Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][N:20]3[C:29](=[O:30])[CH2:28][C:23]4([CH2:27][CH2:26][CH2:25][CH2:24]4)[CH:22]([OH:31])[C:21]3=[O:32])[CH2:12][CH2:11]2)=[N:2]1>C(#N)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([CH:22]3[O:31][C:29](=[O:30])[CH2:28][C:23]43[CH2:27][CH2:26][CH2:25][CH2:24]4)=[O:32])[CH2:12][CH2:11]2)=[N:2]1
Reactant: O=C1CC2(CCCC2)C(O)C(=O)N1CCCCN1CCN(c2nsc3ccccc23)CC1
Solvent: CC#N
Product: O=C1CC2(CCCC2)C(C(=O)NCCCCN2CCN(c3nsc4ccccc34)CC2)O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.7 %

Procedure:
A mixture of 8-[4-[4-(1,2-benzisothiazol-3 yl)-1piperazinyl]butyl]-6-hydroxy-8-azaspiro[4.5]decane-7,9dione (1.14 g, 2.5 mmol) and KF-Al2O3 (0.36 g, ~1 equiv) in acetonitrile (25 mL) was vigorously stirred at room temperature under Ar for 4 h. The supernatant was then decanted and replaced with fresh acetonitrile (25 mL), and stirring was continued for 4 h. This process was repeated until the residue contained no more starting material (5× in total). The combined supernatants were evaporated and the resulting gum was purified by flash chromatography (EtOAc, then EtOAc acetone (1:1) to give the title compound (0.75 g, 66%) as an off-white foam. A 650 mg sample of the title compound was dissolved in excess ethanolic HCl and the solution was evaporated to dryness. The residue was taken up in acetone, ether was added and the resulting solid was collected and dried in vacuo to give 620 mg of a cream-colored powder, m.p. 194-197° C. An analytical sample was prepared by trituration with acetone to give the hydrochloride as a white powder; IR (CH2Cl2) 3430, 1785, 1680 cm-1 ; 1H NMR (CDCl3) δ 7.86-7.80 (m, 2H), 7.54-7.36 (m, 2H), 7.29 (b s, 1H), 4.77 (s, 1H), 4.12-4.08 (m, 4H), 3.56-3.50 (m, 2H), 3.47-3.33 (m, 2H), 3.14-3.04 (m, 4H), 2.62, 2.37 (q, J=17.1 Hz, 2H), 2.1-1.4 (b m, 13H); Anal. calcd for C24H32N4O3S/1.4 HCl:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:19]=[CH:18][C:13]([C:14](OC)=[O:15])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:3][CH2:2]1.[NH2:20][NH2:21]>CO>[O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([NH:20][NH2:21])=[O:15])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(S(=O)(=O)N2CCOCC2)cc1
Reactant: NN
Solvent: CO
Product: NNC(=O)c1ccc(S(=O)(=O)N2CCOCC2)cc1
Temperature: 65 °C
Yield: 74 %

Procedure:
Methyl 4-(morpholinosulfonyl)benzoate (135 mg, 0.473 mmol) was added to the hydrazine (30.3 mg, 0.946 mmol) in methanol and refluxed for 8 h at 65° C. Following cooling, reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and then compound was purified by flash chromatography (3% methanol/DCM) to yield the 4-(morpholinosulfonyl)benzohydrazide (102 mg, 0.350 mmol, 74.0% yield) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 7.94 (m, 2H), 7.79 (m, 2H), 3.72 (m, 4H), 2.99 (m, 4H). Mass [M+H]+: 286.0
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:4]=2[N:3]=1.[CH3:20][NH:21][CH3:22]>CO>[Cl:1][C:2]1[N:11]=[C:10]([N:21]([CH3:22])[CH3:20])[C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:4]=2[N:3]=1
Reactant: CNC
Reactant: Fc1ccc(C2CCCc3c(Cl)nc(Cl)nc32)cc1
Solvent: CO
Product: CN(C)c1nc(Cl)nc2c1CCCC2c1ccc(F)cc1
Yield: 99.7 %

Procedure:
A solution of 2,4-dichloro-8-(4-fluorophenyl)-5,6,7,8-tetrahydroquinazoline (115 mg, 0.387 mmol) and excess dimethylamine (1.935 mL, 3.87 mmol) in MeOH (1 mL) was stirred at room temperature for 1 h. The solvent was removed in vacuum to afford 2-chloro-8-(4-fluorophenyl)-N,N-dimethyl-5,6,7,8-tetrahydroquinazolin-4-amine (118 mg, 0.386 mmol, 100% yield). LC-MS (M+H)+=306.2.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[OH:12])[CH3:2].[CH3:13]O>OS(O)(=O)=O>[CH3:13][O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([CH2:1][CH3:2])=[C:4]([OH:12])[CH:5]=1
Reactant: CO
Reactant: CCc1ccc(C(=O)O)cc1O
Agent: O=S(=O)(O)O
Product: CCc1ccc(C(=O)OC)cc1O

Procedure:
To a solution of 4-ethyl-3-hydroxy-benzoic acid (3.76 g, 22.6 mmol) in MeOH (70 mL), cc H2SO4 (0.7 mL) is added. The solution is refluxed overnight, then concentrated to about 30 mL and poured into water. The aqueous layer is extracted with ether (50 mL×4) and the combined organic extracts are neutralized with a saturated aqueous solution of NaHCO3 (50 mL×2), washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to give the title compound as a white powder. TLC, Rf (CH2Cl2/MeOH 95:5)=0.7, MS (LC-MS): 179.2 [M−H]−, tR (HPLC, Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/2.8 min, flow: 1 ml/min): 4.86 min.
Reaction SMILES: [C:1]([C:9]1[C:10]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[C:11]2[C:17]([CH3:18])=[N:16][N:15](CC3OC=CC=3)[C:12]2=[N:13][CH:14]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O>>[CH2:1]([C:9]1[C:10]([N:25]2[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]2)=[C:11]2[C:17]([CH3:18])=[N:16][NH:15][C:12]2=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nn(Cc2ccco2)c2ncc(C(=O)c3ccccc3)c(N3CCNCC3)c12
Agent: O=S(=O)(O)O
Product: Cc1n[nH]c2ncc(Cc3ccccc3)c(N3CCNCC3)c12

Procedure:
5-Benzoyl-1-(2-furanyl)methyl-3-methyl-4-piperazinyl-1H-pyrazolo[3,4-b]pyridine is treated with concentrated sulfuric acid according to the procedure of Example 4 to obtain 5-benzyl-3-methyl-4-(1-piperazinyl)-1H-pyrazolo[3,4-b]-pyridine.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[C:15]([OH:17])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]2[NH:27][S:26](=[O:29])(=[O:28])[CH2:25][C:24]=2[CH:30]=1>>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:18])[C:15]([NH:19][C:20]2[CH:21]=[CH:22][C:23]3[NH:27][S:26](=[O:29])(=[O:28])[CH2:25][C:24]=3[CH:30]=2)=[O:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc2c(c1)CS(=O)(=O)N2
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Product: O=C(Nc1ccc2c(c1)CS(=O)(=O)N2)C(=O)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from (4-benzyl-piperidin-1-yl)-oxo-acetic acid (Example 5b) and 5-amino-1,3-dihydro-2,1-benzisothiazole-2,2-dioxide [J. Het. Chem., 23, 1645. (1986)] according to the method described in Example 2. The filtered crystals are purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent. Melting Point: 181-182° C. (isopropanol)
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:26]#[C:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:8][C:9]=1[N:10]1[CH:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][CH2:13][C@H:12]([N:22]=[N+]=[N-])[C:11]1=[O:25])=[O:4].Cl[Sn]Cl.O[Li].O>CO>[NH2:22][C@H:12]1[CH2:13][CH2:14][CH:15]([CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[N:10]([C:9]2[CH:8]=[C:7]([C:26]#[C:27][C:28]([CH3:30])([CH3:31])[CH3:29])[S:6][C:5]=2[C:3]([OH:4])=[O:2])[C:11]1=[O:25]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)[C@@H](N=[N+]=[N-])CCC1C1CCCCC1
Agent: Cl[Sn]Cl
Agent: [Li]O
Solvent: O
Solvent: CO
Product: CC(C)(C)C#Cc1cc(N2C(=O)[C@@H](N)CCC2C2CCCCC2)c(C(=O)O)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 33.1 %

Procedure:
To the solution of 3-((S)-3-azido-6-cyclohexyl-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (40 mg, 0.09 mmol, 1 equiv) in MeOH (0.5 mL) was added SnCl2 (17 mg, 0.09 mmol, 1 equiv) and the resulting solution was stirred at room temperature for 18 hours. The solvent was then removed under vacuum. The residue was dissolved in THF/H2O/MeOH (0.5 mL/0.5 mL/1.0 mL) and to the solution was added LiOH.H2O (21 mg, 0.48 mmol, 5 equiv). The reaction mixture was stirred at 50° C. for 20 minutes. The organic solvents were removed under vacuum and the residue was acidified to pH=5 by addition of 3.0 N HCl aq. solution. The mixture was extracted with EtOAc. The organic layer was dried over Na2SO4, and concentrated under vacuum. The residue was purified by prep-HPLC (XBridge Prep C 18 5 um, 30×50 mm) in basic condition (0.1% NH4OH, 10%˜45% CH3CN/H2O, 10 min run, 40 ml/min) to give product 12 mg. MS: 403 [M+H+]. 1H-NMR (400 MHZ, CD3OD): δ 6.81 (s, 1H), 3.96 (br, 1H), 3.48 (m, 1H), 2.06 (m, 3H), 1.84 (m, 3H), 1.70 (br, 2H), 1.46 (m, 1H), 1.37 (m, 1H), 1.31 (s, 9H), 1.16 (m, 5H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][OH:12])[C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[C:13](=O)(OCC)[O:14]CC.C([O-])([O-])=O.[K+].[K+]>>[OH:12][CH2:11][C@H:2]1[C@H:3]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:4][C:13](=[O:14])[NH:1]1
Reactant: N[C@@H](CO)[C@@H](O)c1ccccc1
Reactant: CCOC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1N[C@@H](CO)[C@H](c2ccccc2)O1
Temperature: 135 °C
Reaction time: 3 h
Yield: 32.4 %

Procedure:
(1S,2S)-2-Amino-1-phenylpropane-1,3-diol (20.0 g, 120 mmol), diethyl carbonate (29.7 mL, 245 mmol), and K2CO3 (1.65 g, 12.0 mmol) were charged into a flask with mechanical stirrer and a vigreux-column. This suspension was heated in an oil bath at 135° C., to give a yellow solution. The accrued EtOH was distilled off over the vigreux column. The reaction was stirred over a period of 3 h, until no more EtOH could be distilled off. The reaction mixture was then cooled to 50° C., diluted with EtOAc and aqueous NaHCO3. The organic layers were separated, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (550 g SiO2) using EtOAc in heptane from 33% to 100% in order to give the title compound as a beige oil (7.50 g, 33%). 1H NMR (400 MHz, DMSO-d5): 7.87 (br s, 1H), 7.50-7.30 (m, 5H), 5.37 (d, 1H), 5.23-5.17 (m, 1H), 3.70-3.60 (m, 1H), 3.60-3.50 (m, 2H).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Si:23]([O:30][C@@H:31]1[CH2:36][CH2:35][C@H:34]([CH:37]([OH:48])[C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39])[CH2:33][CH2:32]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>ClCCl>[Si:23]([O:30][C@@H:31]1[CH2:32][CH2:33][C@H:34]([C:37](=[O:48])[C:38]([O:40][CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[O:39])[CH2:35][CH2:36]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](C(O)C(=O)OCc2ccccc2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](C(=O)C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 69.5 %

Procedure:
A Dess-Martin reagent (1.2 g, 2.76 mmol) was added to a solution of benzyl 2-(cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)-2-hydroxyacetate (650 mg, 1.72 mmol) in dichloromethane (10 ml) at room temperature, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was quenched with 10% sodium thiosulfate and was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, was washed with saturated brine, and was dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The residue was chromatographed on silica gel column (hexane:ethyl acetate=95:5) to give the title compound as a yellow oil (450 mg, yield 69%).
Reaction SMILES: [N:1]1([CH2:7][C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[NH:14][C:13](=S)[C:12]3[CH:22]=[CH:23][CH:24]=[N:25][C:11]2=3)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:26](OCC)(=[O:29])[NH:27][NH2:28]>>[N:1]1([CH2:7][C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]3[C:26](=[O:29])[NH:27][N:28]=[C:13]3[C:12]3[CH:22]=[CH:23][CH:24]=[N:25][C:11]2=3)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CN1CCCCC1)N1c2ccccc2NC(=S)c2cccnc21
Reactant: CCOC(=O)NN
Product: O=C(CN1CCCCC1)N1c2ccccc2-n2c(n[nH]c2=O)-c2cccnc21

Procedure:
In the manner given in Example 13, 6,11-dihydro-11-(piperidinoacetyl)-5H-pyrido[2,3-b][1,5]benzodiazepin-5-thione is heated to about 200° C. with ethyl carbazate to give 2,9-dihydro-9-(piperidinoacetyl)-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]benzodiazepin-3-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[CH:35][C:6]([C:7]([N:9]([CH2:11][C:12]2[NH:13][C:14]3[C:19]([C:20]=2[C:21]2[C:31]#[C:30][C:24]4[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:23]=4[CH:22]=2)=[CH:18][CH:17]=[C:16]([C:32]([OH:34])=[O:33])[CH:15]=3)[CH3:10])=[O:8])=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]>CN(C)C=O>[CH2:44]([O:43][C:41]([CH2:40][N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[C:16]([C:32]([OH:34])=[O:33])[CH:15]=2)[C:20]([C:21]2[C:31]#[C:30][C:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:23]=3[CH:22]=2)=[C:12]1[CH2:11][N:9]([C:7](=[O:8])[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:36][CH:35]=1)[CH3:10])=[O:42])[CH3:45]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(C(=O)N(C)Cc2[nH]c3cc(C(=O)O)ccc3c2-c2c#cc3c(c2)CCCCC3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(CN(C)C(=O)c2ccc(OC)cc2)c(-c2c#cc3c(c2)CCCCC3)c2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2-{[(4-methoxy-benzoyl)-methyl-amino]-methyl}-3-(benzocyclohept-1-enyl)-1H-indole-6-carboxylic acid on Wang resin (100 mg; prepared according to the procedure outlined in Example 10) in dimethylformamide (1.5 mL) was added sodium hydride (60% in mineral oil; 20 mg) and the mixture was stirred at room temperature for 30 min. Ethyl bromoacetate (0.1 mL) was added and the mixture was stirred for 3 h. The mixture was filtered, washed with water (1×1.5 mL), tetrahydrofuran (2×1.5 mL), dichloromethane (2×1.5 mL), and dried. The product was cleaved from the resin by treatment with 1:1 trifluoroacetic acid/dichloromethane for 1 h; 1H NMR (DMSO-d6) δ 1.15 (t, 3 H), 2.10 (m, 2 H), 2.20 (m, 2 H), 2.70 (s, 3 H), 2.80 (m, 2 H), 3.80 (s, 3 H), 4.05 (q, 2 H), 4.80 (s, 2 H), 5.20 (br s, 2 H), 6.35 (t, 1 H), 6.80 (d, 1 H), 6.97 (d, 2 H), 7.08 (m, 2 H), 7.20 (m, 1 H), 7.38 (d, 2 H), 7.55 (d, 1 H), 7.80 (d, 1 H), 7.95 (s, 1 H), 11.40 (br s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][O:15][CH2:16][C:17]3[CH:18]=[C:19]([C:26]([F:29])([F:28])[F:27])[CH:20]=[C:21]4[C:25]=3[NH:24][N:23]=[CH:22]4)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:30]([BH3-])#N.[Na+].C=O.C(O)(=O)C>C(#N)C.C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][O:15][CH2:16][C:17]3[CH:18]=[C:19]([C:26]([F:27])([F:28])[F:29])[CH:20]=[C:21]4[C:25]=3[NH:24][N:23]=[CH:22]4)[CH2:13][CH2:12][N:11]([CH3:30])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: Fc1ccc(C2(COCc3cc(C(F)(F)F)cc4cn[nH]c34)CCNCC2)cc1
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CN1CCC(COCc2cc(C(F)(F)F)cc3cn[nH]c23)(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 7-(((4-(4-fluorophenyl)piperidin-4-yl)methoxy)methyl)-5-(trifluoromethyl)-1H-indazole (50 mg, 0.123 mmol) and sodium cyanoborohydride (7.7 mg, 0.123 mmol) in acetonitrile (1 mL) at room temperature was added formalin (25 μL). To this was added 1 drop of acetic acid. After 5 min, a second drop of acetic acid was added and the reaction stirred at room temperature for 15 min. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was washed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated. The product was purified by preparative HPLC. The trifluoroacetic acid salt was loaded onto a strong cation exchange cartridge in methanol. The cartridge was washed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 28 mg (54%). 1H-NMR (CDCl3, 500 MHz) δ 9.81 (bs, 1H), 8.06 (s, 1H), 7.94 (s, 1H), 7.33 (m, 2H), 7.26 (s, 1H), 7.12 (m, 2H), 4.73 (s, 2H), 3.54 (s, 2H), 2.55 (m, 2H), 2.22 (m, 7H), 1.96 (m, 2H); 13C-NMR (CDCl3, 126 MHz) δ 162.6, 160.6, 139.6, 135.4, 128.7, 128.6, 124.7 (q, J=272 Hz), 123.3 (q, J=32 Hz), 122.9, 121.8, 120.3 (q, J=2.9 Hz), 118.4 (q, J=4.8 Hz), 115.8, 115.6, 80.4, 71.9, 51.8, 46.3, 40.3, 32.9. Mass spec.: 422.13 (MH)+. Accurate mass spec.: m/z 422.1836 [MH]+, Δ=4.6 ppm.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:30]=[CH:29][C:9]([C:10]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21][C:19]3=[O:20])[CH2:14][CH2:13]2)=[O:11])=[CH:8][CH:7]=1.[CH3:31][N:32]=[C:33]=[O:34]>CC(C)=O>[CH3:31][NH:32][C:33](=[O:34])[NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([N:12]2[CH2:13][CH2:14][CH:15]([N:18]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21][C:19]3=[O:20])[CH2:16][CH2:17]2)=[O:11])=[CH:29][CH:30]=1
Reactant: NCCCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Reactant: CN=C=O
Solvent: CC(C)=O
Product: CNC(=O)NCCCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1

Procedure:
1-{1-[4-(3-Aminopropoxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (0.5 g), methylisocyanate (0.15 ml) and acetone (10 ml) are heated at 100° C. for 18 hours in an autoclave. Acetone is distilled off and the residue is purified by silica gel column chromatography (solvent: methylene chloride:methanol=100-50:1) to give 1-{1-[4-(3-(3-methylureido)propoxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (0.19 g).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]2[CH:20]=[C:21]([C:26]3[S:30][C:29]([C:31]4([OH:39])[CH2:36][O:35]C(C)(C)[O:33][CH2:32]4)=[N:28][CH:27]=3)[CH:22]=[C:23]([CH3:25])[CH:24]=2)[N:13]=1)(C(C)(C)C)(C)C.Cl>O1CCCC1.CO>[OH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]2[CH:20]=[C:21]([C:26]3[S:30][C:29]([C:31]([OH:39])([CH2:36][OH:35])[CH2:32][OH:33])=[N:28][CH:27]=3)[CH:22]=[C:23]([CH3:25])[CH:24]=2)[N:13]=1
Reactant: Cc1cc(Nc2nccc(OCCO[Si](C)(C)C(C)(C)C)n2)cc(-c2cnc(C3(O)COC(C)(C)OC3)s2)c1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(OCCO)n2)cc(-c2cnc(C(O)(CO)CO)s2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 56.3 %

Procedure:
To a solution of 5-[5-(3-{[4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)pyrimidin-2-yl]amino}-5-methylphenyl)-1,3-thiazol-2-yl]-2,2-dimethyl-1,3-dioxan-5-ol (185 mg, 0.32 mmol) in tetrahydrofuran (1.6 mL) was added hydrochloric acid (1.0 N, 970 μL, 0.97 mmol) at room temperature. The mixture was stirred at room temperature for 2.5 h, then diluted with methanol, filtered, and purified by reverse phase HPLC (10:90 to 90:10 acetonitrile:water with a 0.1% trifluoroacetic acid modifier). The combined fractions were dried on a lyophilizer, dissolved in methanol, and the TEA salt converted to the free base using StratoSpheres SPE PL-HCO3 MP-Resin (0.9 mmol) cartridges to give 2-[5-(3-{[4-(2-hydroxyethoxy)pyrimidin-2-yl]amino}-5-methylphenyl)-1,3-thiazol-2-yl]propane-1,2,3-triol (75 mg, 0.18 mmol, 56% yield) as a white foam. MS ESI: [M+H]+ m/z 419.1. 1H NMR (500 MHz, DMSO-d6) δ 9.65 (dd, J=4.3, 15.1, 1H), 8.21 (d, J=5.7, 1H), 7.96 (s, 1H), 7.90 (s, 1H), 7.47 (s, 1H), 7.09 (s, 1H), 6.31 (s, 1H), 4.39 (s, 2H), 3.79-3.72 (m, 2H), 3.72-3.63 (m, 4H), 2.30 (s, 3H). rhSYK activity=+++
Reaction SMILES: [CH2:1]([S:5](Cl)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].Cl.[N:10]1[C:19]2[CH2:18][CH2:17][NH:16][CH2:15][C:14]=2[CH:13]=[CH:12][C:11]=1[C:20]([O:22][CH3:23])=[O:21]>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH2:1]([S:5]([N:16]1[CH2:17][CH2:18][C:19]2[N:10]=[C:11]([C:20]([O:22][CH3:23])=[O:21])[CH:12]=[CH:13][C:14]=2[CH2:15]1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS(=O)(=O)Cl
Reactant: COC(=O)c1ccc2c(n1)CCNC2
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCCCS(=O)(=O)N1CCc2nc(C(=O)OC)ccc2C1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a microwave vial containing n-butanesulfonyl chloride (0.0352 g, 0.225 mmol), was added methyl 5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylate hydrochloride (0.0288 g, 0.15 mmol), TEA (0.167 mL, 1.2 mmol), DMAP (1.83 mg, 0.015 mmol), and DMF (2 mL). The mixture was shaken at rt for 13 h. The solvent was then completely evaporated to yield a solid. LC-MS: (FA) ES+ 313.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH2:10])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:11][C:12](=[CH:16][CH3:17])[C:13]([OH:15])=[O:14].C1(O)C=CC(O)=CC=1>C1(C)C=CC=CC=1>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][CH:16]([CH3:17])[CH:12]([CH3:11])[C:13]([OH:15])=[O:14])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Nc1ccc2ncsc2c1
Reactant: CC=C(C)C(=O)O
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: CC(Nc1ccc2ncsc2c1)C(C)C(=O)O
Yield: 6 %

Procedure:
Benzothiazol-6-ylamine (1 g, 6.667 mmol) was reacted with 2-methyl-but-2-enoic acid (1 g, 9.99 mmol), benzene-1,4-diol (51.38 mg, 0.467 mmol) and toluene (6 mL) to afford the crude product. Purification by column chromatography on silica gel (50% ethyl acetate in hexane) afforded 100 mg of the product (6.02% yield).
Reaction SMILES: C[CH:2]([CH:6]1[C:10]2=[C:11]([S:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[C:12]3[C:13](Br)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4].C([Sn](CCCC)(CCCC)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)CCC>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([S:20][C:11]2[C:12]3[C:13]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]3[CH2:8][CH2:7][CH:6]([CH2:2][C:3]([OH:5])=[O:4])[C:10]=23)=[CH:22][CH:23]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: CC(C(=O)[O-])C1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Product: O=C(O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(-c3ccccc3)cc(F)cc12

Procedure:
Starting from (+/−)-methyl{8-bromo-9-[(4-chlorophenyl)thio]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetate (200 mg, 0.43 mmol) and tributyl(phenyl)stannane the title compound was synthesized following the procedures described in Example 42 and Step 10 of Example 7.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[Cl:11][C:12]1[CH:19]=[C:16]([CH:17]=O)[C:15]([OH:20])=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[O:20][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[NH:8][CH2:17][C:16]=2[CH:19]=1
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: O=Cc1cc(Cl)ccc1O
Product: Clc1ccc2c(c1)CNc1ccccc1O2

Procedure:
2-chloro-10,11-dihydrodibenz[b,f][1,4]-oxazepine (42) is prepared in the manner described in Example 40, using 2-chloronitrobenzene and 5-chlorosalicylaldehyde.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:21]([O:23]CC)=[O:22])[C:6](=[O:20])[N:7]2[C:12]=1[CH:11]=[C:10]([N:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)[CH:9]=[CH:8]2)[CH3:2].[OH-].[Na+].[ClH:28]>C1COCC1>[ClH:28].[CH2:1]([C:3]1[CH:4]=[C:5]([C:21]([OH:23])=[O:22])[C:6](=[O:20])[N:7]2[C:12]=1[CH:11]=[C:10]([N:13]1[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]1)[CH:9]=[CH:8]2)[CH3:2]
Reactant: CCOC(=O)c1cc(CC)c2cc(N3CCN(C)CC3)ccn2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1cc(C(=O)O)c(=O)n2ccc(N3CCN(C)CC3)cc12
Temperature: 75 °C
Reaction time: 4.5 h
Yield: 68 %

Procedure:
To a solution of 171 mg (0.5 mmol) of ethyl 1-ethyl-8-(4-methylpiperazin-1-yl)-4H-quinolizin-4-one-3-carboxylate, from Step 1, in 4 mL of THF was added 4.0 mL of a 1.0N aqueous sodium hydroxide solution and the reaction mixture was heated, with stirring, at 75° C. for 4.5 hours. The reaction mixture was cooled to ambient temperature and adjusted to pH 2 with 5 mL of 1N aqueous hydrochloric acid solution. The aqueous solution was concentrated in vacuo to ~5 mL and the solid was collected by filtration and dried in vacuo to afford 120 mg (68% yield) of the title compound, m.p. 293°-294° C. (dec); MS DCI-NH3 : 316 (M-Cl)+ 90%, 272 ((M-Cl)-CO2H)+ base; IR (KBr): 3420 (OH), 1695 (C=O), 1640 (C=O) cm-1 ; 1H NMR (TFA) d 1.47 (t, 3H, J=7.5 Hz), 3.00 (q, 2H, J=7.5 Hz), 3.23 (s, 3H), 3.55 (dd, 2H, J=9 Hz), 4.12 (m, 4H), 4.65 (d, 2H, J=15 Hz), 7.40 (s, 1H), 7.67 (d, 1H, J=9 Hz), 8.18 (s, 1H), 9.20 (d, 1H, J=7.5 Hz). Analysis calculated for C17H22ClN3O3 : C, 56.59; H, 6.42; N, 11.64. Found: C, 56.86; H, 6.19; N, 11.60.