Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[N:8][N:7]=1.[O:19]1[CH2:24][O:23][CH2:22][O:21][CH2:20]1.FC(F)(F)C(O)=O.C(OO)(C)(C)C>C(#N)C.O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:20]2[O:21][CH2:22][O:23][CH2:24][O:19]2)=[N:8][N:7]=1
Reactant: Cc1cccc(Nc2nncc3ccccc23)c1
Reactant: C1OCOCO1
Agent: CC(C)(C)OO
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: Cc1cccc(Nc2nnc(C3OCOCO3)c3ccccc23)c1
Temperature: 80 °C
Reaction time: 17 h

Procedure:
To a suspension of 9.6 g (40.8 mmol) 1-(3-methylanilino)phthalazine and 173 g 1,3,5-trioxane in 570 ml acetonitrile, 3.12 ml (40.8 mmol) trifluoroacetic acid, 11.0 ml (80% in tBuOOtBu; 87.4 mmol) tBuOOH and 190 mg (0.68 mmol) FeSO4.7 H2O are added, and the mixture stirred for 17 h at 80° C. The cooled reaction mixture is partly evaporated in the RE, diluted with EtOAc and water and adjusted to an alkaline pH with 1 N NaOH. The aqueous phase is separated off and twice extracted with EtOAc. The organic phases are washed twice with water and brine, dried (Na2SO4) and evaporated. Column chromatography (SiO2; EtOAc/toluene 1:3; applied as solution in dichloromethane/acetone 9:1) yields the title compound after crystallization with the addition of DIPE; m.p. 161° C.; DC (EtOAc/toluene 1:3) Rf=0.27; 1H-NMR (DMSO-d6) 9.27 (s, HN), 8.74 (m, 1H), 8.61 (m, 1H), 8.00 (m, 2H), 7.72 (s, 1H), 7.68 (d, 1H), 7.25 (t, 1H), 6.89 (d, 1H), 6.39 (s, 1H), 5.47 (d, 2H), 5.41 (d, 2H), 2.33 (s, 3H); FAB-MS (M+H)+=324; anal. calc.(C18H17N3O3) C, 66.86%; H, 5.30%; N, 13.00%; meas. C, 66.83%; H, 5.36%; N, 12.81%.
Reaction SMILES: C1([N:4]([CH2:6][C:7]2[CH:34]=[N:33][C:10]3[O:11][C:12]4[C:17]([N:18]5[CH2:23][CH2:22][O:21][CH2:20][CH2:19]5)=[N:16][C:15]([C:24]5[CH:32]=[CH:31][CH:30]=[C:29]6[C:25]=5[CH:26]=[CH:27][NH:28]6)=[N:14][C:13]=4[C:9]=3[CH:8]=2)[CH3:5])CC1.[BH3-]C#N.[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC([O-])=O.[Na+].Cl.[CH:59]1([CH2:62]NC)[CH2:61][CH2:60]1>CN(C=O)C.CO.C(Cl)Cl>[CH:59]1([CH2:62][N:4]([CH2:6][C:7]2[CH:34]=[N:33][C:10]3[O:11][C:12]4[C:17]([N:18]5[CH2:19][CH2:20][O:21][CH2:22][CH2:23]5)=[N:16][C:15]([C:24]5[CH:32]=[CH:31][CH:30]=[C:29]6[C:25]=5[CH:26]=[CH:27][NH:28]6)=[N:14][C:13]=4[C:9]=3[CH:8]=2)[CH3:5])[CH2:61][CH2:60]1
Reactant: CNCC1CC1
Reactant: CN(Cc1cnc2oc3c(N4CCOCC4)nc(-c4cccc5[nH]ccc45)nc3c2c1)C1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: CN(Cc1cnc2oc3c(N4CCOCC4)nc(-c4cccc5[nH]ccc45)nc3c2c1)CC1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of compound 23 (as per Example S above) (19 mg, 0.048 mmol, leg), NaBH3CN (6.0 mg, 0.096 mmol. 2 eq), NaBH(OAc)3 (31 mg, 0.144 mmol, 3 eq), NaOAc (15.7 mg, 0.19 mmol, 4 eq) in a mixture of anhydrous CH2Cl2 (2 mL), MeOH (2 mL) and DMF (0.5 mL) was added cyclopropylmethyl-methyl-amine hydrochloride (23 mg, 0.19 mmol, 4 eq) under Ar(g). The reaction mixture was stirred at rt overnight. Solvents were removed in vacuo. Then, the residue was partitioned with H2O (10 mL) and extracted with CH2Cl2 (3×10 mL) and EtOAc (2×10 mL). The combined organic extracts were dried over MgSO4 and the solvent was removed in vacuo. The residue was further purified by silica gel column chromatography with CH2Cl2/MeOH (1:0-47:3) to yield the product, T, as a white solid (8.35 mg, 37%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](/[N:11]=[C:12](/[NH:25][C:26](=[O:35])[CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)\[NH:13][CH2:14][CH2:15][CH2:16][C@H:17]2[C:20](=[O:21])[NH:19][C@@H:18]2[C:22]([OH:24])=[O:23])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:36](O)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[C:1]1([CH2:7][CH2:8][C:9](/[N:11]=[C:12](/[NH:25][C:26](=[O:35])[CH2:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)\[NH:13][CH2:14][CH2:15][CH2:16][C@H:17]2[C:20](=[O:21])[NH:19][C@@H:18]2[C:22]([O:24][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:23])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CCc1ccccc1)/N=C(\NCCC[C@H]1C(=O)N[C@@H]1C(=O)O)NC(=O)CCc1ccccc1
Reactant: OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CCc1ccccc1)/N=C(\NCCC[C@H]1C(=O)N[C@@H]1C(=O)OCc1ccccc1)NC(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 148 (74 mg, 1.0 eq.) in DMF (1.5 mL) was added benzyl alcohol (19 uL, 1.2 eq.), EDC-HCl (35 mg, 1.2 eq.), HOBt (24 mg, 1.2 eq.) and DIEA (60 μL eq.). The reaction was stirred at room temperature for 16 hours and then diluted with ethyl acetate and washed with 1N HCl. The aqueous layer was then washed with ethyl acetate (2×10 mL). The combined organics were then washed with saturated NaHCO3 (2×10 mL), water (10 mL), dried over magnesium sulfate and concentrated in vacuo to give the crude product (55 mg) as a colorless oil. The product was purified by silica gel chromatography using a gradient elution from 20% EtOAc in hexanes to 50% EtOAc in hexanes to yield 149 (50 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH2:10][CH2:11][N:12]=2)=[C:4]([CH3:13])[CH:3]=1.[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([Br:14])=[CH:11][N:12]=2)=[C:4]([CH3:13])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Br)ccc1C1=NCCO1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(Br)ccc1-c1ncc(Br)o1
Temperature: 85 °C
Yield: 13.7 %

Procedure:
2-(4-Bromo-2-methylphenyl)-4,5-dihydro-1,3-oxazole (0.33 g, 1.38 mmol, from Step A) was dissolved in carbon tetrachloride. AIBN (0.003 g) and N-bromosuccinimide (0.18 g, 4.14 mmol) were sequentially added, the mixture was degassed with argon for 5 min and then heated at 85° C. for 24 h. The reaction was filtered, diluted with methylene chloride (200 mL) and washed with saturated sodium bisulfite (2×100 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel chromatography eluting with 3% ethyl acetate/hexanes yielded 60 mg of the desired product: 1H NMR (500 MHz, CDCl3) δ 7.83 (d, J=8.5 Hz, 1H), 7.49 (s, 1H), 7.45 (d, J=8.2 Hz, 1H), 7.16 (s, 1H), 2.67 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH:12]([CH2:17][CH2:18][CH3:19])[C:13]([O:15]C)=[O:14])=[C:10]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[C:9]2[C:4](=[CH:5][C:6]3[CH2:29][CH2:28][CH2:27][C:7]=3[CH:8]=2)[N:3]=1.[OH-].[Na+]>CO.C(O)C>[CH3:1][C:2]1[C:11]([CH:12]([CH2:17][CH2:18][CH3:19])[C:13]([OH:15])=[O:14])=[C:10]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[C:9]2[C:8]3[CH2:29][CH2:28][CH2:27][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc2cc3c(cc2c1-c1ccc(C)cc1)CCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: CCCC(C(=O)O)c1c(C)nc2ccc3c(c2c1-c1ccc(C)cc1)CCC3
Temperature: 60 °C
Yield: 1 %

Procedure:
To a solution of methyl 2-(2-methyl-4-p-tolyl-7,8-dihydro-6H-cyclopenta[g]quinolin-3-yl)pentanoate and methyl 2-(3-methyl-4-p-tolyl-8,9-dihydro-6H-cyclopenta[g]quinolin-3-yl)pentanoate (0.316 g; 0.81 mmol) in a mixture methanol-ethanol (2:1) (24 mL) was added a 5% sodium hydroxide solution (24.46 mmol; 19.5 mL) and the reaction mixture was heated to 60° C. for 18 h. The organic volatiles were removed under reduced pressure and the remaining basic solution was acidified to pH 2 with a 1N hydrochloric solution and the aqueous layer was extracted with ethyl acetate. The organics were combined, dried over magnesium sulfate and concentrated under reduced pressure. Purification by preparative HPLC (method 1) furnished 0.003 g (1%) of 2-(3-methyl-1-p-tolyl-8,9-dihydro-7H-cyclopenta[f]quinolin-2-yl)pentanoic acid. ESI/APCI(+): 374 (M+H). 1H NMR (CDCl3) δ 7.90 (d, J=8.35 Hz, 1H, H-9); 7.53 (d, J=8.35 Hz, 1H, H-8); 7.27 (bs, 1H, H-6′); 7.26 (bs, 1H, H-5′); 7.25 (d, J=8.2 Hz, 1H, H-3′); 7.06 (d, J=8.2 Hz, 1H, H-2′); 3.83 (t, J=6.7 Hz, 1H, H-12); 2.89, (m, 2H, H-7); 2.72 (s, 3H, H-10); 2.47 (s, 3H, H-7′); 2.22 (m, 1H, H-5); 2.18 (m, 1H, H-13); 2.02 (m, 1H, H-5); 1.84 (m, 1H, H-6); 1.76 (m, 1H, H-6); 1.63 (m, 1H, H-13); 1.19 (m, 1H, H-14); 0.97 (m, 1H, H-14); 0.737 (t, J=7.3 Hz, 3H, H-15). 13C NMR (CDCl3) δ 177.4 (C-11); 155.7 (C-2); 148.1 (C-4); 145.4 (C-9a); 143.1 (C-7a); 139.8 (C-4b); 137.9 (C-4′); 136.6 (C-1′); 131.5 (C-3); 129.8 (C-2′); 129.7 (C-3′); 128.9 (C-6′); 128.5 (C-5′); 126.7 (C-9); 126.6 (C-8); 124.1 (C-4a); 46.04 (C-12); 34.12 (C-5); 33.12 (C-7); 32.77 (C-13); 25.25 (C-6); 23.50 (C-10); 21.44 (C-14); 21.40 (C-7′); 14.14 (C-15).
Reaction SMILES: CC1C=CC(S(O[C:12]2[C:13]3[CH2:23][CH2:22][CH2:21][CH2:20][C:19](C)(C)[C:14]=3[N:15]=[C:16]([NH2:18])[N:17]=2)(=O)=O)=CC=1.[NH:26]1[CH2:30]C[C@@H:28]([NH:31][C:32](=O)OC(C)(C)C)[CH2:27]1>>[N:26]1([C:12]2[C:13]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:14]=3[N:15]=[C:16]([NH2:18])[N:17]=2)[CH2:27][CH2:28][NH:31][CH2:32][CH2:30]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCCC3(C)C)cc1
Product: Nc1nc2c(c(N3CCNCC3)n1)CCCCC2

Procedure:
The title compound was prepared according to the procedure of Example 1E, substituting the product from Example 13C for the product of Example 1D and substituting piperazine for (R)-tert-butyl pyrrolidin-3-ylcarbamate. 1H NMR (300 MHz, CD3OD) δ 3.38 (m, 4H), 3.21 (, 4H), 2.74 (m, 2H), 2.62 (m, 2H), 1.86 (m, 2H), 1.57-1.71 (m, 4H). MS (DCI+) m/z 248 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5](=[O:18])[C:6]([CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)[CH3:7].[I-].[Na+].[CH:21]([C:24]1[NH:25][CH:26]=[CH:27][N:28]=1)([CH3:23])[CH3:22].C(N(CC)CC)C>CN(C=O)C.O>[CH:21]([C:24]1[N:25]([CH2:2][CH2:3][O:4][C:5](=[O:18])[C:6]([CH3:17])([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)[CH3:7])[CH:26]=[CH:27][N:28]=1)([CH3:23])[CH3:22]
Reactant: CC(C)c1ncc[nH]1
Reactant: CC(C)(C(=O)OCCBr)c1cccc([N+](=O)[O-])c1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1nccn1CCOC(=O)C(C)(C)c1cccc([N+](=O)[O-])c1
Temperature: 100 °C
Yield: 19.5 %

Procedure:
To a solution of 2-methyl-2-(3-nitro-phenyl)-propionic acid 2-bromo-ethyl ester (1.5 g, 4.74 mmol) in DMF (8 mL) was added sodium iodide (0.73 g, 4.87 mmol) and heated at 100° C. for 1 h. 2-Isopropyl-imidazole (2.15 g, 19.5 mmol) and triethylamine (2 mL, 14.6 mmol) were added and then refluxed for 4 h. The reaction was diluted with water and extracted with DCM. The organic layer was washed thoroughly with water, dried over sodium sulfate and evaporated to obtain crude compound. Purification by column chromatography on silica gel (60-120 mesh), eluting with 30% ethyl acetate/hexane gave 2-methyl-2-(3-nitro-phenyl)-propionic acid 2-(2-isopropyl-imidazol-1-yl)-ethyl ester (320 mg, 20%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10].[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ncccc1C(=O)c1cc(Cl)ccc1N
Product: Cc1ncccc1C(=O)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone (243 mg, 1.0 mmol) and 4-tert-Butyl-benzenesulfonyl chloride (232 mg, 1.0 mmol) and purified by HPLC. 1H NMR (CDCl3) δ 10.71 (br s, 1H, NH), 8.63 (dd, 1H, J=5.1 Hz, J=1.6 Hz), 7.83 (d, 1H, J=8.8 Hz), 7.73 (dm, 2H, J=8.4 Hz), 7.49 (dd, 1H, J=8.8 Hz, J=2.6 Hz), 7.43 (dm, 2H, J=8.5 Hz), 7.27 (dd, 1H, J=9.5 Hz, J=1.8 Hz), 7.18 (dd, 1H, J=7.7 Hz, J=4.8 Hz), 7.13 (d, 1H, J=2.6 Hz), 2.29 (s, 3H), 1.29 (s, 9H). MS: m/z 443 (M +1).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH:22]1[CH2:26][CH2:25][C:24]([C:27]#[N:28])=[CH:23]1>CN(C)C=O.O>[C:27]([C:24]1[CH2:25][CH2:26][C@@H:22]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)[CH:23]=1)#[N:28]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#CC1=CC(Br)CC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN([C@H]2C=C(C#N)CC2)CC1
Reaction time: 0.17 h
Yield: 39.4 %

Procedure:
To a stirred solution of tert-butyl piperazine-1-carboxylate (59.5 g, 320 mmol) in dimethyl formamide (400 ml) was added triethylamine (134 ml, 959 mmol) at 25° C. and stirred the reaction mixture for 10 minutes. To this was added 3-bromocyclopent-1-enecarbonitrile (55 g, 320 mmol) and the reaction mixture was stirred for 3 h. The progress of reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. The residue obtained was diluted with water (250 ml) and extracted with ethyl acetate (3×250 ml). The combined organic layer was dried over anhydrous sodium sulphate. The solvent in the organic layer was evaporated under reduced pressure to obtain crude product. The crude product purified by flash column chromatography over silica gel (100-200 mesh) using 40% ethyl acetated in hexane as an eluent to obtain the title compound (35 g, 126 mmol, 39.5% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:13])[C:5]([NH2:12])=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[C:14]1(=O)[O:19][CH2:18][CH2:17][CH2:16][CH2:15]1>Cl>[Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]2[N:12]=[C:14]([CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[NH:13][C:4]=2[CH:3]=1
Reactant: O=C1CCCCO1
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1N
Agent: Cl
Product: OCCCCc1nc2cc(C(F)(F)F)c(Cl)cc2[nH]1
Temperature: 135 °C
Yield: 84.6 %

Procedure:
4-chloro-5-(trifluoromethyl)benzene-1,2-diamine (5.00 g, 23.74 mmol) was dissolved in HCl solution (4 M solution) (18.85 ml) at r.t. and delta-valerolactone (2.62 g, 26.12 mmol) was added slowly. The reaction was heated to 135° C. for 2 hrs then slowly cooled to r.t. The reaction was quenched by the addition of sat. NaHCO3 solution (200 ml) to pH 8. The mixture was extracted with EtOAc (3×150 ml) and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the crude product as a brown solid which was triturated with ether (100 ml) to give the pure product (5.88 g, 84%): MS (ESI+) for C12H12ClF3N2O m/z 293.4 [M+H]+; LC purity 90% (ret. time, 1.49 min); 1H NMR (250 MHz, CHLOROFORM-d) δ ppm 1.39-1.72 (2H, m), 1.71-1.94 (2H, m), 2.87 (2H, t, J=7.61 Hz), 3.58 (2H, t, J=6.09 Hz), 7.42-7.96 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]3[CH:11]=[C:10]([C:12](OCC)=[O:13])[N:9]=[C:7]3[S:8][C:4]=2[CH:3]=1.[Li+].[BH4-].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[F:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]3[CH:11]=[C:10]([CH2:12][OH:13])[N:9]=[C:7]3[S:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1cn2c(n1)sc1cc(F)ccc12
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: C1CCOC1
Product: OCc1cn2c(n1)sc1cc(F)ccc12
Reaction time: 1 h

Procedure:
7-Fluoro-imidazo[2,1-b]-benzthiazole-2-methanol was prepared starting from Ethyl 7-fluoro-imidazo[2,1-b]-benzthiazole-2-carboxylate (2.64 g, 0.01 mol) and LiBH4 (50 mg) in THF at refluxing temperature for 2 hrs. at the end, reaction mixture was quenched with ice cold water and acidified with 10 N. HCl. Reaction mixture was stirred for 1 hr and nuetralized with K2CO3. The separated residue was extracted with chloroform:methanol (3:1) and dried over anhydrous MgSO4. It was filtered and concentrated. The crude reaction mixture was found to be pure and taken to next step with out any purification. Yeild: 1.5 g (68%) Semi solid; M+H 223.
Reaction SMILES: CO[C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].S(Cl)(Cl)=O.[CH2:16]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:17][CH2:18][CH2:19][CH3:20].[Cl-].[Al+3].[Cl-].[Cl-].[OH-].[Na+]>C(O)C>[CH2:16]([C:21]1[CH:22]=[CH:23][C:24]([C:3]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:11])=[CH:25][CH:26]=1)[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: COC(=O)CCCCC(=O)O
Reactant: CCCCCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: CCCCCc1ccc(C(=O)CCCCC(=O)O)cc1

Procedure:
Adipic acid monomethyl ester (35 g; 0.44 mole) is converted to the acid chloride with thionyl chloride (50 g) in a manner analogous to that described in Example 1. This product is reacted with pentylbenzene (400 ml) and aluminum chloride (80 g) and the reaction product isolated as a colorless oil (25 g; b.p. 165°-174° C. @0.15 mm) and identified as methyl 5-(4-n-pentylbenzoyl) pentanoate. This ester (5 g; 0.017 mole) is hydrolysed with sodium hydroxide in aqueous ethanol and the product isolated as in Example 1. Recrystallization from aqueous ethanol gives 5-(4-n-pentylbenzoyl)pentanoic acid (4.0 g) as colorless crystals, m.p. 84°-86° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:17][CH:18]1[CH2:22][NH:21][C:20](=[O:23])[CH2:19]1.[H-].[Na+].[Na].[Br-]>CN(C=O)C>[C:1]([O:5][C:6](=[O:15])[N:7]([C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=1)[CH2:17][CH:18]1[CH2:19][C:20](=[O:23])[NH:21][CH2:22]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccnc(NC(=O)OC(C)(C)C)c1
Reactant: O=C1CC(CBr)CN1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccnc(N(CC2CNC(=O)C2)C(=O)OC(C)(C)C)c1

Procedure:
(4-Methylpyridin-2-yl)carbamic acid tert-butyl ester was alkylated with 4-bromomethylpyrrolidin-2-one by deprotonation in DMF at 0° C. with NaH and treating the sodium salt with the bromide at room temperature. After dilution of the reaction mixture with ethyl acetate and washing with saturated aqueous NaHCO3 the crude product was purified by chromatography on silica gel (ethyl acetate/hexane) to yield (14) as yellow oil.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])C=C.CN(C)[C:18]1[CH:23]=CC=C[CH:19]=1>>[Cl:15][C:13]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([OH:4])[C:14]=1[CH2:23][CH:18]=[CH2:19]
Reactant: C=CCOc1cc(Cl)ccc1C(=O)OC
Reactant: CN(C)c1ccccc1
Product: C=CCc1c(Cl)ccc(C(=O)OC)c1O
Yield: 71.1 %

Procedure:
A solution of methyl 2-allyloxy-4-chlorobenzoate (3f) (50.6 g, 0.22 mol) in 100 ml of N,N-dimethylaniline was heated under argon in an oil bath at 190°-205° C. for 20 hours. The solvent was removed by distillation and the residue purified by column chromatography (silica gel, CH2Cl2 /hexane) to give 4f (36.0 g, 71.1% yield) as a very light oil. IR (nujol) 1665 (C=0) cm-1. NMR (CDCl3) δ 11.23 (s, 1H, OH), 7.47 (d, 1H, J=9 Hz, aromatic proton meta to Cl), 6.77 (d, 1H, aromatic proton alpha to Cl), 6.17-4.77 (m, 3H, olefinic orotons), 3.87 (s, 3H, CH3) and 3.50 (m, 2H, CH2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]3[N:15]=2)[CH:5]=[C:6]([OH:8])[CH:7]=1.Cl.Cl[CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]3[N:15]=2)[CH:5]=[C:6]([O:8][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:7]=1
Reactant: ClCCN1CCOCC1
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(O)cc(F)c3)nc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cc(OCCN4CCOCC4)c3)nc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
(R)-ethyl 5-(2-(3-fluoro-5-hydroxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (167 mg, 0.451 mmol), 4-(2-chloroethyl)morpholine hydrochloride (168 mg, 0.902 mmol), and K2CO3 (312 mg, 2.25 mmol) were suspended in DMF (5 mL) and stirred at ambient temperature for 15 hours. The crude reaction mixture was purified by reverse phase HPLC (0-60% acetonitrile/water) to provide the title compound (218 mg, 100% yield). MS (apci) m/z=484.1 (M+H).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][C:15]2[N:16]([CH3:24])[N:17]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:19]=2)=[O:13])=[CH:7][CH:6]=1)C.CC(C[AlH]CC(C)C)C.C(OCC)(=O)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:20]([C:18]1[CH:19]=[C:15]([NH:14][C:12]([NH:11][C:8]2[CH:7]=[CH:6][C:5]([CH2:4][OH:3])=[CH:10][CH:9]=2)=[O:13])[N:16]([CH3:24])[N:17]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CCOC(=O)c1ccc(NC(=O)Nc2cc(C(C)(C)C)nn2C)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cn1nc(C(C)(C)C)cc1NC(=O)Nc1ccc(CO)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a dry flask is added 872 mg (2.5 mmol) of 4-[3-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-ureido]-benzoic acid ethyl ester in 30 mL dry methylene chloride and cooled to 0° C. Next, 10.12 mL of 1M DIBAL in hexanes (4 eq., 10.12 mmol) is added and the reaction is allowed to reach room temperature. The mixture is then stirred for 1 hour, and 60 mL of ethyl acetate and 100 mL of sodium tartrate saturated aqueous solution are added, and the mixture is stirred for another 30 min. Then the organic layer is separated and washed with water and dried over magnesium sulfate, filtered, and evaporated to a white solid weighing 720 mg (2.4 mmoles, 95%, ES+(m/z) 303 [M+H]).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[O:15]CC1C=CC=CC=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:23])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[OH:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: Cc1ccc(CC(=O)OC(C)(C)C)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(CC(=O)OC(C)(C)C)c(O)c1

Procedure:
To a solution of [4-methyl-2-(phenylmethoxy)phenyl]acetic acid tert-butyl ester (10.67 g, 34.2 mmol) in 125 ml of ethanol was added palladium black (200 mg), the mixture was hydrogenated (using a hydrogen balloon) at 30° C. for 10 hr. After the starting material disappeared completely (detected by TLC), the solid was filtered off, and the solvent was evaporated to give a crude product of (2-hydroxy-4-methylphenyl)acetic acid tert-butyl ester, 7.32 g (96%) as white solid. 1H NMR (CDCl3) δ: 7.931 (1H, s, br), 6.955 (1H, d, J=7.56 Hz), 6.799 (1H, s), 6.688 (1H, d, J=7.81 Hz), 3.551(2H, S), 2.299 (3H, s), 1.472 (9H, s) ppm.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:10])[CH2:2]1.Cl[CH2:19][C:20]([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1)=[O:21]>CN(C)C=O>[N:22]1([C:20](=[O:21])[CH2:19][N:1]2[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:10])[CH2:2]2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1
Reactant: O=C(NCC1CNCCO1)Nc1ccccc1
Reactant: O=C(CCl)N1CCc2ccccc21
Solvent: CN(C)C=O
Product: O=C(NCC1CN(CC(=O)N2CCc3ccccc32)CCO1)Nc1ccccc1
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
To a stirred solution of Intermediate 7 (0.01 g) in N,N-dimethylformamide (0.5 ml) was added 1-(2-chloroacetyl)indoline (0.0092 g). The mixture was stirred at 22° C. for 17 h before tris-(2-aminoethyl)amine polystyrene (Argonaut Technologies, 0.01 g @ 4.46 mmol/g) and polystyrene methyl isocyanate (Argonaut Technologies, 0.033 g @ 1.39 mmol/g) was added. Stirring was continued for a further 30 min before the mixture was purified by solid phase extraction (1 g Isolute SCX sulphonic acid column), eluting with methanol followed by 10% 0.880 ammonia solution in methanol. The basic fraction was evaporated in vacuo to give the title compound as a white solid (0.012 g). LC/MS (System A) Rt 2.69 min, Mass Spectrum m/z 394 [MH+].