Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]([CH:9]([CH3:11])[CH3:10])[C:4]([O:6]CC)=O)#[N:2].[CH2:12]([NH:14][C:15]([NH2:17])=[O:16])[CH3:13].C[O-].[Na+].Cl>CO.O>[CH2:12]([N:14]1[C:1]([NH2:2])=[C:3]([CH:9]([CH3:10])[CH3:11])[C:4](=[O:6])[NH:17][C:15]1=[O:16])[CH3:13]
Reactant: CCNC(N)=O
Reactant: CCOC(=O)C(C#N)C(C)C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCn1c(N)c(C(C)C)c(=O)[nH]c1=O
Reaction time: 12.25 h
Yield: 70.8 %

Procedure:
A flask was charged with ethyl 2-cyano-3-methylbutanoate (3b, 20.72 g, 133.5 mmol), ethyl urea (3a, 12.35 g, 140.2 mmol) and MeOH (97.2 mL). To the slurry at room temperature was added sodium methoxide in methanol (25% w/w soln, 36.8 mL), mild exotherm detected. The heterogeneous reaction mixture was then heated to reflux. The reaction was refluxed for 4-12 h. Upon reaction completion, as determined by TLC analysis, the reaction mixture was concentrated and solvent exchanged to acetonitrile (ACN) through 3×50 mL co-evaporations leaving a basic 1-2 vol. solution in ACN. To the reaction mixture was added 1-2 vol. of water followed by a pH adjustment with 2N HCl (aq.). As the pH approached 10, white to off-with solids began forming and, as the pH was further reduced to 3 to 4, (by pH paper) white slurry resulted. This slurry was aged for 0.5 to 24 h and then filtered. The resulting solids were washed with 1 vol. of water and 2×2 vol. MTBE. The white to off-white solids were then dried in a vacuum oven at 40 to 50° C. giving 18.63 g (60%) of 1-ethyl-5-isopropyl-6-amino uracil 2 (HCl salt).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]2[CH:13]=[CH:14][C:15]([C:17](O)=O)=[CH:16][C:4]=2[N:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH2:27].N>>[N:20]1[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[NH:27][C:17]=1[C:15]1[CH:14]=[CH:13][C:5]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:2]([CH3:1])=[N:3][C:4]=2[CH:16]=1
Reactant: Cc1nc2cc(C(=O)O)ccc2n1-c1ccccc1
Reactant: Nc1ccccc1N
Agent: N
Product: Cc1nc2cc(-c3nc4ccccc4[nH]3)ccc2n1-c1ccccc1
Temperature: 120 °C
Reaction time: 20 h
Yield: 130.6 %

Procedure:
A 2-neck flask (20 mL) equipped with reflux condenser was charged with 2-methyl-1-phenylbenzimidazole-5-carboxylic acid (see Synthesis Example 1-3) (0.15 g, 0.59 mmol) and polyphosphoric acid (approx. 2 g), and this was heated to 120° C. To this was added 1,2-diaminobenzene (0.09 g, 0.83 mmol), and this was heated to 160° C. and stirred under those conditions for 20 hours. After being allowed to cool to room temperature, ice was added and concentrated aqueous ammonia (28%) was added to the liquid to give approx. pH 9. The precipitated crystals were filtered off, these were washed with distilled water (approx. 3 mL, 2 times), and then dried to yield the title compound (0.25 g, quant.) as greenish pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([F:28])[CH:19]=2)=[N:4][C:5]([C:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH:9]=2)=[CH:6][N:7]=1.[H][H]>CO.[Pd]>[NH2:1][C:2]1[C:3]([C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([F:28])[CH:19]=2)=[N:4][C:5]([CH:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[CH:6][N:7]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(-c2nc(C3=CCC4(CC3)OCCO4)cnc2N)cc1F
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(-c2nc(C3CCC4(CC3)OCCO4)cnc2N)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 4-(3-amino-6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyrazin-2-yl)-2-fluorobenzoate (6.1 g, 15.83 mmol) was dissolved in MeOH (150 mL) and EtOAc (80 mL) the reaction mixture was flushed with N2 for 15 min, Then Pd—C (DEGASSA) (6 g, 5.64 mmol) was added, the reaction mixture was then charged with hydrogen balloon and stirred at room temperature overnight. The reaction mixture was filtered through Celite, which was washed with EtOAc and methanol. The filtrate was concentrated to yield the crude product, which was used in the next step reaction without purification. LCMS (m/z): 388.0 (MH+), 0.79 min.
Reaction SMILES: Cl.N=CCO[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=O.[NH2:14][CH:15]([C:19]([NH2:21])=[O:20])[C:16]([NH2:18])=[O:17]>CO>[C:19]([C:15]1[N:14]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:18][C:16]=1[OH:17])(=[O:20])[NH2:21]
Reactant: NC(=O)C(N)C(N)=O
Reactant: CCOC(=O)CC(=O)OCC=N
Agent: Cl
Solvent: CO
Product: CCOC(=O)Cc1nc(C(N)=O)c(O)[nH]1
Reaction time: 1 h
Yield: 72.7 %

Procedure:
Ethyl iminoethoxycarbonylacetate hydrochloride (49.59 g) and aminomalonamide (24.7 g) were added to anhydrous methanol (500 ml) under ice-cooling while stirring. After stirring was continued for 1 hour, the mixture was refluxed for 41/2 hours and then cooled with ice. The precipitated crystals were collected, washed with ethanol and diisopropyl ether and dried under vacuum to give ethyl 4-carbamoyl-5-hydroxy-1H-imidazole-2-acetate (32.69 g, 72.7%). m.p. 241°-241.5° C. (decomposition)
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[N:22]=[C:23]([N:31]4[CH2:35][CH2:34][CH2:33][C@H:32]4[CH2:36][NH2:37])[C:24]4[S:29](=[O:30])[CH2:28][CH2:27][C:25]=4[N:26]=3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.[C:38]1([N:44]=[C:45]=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:16][CH2:17][N:18]([C:21]3[N:22]=[C:23]([N:31]4[CH2:35][CH2:34][CH2:33][C@H:32]4[CH2:36][NH:37][C:45]([NH:44][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[O:46])[C:24]4[S:29](=[O:30])[CH2:28][CH2:27][C:25]=4[N:26]=3)[CH2:19][CH2:20]2)=[CH:11][CH:10]=1
Reactant: O=C=Nc1ccccc1
Reactant: NC[C@@H]1CCCN1c1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1S(=O)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC[C@@H]1CCCN1c1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1S(=O)CC2)Nc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
100 mg C—((S)-1-{2-[4-(4-chloro-phenyl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-4-yl}-pyrrolidin-2-yl)-methylamine trifluoroacetate, Diastereomer 2 (Example 226) (see scheme 3, 3.17.2) are placed in 2 ml dichloromethane and 30 μl phenylisocyanate are added. The reaction mixture is stirred for 4 hours at ambient temperature and then evaporated to dryness. The product is purified by preparative HPLC (method A). 64 mg of the product are obtained as a powder. Analytical HPLC-MS (method D): RT=1.33 min.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:16]([F:19])([F:18])[F:17])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([OH:15])=O)[CH:7]=[CH:6]2)#[N:2].[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([NH:28][NH2:29])=O>>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[O:15][C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[CH:7]2)=[N:29][N:28]=1
Reactant: N#Cc1ccc2c(ccn2CC(=O)O)c1C(F)(F)F
Reactant: NNC(=O)c1ccccn1
Product: N#Cc1ccc2c(ccn2Cc2nnc(-c3ccccn3)o2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 35C from [5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]acetic acid and 2-pyridinecarbohydrazide: MS (ES) m/z 370 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24]C(OC(C)(C)C)=O)[CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O.ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(OC2CCN(C(=O)OCc3ccccc3)CC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cccc(OC2CCN(C(=O)OCc3ccccc3)CC2)c1
Temperature: 22 °C
Reaction time: 1 h

Procedure:
4-(3-tert-Butoxycarbonylamino-phenoxy)-piperidine-1-carboxylic acid benzyl ester (11.8 g, 27.6 mmol) is dissolved in a solution of trifluoroacetic acid in dichloromethane (25% v/v, 20 mL). The reaction mixture is stirred at 22° C. for 60 min. After removal of the solvent, the oily residue is dissolved in dichloromethane (250 mL) and neutralized with 0.2 N aqueous sodium hydroxide solution (250 mL) and extracted with dichloromethane (10×100 mL) followed by ethyl acetate (5×100 mL). The combined organic phases are dried over anhydrous sodium sulfate. After removal of solvent, the crude product is purified on silica gel chromatography with dichloromethane-methanol to give a light brown oil (4.84 g, 54%, ES+(m/z) 327.3 [M+H]).
Reaction SMILES: [CH2:1]([N:3]([CH2:12][CH3:13])[C:4](=[O:11])[C:5]1C=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:2].[S:14]1C=CC=C1CC(Cl)=O.C(NCC)C>>[CH2:1]([N:3]([CH2:12][CH3:13])[C:4](=[O:11])[CH2:5][C:6]1[S:14][CH:9]=[CH:8][CH:7]=1)[CH3:2]
Reactant: O=C(Cl)Cc1cccs1
Reactant: CCN(CC)C(=O)c1ccccc1
Solvent: CCNCC
Product: CCN(CC)C(=O)Cc1cccs1

Procedure:
The product of Example 42 was followed using 2-thiopheneacetyl chloride and diethylamine giving the desired product as an oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:8]([NH:10][C@@H:11]([C:13]([NH:15][CH2:16][C:17]([NH:19][CH2:20][C:21]([OH:23])=O)=[O:18])=[O:14])[CH3:12])=[O:9])[CH3:7])=[O:4].Cl.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>CN(C=O)C.O>[NH:1]1[C:21](=[O:23])[CH2:20][NH:19][C:17](=[O:18])[CH2:16][NH:15][C:13](=[O:14])[C@@H:11]([CH3:12])[NH:10][C:8](=[O:9])[C@H:6]([CH3:7])[NH:5][C:3](=[O:4])[CH2:2]1
Reactant: C[C@H](NC(=O)CN)C(=O)N[C@H](C)C(=O)NCC(=O)NCC(=O)O
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1NC(=O)CNC(=O)CNC(=O)CNC(=O)[C@@H](C)NC1=O
Temperature: -25 °C
Reaction time: 48 h
Yield: 60 %

Procedure:
This compound was synthesized by the method of Veber, D. F. et al, J. Org. Chem., 44, 3101-5 (1979). To a solution of Gly-Ala-DAla-Gly-Gly.HCl prepared as in Example 33D (12.9 g, 35.0 mmol) in anhydrous DMF (4400 ml) was added enough TEA to adjust the pH to ~8 (measured by spotting the reaction mixture on moistened Hydrion paper) and the resulting mixture was cooled to -25° C. To this mixture was added DPPA (9.20 ml, 43.0 mmol) dropwise over 5 min. The reaction was stored at -25° C. (internal temperature) for 48 h thereafter. During this time the pH was monitored periodically (as described above) and maintained at ~8 by the addition of TEA. After this time the reaction mixture was allowed to stand at 0° C. for 48 h. Again the pH was monitored periodically and maintained at ~8 by the addition of TEA. After this time the reaction mixture was diluted with water (4400 ml) and stirred with Bio-Rad AG 501-X8 (mixed-bed) resin (200 g) for 6 h. The resin was separated by filtration and the solution was concentrated to dryness. Trituration of the residue with refluxing THF (250 ml) for 3 h, filtration of the hot THF and drying at high vacuum afforded 6.61 g (60% yield) of the product as a white powder: 1H NMR (DMSO-d6) δ 1.15-1.32 (m, 6 H), 3.45-4.00 (m, 6 H), 4.10-4.38 (m, 2 H), 7.81 (d, J=7.8 Hz, 1 H), 7.97 (t, J=6.6 Hz, 1 H), 8.10 (m, 2 H), 8.18 (d, J=7.5 Hz, 1 H).
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH2:27][CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.[N+](C1C=CC(OC(=O)[NH:49][C:50]2[CH:55]=[CH:54][C:53]([N:56]3[CH2:60][CH2:59][CH2:58][CH2:57]3)=[CH:52][CH:51]=2)=CC=1)([O-])=O>>[N:56]1([C:53]2[CH:54]=[CH:55][C:50]([NH:49][C:6]([N:8]3[CH2:13][CH2:12][CH:11]([C:14]4[C:23]5[C:18](=[CH:19][C:20]([O:26][CH2:27][CH2:28][CH2:29][N:30]6[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]6)=[C:21]([O:24][CH3:25])[CH:22]=5)[N:17]=[CH:16][N:15]=4)[CH2:10][CH2:9]3)=[O:5])=[CH:51][CH:52]=2)[CH2:57][CH2:58][CH2:59][CH2:60]1
Reactant: COc1cc2c(C3CCN(C(=O)OC(C)(C)C)CC3)ncnc2cc1OCCCN1CCN(C)CC1
Reactant: O=C(Nc1ccc(N2CCCC2)cc1)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: COc1cc2c(C3CCN(C(=O)Nc4ccc(N5CCCC5)cc4)CC3)ncnc2cc1OCCCN1CCN(C)CC1

Procedure:
The title compound was prepared from 4-{6-Methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinazolin-4-yl}-piperidine-1-carboxylic acid tert-butyl ester, prepared as described in Example 207a, and (4-pyrrolidin-1-yl-phenyl)-carbamic acid 4-nitro-phenyl ester hydrochloride, prepared as described in Example 74a, using essentially the protocol given for Example 170c. 1H-NMR (400 MHz, CDCl3) δ 9.07 (s, 1H), 7.34 (s, 1H), 7.25 (s, 1H), 7.19 (m, 2H), 6.52 (m, 2H), 6.24 (s, 1H), 4.27 (m, 4H), 4.04 (s, 3H), 3.57 (tt, 1H), 3.26 (m, 4H), 3.14 (td, 2H), 2.58 (m, 2H), 2.64-2.35 (br, 8H), 2.30 (s, 3H), 2.20-2.08 (m, 4H), 2.04-1.93 (m, 6H). LC/MS (ESI): calcd mass 587.4, found 588.4 (MH)+.
Reaction SMILES: [CH3:1][N:2]1[CH:11]2[C:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: COc1cccc2sc(Cl)nc12
Reactant: CN1C(=O)CCC2(C)c3ccc(S)cc3CCC12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc2sc(Sc3ccc4c(c3)CC[C@H]3N(C)C(=O)CC[C@]43C)nc12
Yield: 66.3 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-4-methoxybenzothiazole (92 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (4×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 107 mg (66%) of the title compound as an off white solid. mp 200°-205°. FDMS: m/e=424. α[D]589 =+60.56 (c=0.96, chloroform).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[Cl:7][C:8]1[CH:9]=[C:10]([B:15]([CH:17]([O:24][CH:25]([B:32]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[C:36]([Cl:41])[CH:35]=2)[OH:33])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)O)[CH:11]=[CH:12][C:13]=1[CH3:14]>C(O)C>[Cl:7][C:8]1[CH:9]=[C:10]([B:15]([CH:17]([O:24][CH:25]([B:32]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[C:36]([Cl:41])[CH:35]=2)[O:33][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])[CH:11]=[CH:12][C:13]=1[CH3:14]
Reactant: CN(C)CCO
Reactant: Cc1ccc(B(O)C(OC(B(O)c2ccc(C)c(Cl)c2)c2ccccc2)c2ccccc2)cc1Cl
Solvent: CCO
Product: Cc1ccc(B(OCCN(C)C)C(OC(B(OCCN(C)C)c2ccc(C)c(Cl)c2)c2ccccc2)c2ccccc2)cc1Cl

Procedure:
The entitled compound (5 mg) was obtained by allowing 22 mg of N,N-dimethylethanolamine to act on 99 mg of bis(4,4′-(3-chloro-4-methylphenyl-hydroxyboryl)benzyl) ether in 0.5 mL of ethanol.
Reaction SMILES: [CH2:1]([C:8]1[S:9][CH:10]=[C:11]([C:13](O)=[O:14])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([C:8]1[S:9][CH:10]=[C:11]([CH2:13][OH:14])[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1csc(Cc2ccccc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1csc(Cc2ccccc2)n1

Procedure:
2-Benzyl-4-thiazolecarboxylic acid is converted to the methyl ester and the ester is reduced with lithium aluminium hydride in tetrahydrofuran to give 2-benzyl-4hydroxymethylthiazole. Using this compound as the starting material in the procedure of Example 1 gives N-methyl-N'-[2-((2-benzyl-4-thiazolyl)metylthio)ethyl]-thiourea.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[NH:19]1[C:23](=[O:24])[CH2:22][CH2:21][CH:20]1[C:25](O)=[O:26].C(N(CC)CC)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(#N)C>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:25]([CH:20]2[NH:19][C:23](=[O:24])[CH2:22][CH2:21]2)=[O:26])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: O=C1CCC(C(=O)O)N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)C2CCC(=O)N2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (1.00 g, 3.43 mmol), DL-pyroglutamic acid (0.49 g, 3.78 mmol), triethylamine (0.73 g, 7.20 mmol), EDCI (0.72 g, 3.78 mmol) and HOBt (0.58 g, 3.78 mmol) in acetonitrile (30 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and 10% sodium hydrogen carbonate solution. The resulting white precipitate was collected by filtration and washed with diethyl ether to afford the title compound (1.03 g, 91%) as a off-white solid, mp 290° C.
Reaction SMILES: CC([CH:5]1[CH2:10][N:9]([CH2:11][CH:12]2[C:21]3[C:16](=[C:17]([Br:22])[CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][O:13]2)[CH2:8][CH2:7][N:6]1C([O-])=O)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[Br:22][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:16]=1[CH2:15][CH2:14][O:13][CH:12]2[CH2:11][N:9]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:10]1
Reactant: CC(C)(C)C1CN(CC2OCCc3c(Br)cccc32)CCN1C(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Brc1cccc2c1CCOC2CN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1,1-dimethylethyl-4-[(5-bromo-3,4-dihydro-1H-isochromen-1-yl)methyl]piperazine-1-carboxylate (480 mg, 1.2 mmol) in 10 mL of DCM was added 10 mL of 4N HCl/dioxane, and then stirred at room temperature for 2 hours. The solvents was removed under vacuum to afford 1-[(5-bromo-3,4-dihydro-1H-isochromen-1-yl)methyl]piperazine.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:13](=[C:14]([OH:16])[CH:15]=1)[C:12](=[CH2:17])[C:11]1([OH:19])[O:18][N:6]2[CH2:7][CH:8]2[CH:10]1[NH:9]2.C(O[C:24](=[O:26])[CH3:25])(=O)C>N1C=CC=CC=1>[C:2]([O:16][C:14]1[CH:15]=[C:3]([CH2:2][O:1][C:24](=[O:26])[CH3:25])[CH:4]=[C:5]2[C:13]=1[C:12](=[CH2:17])[C:11]1([OH:19])[O:18][N:6]2[CH2:7][CH:8]2[CH:10]1[N:9]2[C:14](=[O:16])[CH3:13])(=[O:1])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: C=C1c2c(O)cc(CO)cc2N2CC3NC3C1(O)O2
Solvent: c1ccncc1
Product: C=C1c2c(OC(C)=O)cc(COC(C)=O)cc2N2CC3C(N3C(C)=O)C1(O)O2
Reaction time: 8 h

Procedure:
4-Hydroxymethyl-8-methylene-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-triene-6,9-diol (10 mg) was dissolved in pyridine (1 ml). To this solution was added acetic anhydride (100 μl), and the mixture was allowed to stand at room temperature overnight. The reaction mixture was evaporated to dryness in vacuo and the residual oil was subjected to preparative thin layer chromatography, which was developed with a mixture of methanol and chloroform (5:95, v/v) to give 4-acetoxymethyl-11-acetyl-9-hydroxy-8-methylene-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6-yl acetate (6 mg).
Reaction SMILES: I[C:2]1[C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=1.[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26].C(N(C(C)C)CC)(C)C>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:21][CH3:22])[N:12]=[CH:11][CH:10]=[C:9]2[O:8][C:7]1[C:2]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])=[N:3][C:4]([CH3:23])=[CH:5][CH:6]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2nccc(Oc3ccc(C)nc3C#C[Si](C)(C)C)c2cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.6 %

Procedure:
4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxyquinoline (compound 116) (84 mg), trimethylsilylacetylene (39 mg), and bis(triphenylphosphine)palladium(II) chloride (14 mg) were dissolved in tetrahydrofuran (1 ml) to prepare a solution. Diisopropylethylamine (0.2 ml) and copper iodide (3.8 mg) were added to the solution, and the mixture was stirred at room temperature for 18 hr. The reaction solution was filtered, the solvent was then removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform to give the title compound (45 mg, yield 58%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:15])=[CH:5][C:6]([CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:7][CH:8]=1.[C:16]([O-])(O)=O.[Na+]>C(O)=O>[CH3:1][N:2]1[C:3]2[CH:8]=[CH:7][C:6]([CH2:9][N:10]3[CH2:11][CH2:12][CH2:13][CH2:14]3)=[CH:5][C:4]=2[N:15]=[CH:16]1
Reactant: CNc1ccc(CN2CCCC2)cc1N
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: Cn1cnc2cc(CN3CCCC3)ccc21

Procedure:
A solution of 850 mg (4.14 mmol) N1-methyl-4-pyrrolidin-1-ylmethyl-benzene-1,2-diamine in 4 mL formic acid is refluxed for 1.5 h. It is made alkaline with 250 mL semisaturated NaHCO3 solution and extracted twice with 70 mL EtOAc. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[N:10]=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[S:12][C:13]=1[CH2:14]O.C(N(S(F)(F)[F:32])CC)C.O>C1(C)C=CC=CC=1>[F:32][CH2:14][C:13]1[S:12][C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=[N:10][C:9]=1[CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1
Reactant: OCc1sc(-c2cccc(C(F)(F)F)c2)nc1COC1CCCCO1
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: Cc1ccccc1
Product: FCc1sc(-c2cccc(C(F)(F)F)c2)nc1COC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
Under a nitrogen atmosphere at 0° C., to a solution (7 mL) of the compound (500 mg, 1.3 mmol) obtained in Example 89c in toluene was added diethylaminosulfur trifluoride (DAST) (650 mg, 4.0 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=50/50) to give the title compound (350 mg, 70%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH3:13].O=P(Cl)(Cl)[Cl:16]>C(#N)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:16])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH3:13]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc2c(O)ccnc2cc1Br
Solvent: CC#N
Product: Cc1cc2c(Cl)ccnc2cc1Br
Temperature: 90 °C

Procedure:
To a flask charged with 7-bromo-6-methylquinolin-4-ol (0.675 g, 2.84 mmol) was added acetonitrile (14.18 ml) and POCl3 (0.277 ml, 2.98 mmol) and the resulting suspension was heated to 90° C. for 2.5 h affording a brown solution and near complete conversion to desired product. The material was added to cold sat. aq. NaHCO3 and extracted with EtOAc (2×). The combined organics were dried with Na2SO4, filtered, and dried under reduced pressure and purified with an 40 g Silicycle HP column ramping EtOAc in heptane (0-50%, 10% DCM throughout) affording isomer separation, both obtained as off-white solids. The first eluting isomer corresponds to product based on the proton NMR, obtained as a light yellow solid, 7-bromo-4-chloro-6-methylquinoline (240 mg, 0.936 mmol, 33.0% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 8.68 (d, J=4.70 Hz, 1H), 8.31 (s, 1H), 7.99 (s, 1H), 7.43 (d, J=4.69 Hz, 1H), 2.59 (s, 3H). m/z (ESI) 256.1/258.1 (M+H)+.