofuran (5 ml). The mixture was stirred at room temperature for 3 hours. After the addition of a 10% aqueous solution of potassium hydroxide, the mixture was stirred and extraction was conducted with chloroform. The extract was washed with saturated saline and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (Wako Gel C-200, 50 g). Elution with a mixed solvent of n-hexane (60 parts) and ethyl acetate (40 parts) gave N-cyclopropylcarbonyl-2-acetyl-4,5-dimethoxyaniline (2.5 g). This amide product (1.0 g) was suspended in t-butanol (50 ml), and potassium t-butoxide (2.1 g) was added to the suspension, and the mixture was heated under reflux for 15 hours. After the mixture was left to cool, extraction was conducted with a mixed solvent of chloroform (90 parts) and methanol (10 parts). The extract was washed with saturated saline and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (Wako Gel C-200, 30 g). Elution with a mixed solvent of chloroform (97 parts) and methanol (3 parts) gave 2-cyclopropyl-6,7dimethoxy-4(1H)-quinolone (compound 95, 580 mg).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[C:10]([C:12]3[NH:16][N:15]=[N:14][N:13]=3)[CH:9]=[CH:8][N:7]=2)=[N:4][N:3]=[N:2]1.C(N([CH2:22][CH3:23])CC)C.Br[CH2:25][C:26]1[O:30][C:29](=[O:31])[O:28][C:27]=1[CH3:32]>CN(C=O)C>[CH3:25][C:26]1[O:30][C:29](=[O:31])[O:28][C:27]=1[CH2:32][N:2]1[N:3]=[N:4][C:5]([C:6]2[CH:11]=[C:10]([C:12]3[N:16]=[N:15][N:14]([CH2:26][C:27]4[O:28][C:29](=[O:30])[O:31][C:22]=4[CH3:23])[N:13]=3)[CH:9]=[CH:8][N:7]=2)=[N:1]1
Reactant: c1cc(-c2nnn[nH]2)cc(-c2nnn[nH]2)n1
Reactant: Cc1oc(=O)oc1CBr
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1oc(=O)oc1Cn1nnc(-c2ccnc(-c3nnn(Cc4oc(=O)oc4C)n3)c2)n1

Procedure:
A solution of 1.0 g of 2,4-bis(5-tetrazolyl)pyridine, 1.8 ml of triethylamine and 1.83 g of 5-bromomethyl-4-methyl-1,3-dioxol-2-one in 10 ml of abs. DMF was stirred at room temperature for 5 h and then evaporated in vacuo. The residue was purified on a silica gel column (160 g) with n-heptane/ethyl.acetate, gradient 1:1 to 1:3, as eluent. 0.24 g of 11 was obtained, colorless crystals, melting point 150°-152° C. (pentane/CH2Cl2).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:6])[CH2:4][OH:5].[CH3:7][C:8]1[CH:9]=[C:10]([C:25]2[S:29][C:28]([C:30](O)=[O:31])=[N:27][CH:26]=2)[CH:11]=[C:12]([NH:14][C:15]2[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][N:16]=2)[CH:13]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C)C=O.O>[OH:6][C@@H:3]([CH2:4][OH:5])[CH2:2][NH:1][C:30]([C:28]1[S:29][C:25]([C:10]2[CH:11]=[C:12]([NH:14][C:15]3[N:20]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:18]=[CH:17][N:16]=3)[CH:13]=[C:8]([CH3:7])[CH:9]=2)=[CH:26][N:27]=1)=[O:31]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(=O)O)s2)c1
Reactant: NC[C@@H](O)CO
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(=O)NC[C@@H](O)CO)s2)c1
Reaction time: 0.75 h
Yield: 81.7 %

Procedure:
To a solution of (2R)-3-aminopropane-1,2-diol (132 mg, 1.446 mmol), 5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazole-2-carboxylic acid (500 mg, 1.315 mmol), and triethylamine (0.403 mL, 2.89 mmol) in N,N-dimethylformamide (8 mL) was added benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (821 mg, 1.578 mmol). After 45 minutes, water (32 mL) was added to the reaction mixture and the resulting yellow solid was collected by filtration; the solid was then purified by trituration using a mixture of methanol (2 mL), ethyl acetate (3 mL), and dichloromethane (3 mL) followed by filtration and drying in vacuo. The mother liqour from the trituration was concentrated and additional product was purified via column chromatography on silica (Biotage 50 g SNAP column, 97.5:2.5 to 85:15 dichloromethane:methanol). The combined material afforded in N-[(2R)-2,3-dihydroxypropyl]-5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazole-2-carboxamide (487 mg 82% yield) as a yellow solid. MS ESI: [M+H]+ m/z 454.0. 1H NMR (500 MHz, d6-DMSO): δ 10.31 (s, 1H); 8.85 (d, J=4.9 Hz, 1H); 8.53 (t, J=5.9 Hz, 1H); 8.29 (s, 1H); 8.11 (s, 1H); 7.51 (s, 1H); 7.31 (s, 1H); 7.30 (d, J=4.9 Hz, 1H); 4.90 (d, J=5.1 Hz, 1H); 4.64 (t, J=5.7 Hz, 1H); 3.63 (m, 1H); 3.42 (m, 1H); 3.35 (m, 2H); 3.23 (m, 1H); 2.34 (s, 3H). rhSYK activity=+++
Reaction SMILES: N[CH2:2][CH2:3][NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([NH:14][C@H:15]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:18]=3[O:17][B:16]2[OH:28])=[O:13])[CH2:7][CH2:6]1.[Si:29]([O:36]CC=O)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>>[Si:29]([O:36][CH2:2][CH2:3][NH:4][C@H:5]1[CH2:6][CH2:7][C@H:8]([CH2:11][C:12]([NH:14][C@H:15]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:18]=3[O:17][B:16]2[OH:28])=[O:13])[CH2:9][CH2:10]1)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: NCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Product: CC(C)(C)[Si](C)(C)OCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1

Procedure:
Prepared from (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid (Example 15) and 2-(tert-butyldimethylsilyloxy)acetaldehyde following procedure described in Step 1 of Example 15. ESI-MS m/z 505 (MH)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([CH2:10][C:11]([OH:13])=O)=[CH:7][CH:8]=[CH:9][C:2]1=2.C(C1NC=CN=1)(C1NC=CN=1)=O.[CH3:26][NH:27][C@@H:28]1[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]1[N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>O1CCCC1>[CH3:26][N:27]([C@@H:28]1[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]1[N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[C:11](=[O:13])[CH2:10][C:6]1[C:3]2[CH:4]=[CH:5][S:1][C:2]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CN[C@@H]1CCCC[C@H]1N1CCCCC1
Reactant: O=C(O)Cc1cccc2sccc12
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: CN(C(=O)Cc1cccc2sccc12)[C@@H]1CCCC[C@H]1N1CCCCC1
Yield: 71.6 %

Procedure:
A stirred solution of benzo[b]thiophene-4-acetic acid (0.50 g, 2.6 mmol) and carbonyl di-imidazole (0.46 g, 2.8 mmol) in tetrahydrofuran (5 ml) was heated with a solution of trans-(±)-N-methyl-2-(1-piperidinyl)cyclohexanamine (0.46 g, 2.3 mmol) in tetrahydrofuran (2 ml). This mixture was heated to reflux for five minutes, concentrated in vacuo, poured into saturated aqueous sodium bicarbonate (30 ml) and extracted with dichloromethane (2×20 ml) to give an oil which on trituration with diethyl ether gave trans-(±)-N-methyl-N-[2-(1-piperidinyl)cyclohexyl]benzo[b]thiophene-4-acetamide as a crystalline solid (610 mg, 72%); VmaxC=0 (liquid film) 1635 cm-1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12](=O)([O-])[O-].[K+].[K+].CI>>[CH3:12][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Cc1ccc(O)cc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: COc1ccc(C)c([N+](=O)[O-])c1
Yield: 97.5 %

Procedure:
In the manner of Example 8, Step C, the reaction of 25.0 g (0.162 mole) of 4-methyl-3-nitrophenol, 23.3 g (0.168 mole) of potassium carbonate, and 34.1 9 (0.24 mole) of methyl iodide produced 26.4 g of 1-methoxy-4-methyl-3-nitrobenzene as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([NH:16][CH2:17][CH3:18])=[N:7][C:8]3[C:9](I)=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1.[C:21]([NH2:25])(=[O:24])[C:22]#[CH:23].C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl.[Cu]I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([NH:16][CH2:17][CH3:18])=[N:7][C:8]3[C:9]([C:23]#[C:22][C:21]([NH2:25])=[O:24])=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1
Reactant: C#CC(N)=O
Reactant: CCNc1nc2c(I)c[nH]c(=O)c2c2cc(Br)ccc12
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCNc1nc2c(C#CC(N)=O)c[nH]c(=O)c2c2cc(Br)ccc12
Reaction time: 8 h

Procedure:
To a solution of 9-bromo-6-(ethylamino)-4-iodobenzo[c]-1,6-naphthyridin-1(2H)-one (2.5 g, 5.63 mmol) in DMF at room temperature (49.3 ml) was added propiolamide (583 mg, 8.44 mmol), Copper (I) Iodide (161 mg, 0.844 mmol), triethylamine (1.569 ml, 11.26 mmol), and tetrakis(triphenylphosphine) palladium (651 mg, 0.563 mmol). The flask was put under a blanket of argon, sealed and allowed to stir overnight. The next day the reaction was diluted with 100 ml of DCM, which caused the product to precipitate out of solution. The precipitate was collected by filtration, washed with 50 ml of DCM and dried in vacuo to give the product, 3-[9-bromo-6-(ethylamino)-1-oxo-1,2-dihydrobenzo[c]-1,6-naphthyridin-4-yl]prop-2-ynamide. 1H NMR (600 MHz, DMSO-D6) δ 11.76 (br s, 1H), 10.00 (s, 1H), 8.40 (t, 1H), 8.27 (d, 1H), 7.79-7.76, (m, 3H), 7.47 (s, 1H), 3.66 (m, 2H), 1.25 (t, 3H). LRMS (ESI) calc'd for (C17H13BrN4O2) [M+H]+, 385.0; found 385.0.