Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][NH:17][CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[CH2:23]([O:25][C:26](=[O:36])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]=[C:34]=[O:35])[CH:28]=1)[CH3:24].O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][N:17]([C:34]([NH:33][C:29]5[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=5)[C:26]([O:25][CH2:23][CH3:24])=[O:36])=[O:35])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:21][CH:22]=1
Reactant: CCOC(=O)c1cccc(N=C=O)c1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CNCC4)cc1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cccc(NC(=O)N2CCc3c(cnc4c3cnn4Cc3ccc(OC)cc3)C2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
To a solution of 3-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine (0.208 g, 0.707 mmol) in anhydrous dichloromethane (10 mL) was added 3-isocyanato-benzoic acid ethyl ester (0.135 g, 0.707 mmol). The reaction was then shaken at room temperature for 30 minutes. On completion of the reaction water (10 mL) was added and the organic layer was separated. The aqueous layer was extracted with dichloromethane (20 mL). The organic extracts were combined, washed with brine (2×20 mL), dried using sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified using flash column chromatography (SiO2, gradient from 50% EtOAc in hexanes to 66% EtOAc in hexane) to give the pure desired product, ethyl 3-(3-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7-carboxamido)benzoate (0.265 g, 77%) as a white solid. M.p.=>80° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.97 (s, 1H), 8.41 (s, 1H), 8.2 (s, 1H), 8.14-8.1 (m, 1H), 7.85-7.8 (m, 1H), 7.57-7.53 (m, 1H), 7.39 (t, J=7.6 Hz, 1H), 7.21-7.16 (m, 2H), 6.88-6.82 (m, 2H), 5.59 (s, 2H), 4.81 (s, 2H), 4.31 (q, J=7.2 Hz, 2H), 3.84 (t, J=6 Hz, 2H), 3.69 (s, 3H), 3.15 (t, J=6 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H); LCMS [M+H]: 486.
Reaction SMILES: [CH3:1][N:2]1[C@H: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[C:35]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:34]([C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=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[C:35]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[C:34]([C:42]5[CH:43]=[CH:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=5)[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: COc1ccc(-c2c(-c3ccccc3)c(Cl)nc3ccccc23)cc1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(-c3ccccc3)c(Sc3ccc4c(c3)CC[C@H]3N(C)C(=O)CC[C@]43C)nc3ccccc23)cc1
Yield: 42.7 %

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 (60 mg, 0.23 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-3-phenyl-4-(4-methoxyphenyl)quinoline (95 mg, 0.27 mmol) and 1 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 (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography ethyl acetate eluent) to give 56 mg (43%) of the title compound as an off white solid. mp 239°-242° FDMS: m/e=570. α[D]589 =+45.00 (c=1.40, chloroform).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[CH2:16]([O:20][C:21](Cl)=[O:22])[CH2:17][CH2:18][CH3:19]>N1C=CC=CC=1>[C:21](=[O:22])([O:20][CH2:16][CH2:17][CH2:18][CH3:19])[O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCOC(=O)Cl
Solvent: c1ccncc1
Product: CCCCOC(=O)Oc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
0.390 G. of 4'-cyano-4-hydroxy-biphenyl are dissolved in 4.0 ml. of absolute pyridine and reacted 0.328 g. of chloroformic acid n-butyl ester as in Example 1. The 0.579 g. of colorless oil obtained according to the procedure described in Example 1 crystallizes after trituration. The crystals are dissolved in benzene and chromatographed on 40 g. of silica gel. Benzene elutes 0.521 g. of colorless crystals which are recrystallized from ether/hexane up to constant melting point and clearing point. The pure 4'-cyano-4-biphenylyl n-butyl carbonate obtained melts at 64.8°-65.7° and is liquid crystalline (monotrope) upon cooling to 64.3°. UV (EtOH): ε270 = 26,300.
Reaction SMILES: Cl[CH:2]1[C:8]([CH3:10])([CH3:9])[CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[O:11].S([O-])([O-])(=O)=[O:13].[NH4+].[NH4+]>O>[CH3:10][C:8]1([CH3:9])[CH2:7][CH2:6][CH2:5][NH:4][CH:2]1[C:3]([OH:11])=[O:13]
Reactant: CC1(C)CCCNC(=O)C1Cl
Reactant: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: O
Product: CC1(C)CCCNC1C(=O)O
Temperature: 150 °C
Yield: 79.5 %

Procedure:
A suspension of 7.0 g (0.04 moles) of 3-chloro-4,4-dimethyl-2-oxoperhydroazepine and 13.84 g (0.043 moles) of Ba(OH)2.8H2O in 150 ml of water, was heated in a Parr apparatus at 150° C. for 4 hours. Then, 5.79 g (0.043 moles) of ammonium sulphate were added. The precipitate was filtered off, and the solution was evaporated in vacuo to dryness. The residue was treated with hot 2-propanol nd filtered, to yield 5 g of the title compound. M.P. >305° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[C:4]#[CH:5].Br[CH2:8][C:9]([O:11][CH3:12])=[O:10].Cl>O1CCCC1>[CH2:3]([O:6][CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:4]#[CH:5]
Reactant: C#CCO
Reactant: COC(=O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCOCC(=O)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mechanically stirred suspension of sodium hydride (60 5% dispersion in mineral oil) (50 g, 1.25 mol) in tetrahydrofuran (800 mL) at 0° C. under nitrogen was treated dropwise with a solution of propargyl alcohol (84 g, 1.5 mol) in tetrahydrofuran (175 mL), stirred at 0° C. for 1 hour, treated with a solution of methyl bromoacetate in tetrahydrofuran (250 mL) over 15 minutes, stirred at 0° C. for 30 minutes, stirred at ambient temperature for 2 hours, and treated with 2M HCl (800 mL). The organic layer was isolated and the aqueous layer was extracted with ethyl acetate (2×, 500 mL). The combined organic layers were washed with brine (200 mL), dreid (MgSO4), filtered, concentrated and distilled (bp 75-85° C. at 20 torr) to provide the title compound (83 g).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16](I)[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)=[N:6]1.[NH2:31][C@H:32]1[CH2:37][CH2:36][C@H:35]([OH:38])[CH2:34][CH2:33]1>CN1CCCC1=O>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16]([NH:31][C@H:32]3[CH2:37][CH2:36][C@H:35]([OH:38])[CH2:34][CH2:33]3)[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)=[N:6]1
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(I)c21
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: CN1CCCC1=O
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(N[C@H]3CC[C@H](O)CC3)c21
Temperature: 150 °C

Procedure:
Under argon atmosphere, 200 mg (purity 62%, 0.24 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 15A) was suspended in 4 ml of absolute 1-methyl-2-pyrrolidone and 555 mg (4.82 mmol) of trans-4-aminocyclohexanol was added. The mixture was heated in the microwave at 150° C. for 3 h. After cooling, the reaction mixture was purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→100:0). 91 mg (73% of theor.) of the target compound was obtained.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)(=O)C.O>CO>[CH2:14]([O:13][N:12]=[C:11]([C:8]1[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=1)[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(=O)Oc1ccc(C(=NOCc2ccccc2)OCc2ccccc2)cc1
Solvent: O
Solvent: CO
Product: Oc1ccc(C(=NOCc2ccccc2)OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 96.3 %

Procedure:
To a solution of 4-{(benzyloxy)[(benzyloxy)imino]methyl}phenyl acetate (19) (1.671 g, 4.45 mmol) in dry methanol (30 ml) 3.43 N sodium methoxide solution in methanol (1.3 ml, 4.46 mmol) was added and the reaction mixture was stirred at ambient temperature until the starting material disappeared (ca. 1 hour). The mixture was poured into a mixture of water (60 ml) and saturated NaH2PO4 (30 ml), and extracted with ethyl acetate (2×25 ml). The extract was washed with brine (30 ml) and dried (Na2SO4). The solvent was evaporated and the residue was chromatographed on silicagel (50 g) with benzene-ethyl acetate (9:1) as eluent to give benzyl N-(benzyloxy)-4-hydroxybenzenecarboximidoate (15) (1.428 g, 96%) as an interchangeable mixture (2D TLC) of 2 isomers with Rf 0.62 and Rf 0.49 (toluene-ethyl acetate, 9:1). Major (less polar) isomer of 15: 1H NMR (DMSO-d6, HMDSO) δ: 4.99 (2H, s); 5.09 (2H, s); 6.80 (2H, d, J=8.7 Hz); 7.27-7.53 (10H, m); 7.67 (2H, d, J=8.7 Hz); 9.96 (1H, s). Minor (more polar) isomer of 15: 1H NMR (DMSO-d6, HMDSO) δ: 5.06 (2H, s); 5.24 (2H, s); 6.75 (2H, d, J=8.6 Hz); 7.27-7.53 (10H, m); 7.67 (2H, d, J=8.6 Hz); 9.84 (1H, s).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.N1C=CC=CC=1>O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:9])=[CH:11][CH:12]=2)(=[O:18])=[O:17])=[N:6][CH:7]=1
Reactant: Nc1ccc(I)cn1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(I)cn2)cc1
Temperature: 100 °C
Yield: 86.2 %

Procedure:
A mixture of 5-iodopyridin-2-amine (25.5 g), 4-methylbenzene-1-sulfonyl chloride (23.2 g) and pyridine (250 ml) was heated at 100° C. overnight. The mixture was poured into water (1.2 L) with stirring, and the resulting precipitate was collected by filtration. The solid was washed with water and Et2O successively, and dried in vacuo to give the title compound (37.4 g) as a white solid.
Reaction SMILES: [P:1]([O:10]CCCl)([O:6]CCCl)[O:2]CCCl.[CH3:14][N:15]1[C:19](=[O:20])[N:18]([CH3:21])[CH2:17]P1(=O)OCCCl>C(O)(=O)C.O>[CH3:17][N:18]([CH2:21][P:1](=[O:2])([OH:6])[OH:10])[C:19]([NH:15][CH3:14])=[O:20]
Reactant: CN1CP(=O)(OCCCl)N(C)C1=O
Reactant: ClCCOP(OCCCl)OCCCl
Solvent: CC(=O)O
Solvent: O
Product: CNC(=O)N(C)CP(=O)(O)O

Procedure:
This phosphonic acid is prepared in a similar manner using tris(2-chloroethyl) phosphite as the phosphorus ester reactant. The crude intermediate 1,4-dimethyl-2-(2-chloroethoxy)-1,4,2-diazaphospholidin-5-one-2-oxide (31P nmr -24.9 ppm) is hydrolyzed without isolation from the reaction mixture to give the acid: mp 171°-172° dec. (acetic acid-water).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11](Cl)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.O.[NH:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([N:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C1CCNCC1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Agent: Cl
Solvent: O
Product: COc1ccc(S(=O)(=O)N2CCC(=O)CC2)cc1OC

Procedure:
The title compound was prepared from 3,4-dimethoxybezenesulfonyl chloride and 4-piperidone monohydrate hydrochloride according to the procedure of Intemediate 22 as a white solid; 1H NMR (CDCl3) δ 2.55 (t, J=6.15 Hz, 4H), 3.40 (t, J=6.15 Hz, 4H), 3.93 (s, 3H), 3.95 (s, 3H), 6.97 (d, J=8.46 Hz, 1H), 7.23 (d, J=2.04 Hz, 1H), 7.41 (dd, J=2.10 Hz, 8.49 Hz, 1H); MS (ES) m/z 299.9 (MH+); HRMS for C13H17NO5S: 299.0834; Anal. Calcd. for C13H17NO5S: C, 52.16; H, 5.72; N, 4.68. Found: C, 52.13; H, 5.80; N, 4.59.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[N+:17]([O-])=O)[O:6][CH2:7][CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)[CH:14]=[CH:15][C:16]=1[NH2:17]
Reactant: COc1cc(OCCN2CCCC2)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(OCCN2CCCC2)ccc1N
Yield: 91.8 %

Procedure:
A mixture of 1-[2-(3-methoxy-4-nitro-phenoxy)-ethyl]-pyrrolidine (2.2 g, 8.3 mmol) and 5% Pd—C (0.4 g) in ethyl acetate (70 mL) was shaken under 50 psi of hydrogen for 22 hours. The mixture was filtered through Celite and evaporated, providing 1.8 g of the product, in 89% yield; 1H NMR (DMSO-d6) δ 1.78-1.83 (m, 4H), 2.58-2.63 (m, 4H), 2.86 (t, J=6.0 Hz, 2H), 3.53 (by, 2H), 3.81 (s, 3H), 4.04 (t, J=6.0 Hz, 2H), 6.35 (dd, J=8.4 Hz, J=2.7 Hz, 1H), 6.49 (d, J=2.7 Hz, 1H), 6.61 (d, J=8.4 Hz, 1H).
Reaction SMILES: C([O:3][C:4]1[NH:5][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][C:16]2[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=2[F:23])=[N:7][N:8]=1)C.Cl>>[F:23][C:17]1[CH:18]=[C:19]([I:22])[CH:20]=[CH:21][C:16]=1[NH:15][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[C:6]1[NH:5][C:4](=[O:3])[NH:8][N:7]=1
Reactant: CCOc1nnc(-c2ccncc2Nc2ccc(I)cc2F)[nH]1
Agent: Cl
Product: O=c1[nH]nc(-c2ccncc2Nc2ccc(I)cc2F)[nH]1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
[4-(5-Ethoxy-4H-[1,2,4]triazol-3-yl)-pyridin-3-yl]-(2-fluoro-4-iodo-phenyl)-amine (80 mg) was added conc. HCl (4 mL). The reaction mixture was stirred at 90° C. for 4 hr, cooled and filtered, the solid was washed with water and methanol. Yield: white solid 30 mg. LC-MS (Method A) [5.23 min; 398(M+1)]
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:37]=[CH:36][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C@@H:19]2[CH2:28][CH2:27][C:26]3[CH:25]=[C:24]([O:29]C(=O)C(C)(C)C)[CH:23]=[CH:22][C:21]=3[CH2:20]2)=[CH:7][CH:6]=1)(O)=O.Cl.[CH:39]12[NH:45][CH:42]([CH2:43][CH2:44]1)[CH2:41][CH2:40]2>>[CH:42]12[N:45]([CH2:1][CH2:4][C:5]3[CH:6]=[CH:7][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C@@H:19]4[CH2:28][CH2:27][C:26]5[CH:25]=[C:24]([OH:29])[CH:23]=[CH:22][C:21]=5[CH2:20]4)=[CH:36][CH:37]=3)[CH:39]([CH2:44][CH2:43]1)[CH2:40][CH2:41]2
Reactant: C1CC2CCC1N2
Reactant: CC(C)(C)C(=O)Oc1ccc2c(c1)CC[C@@H](c1ccccc1NCCCc1ccc(CC(=O)O)cc1)C2
Agent: Cl
Product: Oc1ccc2c(c1)CC[C@@H](c1ccccc1NCCCc1ccc(CCN3C4CCC3CC4)cc1)C2
Yield: 23 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]phenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (28 mg) and 7-azabicyclo[2.2.1]heptane hydrochloride (38 mg) according to an analogous synthetic method to Example 715 and purified by LC-MS, the title compound (6.2 mg) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6]([C:9]([F:12])([F:11])[F:10])=[N:7][O:8][C:4]=2[C:3]=1[CH2:15][CH2:16][CH3:17].N1C=CC=CC=1.[O:24](S(C(F)(F)F)(=O)=O)[S:25]([C:28]([F:31])([F:30])[F:29])(=O)=[O:26].[OH-].[Na+]>C(Cl)Cl>[F:29][C:28]([F:31])([F:30])[S:25]([O:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6]([C:9]([F:12])([F:11])[F:10])=[N:7][O:8][C:4]=2[C:3]=1[CH2:15][CH2:16][CH3:17])(=[O:26])=[O:24]
Reactant: CCCc1c(O)ccc2c(C(F)(F)F)noc12
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCc1c(OS(=O)(=O)C(F)(F)F)ccc2c(C(F)(F)F)noc12
Reaction time: 0.5 h

Procedure:
To a solution of 6-hydroxy-7-propyl-3-(trifluoromethyl)-1,2-benzisoxazole (500 mg, 2.04 mmol) in dry CH2Cl2 was added pyridine (0.82 mL, 10.2 mmol) at 0° C. under N2. Tf2O was then added dropwise to the reaction mixture and the resulting mixture stirred for 30 min. 1N NaOH was added and the mixture extracted with CH2Cl2. Combined organic extracts were washed with brine, dried over Na2SO4 and the solvent evaporated in vacuo. The residue was purified by chromatography on silica gel using ethyl acetate and hexane (10:90) to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18](O)=[O:19])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CN(C=O)C>CCOC(C)=O>[C:22]1([NH:21][C:18]([C:13]2[CH:14]=[C:15]3[C:16](=[CH:11][CH:12]=2)[CH2:17][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]3)=[O:19])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(C(=O)O)ccc2C1
Reactant: Nc1ccccc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2cc(C(=O)Nc3ccccc3)ccc2C1
Reaction time: 24 h
Yield: 93.7 %

Procedure:
To 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid (0.2 g, 0.721 mmol) and aniline (0.066 mL, 0.721 mmol) and TEA (0.251 mL, 1.803 mmol) in EtOAc (5 mL) was added a 50% solution of T3P in DMF (0.408 mL, 1.442 mmol). After 24 h, the reaction was partitioned with dilute HCl (10 mL) and EtOAc (20 mL). The organic layer was washed with brine (10 mL) and dried (MgSO4). Purification by silica gel chromatography afforded 0.238 g of Intermediate 19A. MS (ESI) m/z: 352.9 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[Li]CCCC.[Cl:17][C:18]1[CH:19]=C([CH:27]=[CH:28][CH:29]=1)C(N(OC)C)=O>C1COCC1>[Cl:17][C:18]1[CH:19]=[C:11]([C:10]2[O:9][C:3](=[O:8])[CH:4]=[C:5]([OH:6])[CH:7]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: CON(C)C(=O)c1cccc(Cl)c1
Reactant: CCOC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1cc(O)cc(-c2cccc(Cl)c2)o1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 39.4 %

Procedure:
A slurry of 60% NaH (0.790 g, 19.7 mmol) in THF (50 mL) under a N2 atmosphere was cooled to 0° C. and treated with ethyl acetoacetate (2.51 mL, 19.7 mmol). The resulting solution was subsequently treated with n-BuLi (12.3 mL, 19.7 mmol) and stirred for 20 min. at 0° C. to provide an orange solution which was treated via cannula with a solution of 3-chloro-N-methoxy-N-methylbenzamide (2.50 g, 15.15 mmol) in THF (5.0 mL). The mixture was allowed warm to ambient temperature where it was stirred for 14 h before being quenched with 2.0 N HCl. The product was extracted with ethylacetate (3×50 mL), the layers combined, dried with Na2SO4, and the solvent removed in vacuo. The residue was then treated with conc. H2SO4 (20 mL) and the resulting mixture stirred for 18 h at room temperature before being diluted with H2O (200 mL). The product was then extracted with ethylacetate (3×100 mL) being sure to collect all solids. The layers were then combined and diluted with acetone to provide a homogenous solution which was dried with Na2SO4. The solvent was then removed in vacuo and the resulting solid recrystallized from acetone-hexane to provide the title compound (1.33 g, m.p. 254-256° C.). 1H NMR (400 MHz, DMSO-d6) δ11.957 (bs, 1 H), 7.889 (t, 1 H, J =1.5 Hz), 7.839-7.813 (m, 1 H), 7.598-7.524 (m, 2 H), 7.876 (d, 1 H, J=2 Hz), 5.450 (d, 1 H, J=2 Hz).
Reaction SMILES: N[CH2:2][C:3]1[C:4]([CH3:25])=[N:5][C:6]2[N:7]([CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=2)[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16].[O:26](C(OC(C)(C)C)=O)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=O.CCN(CC)CC>C1COCC1>[C:30]([O:29][C:27]([CH2:2][C:3]1[C:4]([CH3:25])=[N:5][C:6]2[N:7]([CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=2)[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])=[O:26])([CH3:33])([CH3:32])[CH3:31]
Reactant: CCOC(=O)c1cn2c(-c3ccc(Cl)cc3Cl)c(CN)c(C)nc2n1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2c(-c3ccc(Cl)cc3Cl)c(CC(=O)OC(C)(C)C)c(C)nc2n1
Reaction time: 2 h
Yield: 40.6 %

Procedure:
To a stirred solution of ethyl 6-(aminomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxylate (Example 54, Step 10, 200 mg, 0.53 mmol) in THF (5 mL) at room temperature was added (BOC)2O (1.0 M in THF, 1.05 mL, 1.05 mmol) and Et3N (0.37 mL, 2.65 mmol). After 2 h, the reaction was concentrated under reduced pressure and diluted with EtOAc. The organic layer was washed with NH4Cl and brine prior to drying over anhydrous MgSO4. Filtration, concentration under reduced pressure and purification by silica gel chromatography gave ethyl 6-((tert-butoxycarbonyl)methyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxylate (100 mg, 40%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:13]=[CH:12][C:11]([CH2:14]CBr)=[C:6]([C:7]([O:9]C)=O)[CH:5]=1.CCN(CC)CC.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][CH2:32][CH2:33][NH2:34]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:14][N:34]([CH2:33][CH2:32][NH:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=1)[C:7]2=[O:9])=[O:17]
Reactant: COC(=O)c1ccc(CCBr)c(C(=O)OC)c1
Reactant: NCCNc1ccccn1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)C(=O)N(CCNc1ccccn1)C2
Temperature: 25 °C

Procedure:
A solution of (5) (511 mg, 1.78 mmol) in toluene (10 ml) was treated with Et3N (744 μl 5.33 mmol) and N1-pyridin-2-yl-ethane-1,2-diamine (244 mg, 1.78 mmol) [prepared by treatment of 2-bromopyridine with excess ethylene diamine and pyridine] and the mixture refluxed for 6 hours. After cooling to room temperature and evaporation of the solvent, the residue was purified by flash chromatography: silica, CH2Cl2/acetone (3:2).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]3[N:21]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=4[O:34][CH3:35])[C:22](=[O:24])[NH:23][C:15]=23)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:43]([C:45]1[CH:52]=[CH:51][CH:50]=[CH:49][C:46]=1[CH2:47]Br)#[N:44].O>CN(C=O)C>[C:1]([O:5][C:6](=[O:36])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]3[N:21]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=4[O:34][CH3:35])[C:22](=[O:24])[N:23]([CH2:47][C:46]4[CH:49]=[CH:50][CH:51]=[CH:52][C:45]=4[C:43]#[N:44])[C:15]=23)[CH2:9]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: N#Cc1ccccc1CBr
Reactant: COc1ccc(Cn2c(=O)[nH]c3c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)cc(C)nc32)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2c(=O)n(Cc3ccccc3C#N)c3c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)cc(C)nc32)c(OC)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.8 %

Procedure:
1.03 g (R)-1-[3-(2,4-dimethoxybenzyl)-5-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl]piperidine-3-carbamic acid tert-butyl ester (2.07 mmol) was dissolved in 5 mL DMF. 0.57 g potassium carbonate (4.14 mmol) was added, and then 0.45 g 2-cyano-benzyl bromide (2.28 mmol) was added. The reaction solution was stirred for 5 h at room temperature, and slowly poured into 100 mL water to precipitate a solid, filtrated, and dried to afford 1.24 g crude product with a yield of 97.9%.