Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:42])([F:41])[C:10]([NH:12][CH2:13][CH2:14][CH2:15][N:16]([CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:40])[C:36]([F:39])([F:38])[F:37])[CH2:17][CH2:18][CH2:19][N:20]([CH2:27][C:28](O)=[O:29])[C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])=[O:11].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:70][CH2:71][CH:72]1[CH2:76][O:75][CH:74]([O:77][CH2:78][CH2:79][CH2:80][C:81]([N:83]([CH2:98][CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][CH2:104][CH2:105][CH2:106][CH2:107][CH2:108][CH2:109][CH2:110][CH3:111])[CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH2:95][CH2:96][CH3:97])=[O:82])[O:73]1>ClCCl>[F:8][C:9]([F:41])([F:42])[C:10]([NH:12][CH2:13][CH2:14][CH2:15][N:16]([CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:40])[C:36]([F:37])([F:38])[F:39])[CH2:17][CH2:18][CH2:19][N:20]([C:21](=[O:26])[C:22]([F:24])([F:25])[F:23])[CH2:27][C:28]([NH:70][CH2:71][CH:72]1[CH2:76][O:75][CH:74]([O:77][CH2:78][CH2:79][CH2:80][C:81]([N:83]([CH2:98][CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][CH2:104][CH2:105][CH2:106][CH2:107][CH2:108][CH2:109][CH2:110][CH3:111])[CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH2:95][CH2:96][CH3:97])=[O:82])[O:73]1)=[O:29])=[O:11]
Reactant: CCCCCCCCCCCCCCN(CCCCCCCCCCCCCC)C(=O)CCCOC1OCC(CN)O1
Reactant: O=C(O)CN(CCCN(CCCNC(=O)C(F)(F)F)CCCNC(=O)C(F)(F)F)C(=O)C(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCN(CCCCCCCCCCCCCC)C(=O)CCCOC1OCC(CNC(=O)CN(CCCN(CCCNC(=O)C(F)(F)F)CCCNC(=O)C(F)(F)F)C(=O)C(F)(F)F)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.9 ml of triethylamine (13.8 mmol), 2 g of [(3-{bis[3-(2,2,2-trifluoroacetylamino)propyl]amino}-propyl)trifluoroacetylamino]acetic acid (trifluoroacetate salt, 3.04 mmol) and 1.8 g of BOP (4.14 mmol) were successively added to 1.65 g of 4-(4-aminomethyl-[1,3]dioxolan-2-yloxy)-N,N-ditetradecylbutyramide (2.76 mmol) dissolved in 30 ml of dichloromethane. The solution was stirred for 1 hour at room temperature.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:24]([NH2:27])([CH3:26])[CH3:25]>>[F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([NH:27][CH:24]([CH3:26])[CH3:25])=[O:6]
Reactant: O=C(O)c1cc(F)ccc1F
Reactant: CC(C)N
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(C)NC(=O)c1cc(F)ccc1F

Procedure:
The title compound was prepared from 2,5-difluorobenzoic acid (10 g, 63.2 mmol), carbonyldiimidazole (9.57 g, 61 mmol) and isopropyl amine (5.15 mL, 60.5 mmol) according to the procedure used for example 84 (Step A) to give near quantitative yield of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]([C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=1[N+:17]([O-])=O)([CH3:9])[C:5](OC)=[O:6]>CC(O)=O.[Fe]>[CH3:1][O:2][C:3]([C:4]1([CH3:9])[C:10]2[C:11](=[CH:12][C:13]([Br:16])=[CH:14][CH:15]=2)[NH:17][C:5]1=[O:6])=[O:20]
Reactant: COC(=O)C(C)(C(=O)OC)c1ccc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: COC(=O)C1(C)C(=O)Nc2cc(Br)ccc21
Temperature: 95 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
A mixture of 2-(4-bromo-2-nitro-phenyl)-2-methyl-malonic acid dimethyl ester (5 g, 14.4 mmol) in AcOH (30 mL) containing iron powder (2.4 g, 43.3 mmol) was stirred at 95° C. for 1 h. After that time a second aliquot of iron powder was added (803 mg, 14.4 mmol) and the stirring was maintained for an additional hour. The solvent was then removed in vacuo and the residue dissolved in EtOAc. The solid was collected by filtration and dissolved in 2 M aqueous HCl (20 mL). The mixture was stirred for 1 h at room temperature and the product was then extracted with DCM (3×). The organic phase was dried over MgSO4 and concentrated in vacuo to give the title compound (2.7 g) as a white solid. MS: [M+H]+=284.
Reaction SMILES: FC(F)(F)C1C=CC(N)=CC=1.C(OC(OCC)OCC)C.ClC1C=CC=CC=1C1NN=C(C2CC2)C=1C(NC1C=CC(C(F)(F)F)=CC=1)=O.ClC1C=CC=CC=1C1NN=C(C2CC2)C=1C(NC1C=CC(C(F)(F)F)=C(C)C=1)=O.[Cl:79][C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][C:81]=1[C:86]1[NH:90][N:89]=[C:88]([CH:91]2[CH2:93][CH2:92]2)[C:87]=1[C:94]([NH:96][C:97]1[CH:102]=[CH:101][C:100]([S:103]([C:106]([F:109])([F:108])[F:107])(=[O:105])=[O:104])=[C:99](C)[CH:98]=1)=[O:95]>>[Cl:79][C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][C:81]=1[C:86]1[NH:90][N:89]=[C:88]([CH:91]2[CH2:92][CH2:93]2)[C:87]=1[C:94]([NH:96][C:97]1[CH:102]=[CH:101][C:100]([S:103]([C:106]([F:109])([F:107])[F:108])(=[O:105])=[O:104])=[CH:99][CH:98]=1)=[O:95]
Reactant: Cc1cc(NC(=O)c2c(C3CC3)n[nH]c2-c2ccccc2Cl)ccc1S(=O)(=O)C(F)(F)F
Agent: Cc1cc(NC(=O)c2c(C3CC3)n[nH]c2-c2ccccc2Cl)ccc1C(F)(F)F
Agent: Nc1ccc(C(F)(F)F)cc1
Agent: O=C(Nc1ccc(C(F)(F)F)cc1)c1c(C2CC2)n[nH]c1-c1ccccc1Cl
Solvent: CCOC(OCC)OCC
Product: O=C(Nc1ccc(S(=O)(=O)C(F)(F)F)cc1)c1c(C2CC2)n[nH]c1-c1ccccc1Cl

Procedure:
By substituting the appropriate amines for 4-(trifluoromethyl)aniline in a, and then by substituting triethyl-2-chloroorthobenzoate for triethylorthoformate in b, the identical process of a gives 5-(2-chlorophenyl)-3-cyclopropyl-4-[4-(trifluoromethyl) phenylaminocarbonyl]pyrazole, 5-(2-chlorophenyl)-3-cyclopropyl-4-(pyrid-2-aminocarbonyl)pyrazole, and 5-(2-chlorophenyl)-3-cyclopropyl-4-[3-methyl-4-(trifluoromethyl) phenylaminocarbonyl]pyrazole and 5-(2-chlorophenyl)-3-cyclopropyl-4-[3-methyl-4-(trifluoromethyl-sulfonyl)phenylaminocarbonyl]pyrazole.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O.[BH3-]C#N.[Na+]>CO.CN1C(=O)N(C)CC1>[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: O=Cc1cccc(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN1CCN(C)C1=O
Solvent: CO
Product: Clc1cccc(CNc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1

Procedure:
Analogously to Example 21, 1.00 mmol of 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine in 26 ml of methanol, 13 ml of DMEU and 3.0 mmol of acetic acid are first reacted with 3-chloro-benzaldehyde and then reduced with 7.00 mmol of NaCNBH3 (5-7 days). 3-(3-Chloro-benzylamino)-4-(3-chloro-phenylamino)-1H-pyrazolo-[3,4-d]pyrimidine is obtained; m.p. 158-163° C.; HPLC: TRet (Grad20-100)=12.4.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:5][C:4](=[O:22])[CH:3]=1.CCN(CC)CC.[CH3:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33](Cl)=O.CC(C)(O)C#N.C([BH3-])#N.[Na+]>C(O)(=O)C.C(#N)C.C(Cl)Cl>[OH:1][C:2]1[CH2:7][C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:5][C:4](=[O:22])[C:3]=1[CH2:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[CH3:33]
Reactant: O=C1C=C(O)CC(CCc2ccccc2)(c2ccccc2)O1
Reactant: Cc1ccccc1C(=O)Cl
Agent: CC(C)(O)C#N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CC(=O)O
Product: Cc1ccccc1CC1=C(O)CC(CCc2ccccc2)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared as described in General Method 8 using the following: 5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (0.250 g, 0.850 mmol), Et3N (0.12 mL, 0.85 mmol), 2-methylbenzoyl chloride (0.11 mL, 0.85 mmol), CH2Cl2 (5.0 mL), acetonitrile (4.0 mL), acetone cyanohydrin (0.04 mL, 0.43 mmol), Et3N (0.24 mL, 1.7 mmol), glacial acetic acid (10.0 mL), sodium cyanoborohydride (0.151 g, 2.4 mmol). Purification was achieved by submitting the final residue to column chromatograpy (SiO2, 100% CH2Cl2 to 2% MeOH in CH2Cl2) to provide a solid (0.195 g, m.p. 109°-111° C.). 1H NMR (400 MHz, DMSO-d6) δ10.886 (bs, 1H), 7.457-7.359 (m, 5H), 7.242 (t, 2H, J=7 Hz), 7.169-7.130 (m, 1H), 7.097 (d, 2H, J=7.5 Hz), 7.001 (d, 1H, J=7.5 Hz), 6.937 (t, 1H, J=7.5 Hz), 6.695 (t, 1H, J=7 Hz), 6.215 (d, 1H, J=7.5 Hz), 3.292 (d, 1H, J=17 Hz), 3.169 (d, 1H, J=17 Hz), 2.643-2.584 (m, 1H), 2.50-2.475 (2H+solvent) 2.296-2.182 (m, 3H), 2.125 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([F:24])[CH:23]=1)[CH2:5][C@H:6]1[C@@H:10]([C@H:11]2[CH2:15][C@@H:14]([O:16]CC=C)[CH2:13][NH:12]2)[O:9][C:8](=[O:20])[NH:7]1.N[C@@H](CC1C=C(F)C=C(F)C=1)[C@@H]([C@H]1COCCN1[CH:35]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)O.FC1C=C(C=C(F)C=1)C[C@H]1[C@@H]([C@H]2CCCCN2C(C2C=CC=CC=2)C2C=CC=CC=2)OC(=O)N1.[Li+].[OH-]>CCO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([F:24])[CH:23]=1)[CH2:5][C@H:6]1[C@@H:10]([C@H:11]2[CH2:15][C@H:14]([OH:16])[CH2:13][N:12]2[CH:35]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[O:9][C:8](=[O:20])[NH:7]1
Reactant: C=CCO[C@H]1CN[C@@H]([C@H]2OC(=O)N[C@H]2Cc2cc(F)cc(F)c2)C1
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1COCCN1C(c1ccccc1)c1ccccc1
Agent: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2CCCCN2C(c2ccccc2)c2ccccc2)O1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@H](O)CN2C(c2ccccc2)c2ccccc2)O1
Reaction time: 8 h

Procedure:
Step L (8): (1S,2S)-2-Amino-1-((R)-4-benzhydrylmorpholin-3-yl)-3-(3,5-difluorophenyl)propan-1-ol. To a solution of (4S,5S)-4-(3,5-difluorobenzyl)-5-((R)-4-benzhydrylmorpholin-3-yl)oxazolidin-2-one (step L (7), 85 mg, 0.18 mmol) in EtOH (2 mL) was added a solution of LiOH (66 mg, 2.75 mmol) in H2O (1 mL). This reaction mixture was brought to 98° C. and stirred for overnight. Solvent was removed and 1N HCl solution (50 mL) was added to the mixture and washed with diethyl ether. The aqueous phase was basified with 50% aqueous NaOH solution. This mixture was extracted with ethyl acetate. The combined organic layer was dried (Na2SO4), and concentrated in vacuo to give 80 mg of the title compound: 1H NMR (CDCl3, 500 MHz) δ 1.94-2.06 (3H, m), 2.30 (1H, dd, J=10, 15 Hz), 2.51-2.59 (1H, m), 2.73-2.81 (1H, m), 2.90 (1H, m), 2.95 (1H, m), 3.08 (1H, m), 3.70 (1H, m), 3.80 (1H, dt, J=5, 10 Hz), 3.91 (1H, m), 4.09 (1H, m), 4.14 (1H, m), 5.05 (1H, s), 6.60-6.68 (3H, m), 7.15-7.31 (6H, m), 7.37 (2H, d, J=10 Hz), 7.42 (2H, d, J=5 Hz). MS (ESI) (M+H)+ 439.20.
Reaction SMILES: Br[CH:2]([CH:6]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=2)[CH:9]=1)[CH3:7])[C:3](Br)=[O:4].[C:20]([NH2:28])(=[S:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:19][O:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:6]([C:2]1[S:27][C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:28][C:3]=1[OH:4])[CH3:7])[CH:17]=[CH:16]2
Reactant: NC(=S)c1ccccc1
Reactant: COc1ccc2cc(C(C)C(Br)C(=O)Br)ccc2c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1ccc2cc(C(C)c3sc(-c4ccccc4)nc3O)ccc2c1
Temperature: 100 °C
Yield: 35.4 %

Procedure:
To a solution of 2-bromo-3-(6-methoxy-2-naphthyl) butyrylbromide (386 mg, 1 mmol) in toluene (20 mL) was added thiobenzamide (137 mg, 1 mmol) and pyridine (0.16 mL, 2 mmol) in toluene (60 mL) at 23° C. The reaction mixture was heated at 100° C. for 4 hours and then cooled and the solvent removed in vacuo. Recrystallization of the residue from ethanol/ether provided the desired product (128 mg). mp 224°-226° C., 1H NMR (60 MHz, DMSO-d6) 1.30 (3H, d, J=7 Hz), 3.82 (3H, s), 3.92 (1H, g, J=7 Hz), 7.1-8.0 (11H, m), 10.55 (1H, s); Mass Spectrum: 361 (M+).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][CH:7]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]3[C:17](=[O:18])[C:16](=[O:19])[C:15]=3[NH:20][C@@H:21]([CH2:33][CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[CH2:22][NH:23]C(=O)CCC[Si](C)(C)C)[CH2:9]2)[CH2:3][CH2:2]1.[ClH:46]>O1CCOCC1.CO>[ClH:46].[NH2:23][CH2:22][C@@H:21]([NH:20][C:15]1[C:16](=[O:19])[C:17](=[O:18])[C:14]=1[N:10]1[CH2:11][CH2:12][CH2:13][CH:8]([CH:7]([O:6][CH2:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:9]1)[CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: C[Si](C)(C)CCCC(=O)NC[C@H](CC1CCCCC1)Nc1c(N2CCCC(C(OCCC3CC3)c3ccccc3)C2)c(=O)c1=O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC[C@H](CC1CCCCC1)Nc1c(N2CCCC(C(OCCC3CC3)c3ccccc3)C2)c(=O)c1=O
Reaction time: 1.5 h
Yield: 99 %

Procedure:
The N—((S)-2-(2-(3-((2-cyclopropylethoxy)(phenyl)methyl)piperidin-1-yl)-3,4-dioxocyclobut-1-enylamino)-3-cyclohexylpropyl)-4-(trimethylsilyl)butanamide (12.3 mg, 0.02 mmol) was dissolved in dioxane (1 mL) and treated with 4M HCl in dioxane (0.5 mL, 2.0 mmol). The solution was allowed to stir for 1.5 h before evaporation of solvent. The residual oil was redissolved in methanol and evaporated under reduced pressure to afford 3-((S)-1-amino-3-cyclohexylpropan-2-ylamino)-4-(3-((2-cyclopropylethoxy)(phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione hydrochloride as an oil (10 mg, >99%). MS ESI+ve m/z 494 (M+1).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C@@H:11]([CH3:14])[C@@H:10]([N:15]([CH3:25])[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[NH:22][CH:23]=[CH:24][C:17]=23)[CH2:9]1)C1C=CC=CC=1.C(O)C>Cl.O.[Pd]>[CH3:25][N:15]([C@@H:10]1[C@H:11]([CH3:14])[CH2:12][CH2:13][NH:8][CH2:9]1)[C:16]1[CH:21]=[CH:20][N:19]=[C:18]2[NH:22][CH:23]=[CH:24][C:17]=12
Reactant: C[C@@H]1CCN(Cc2ccccc2)C[C@@H]1N(C)c1ccnc2[nH]ccc12
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: C[C@@H]1CCNC[C@@H]1N(C)c1ccnc2[nH]ccc12
Reaction time: 8 h
Yield: 236.5 %

Procedure:
A degassed mixture of N-[(3R,4R)-1-benzyl-4-methylpiperidin-3-yl]-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine (0.030 g, 0.000090 mol) and palladium (0.028 g, 0.000026 mol) in ethanol (2 mL, 0.03 mol) and 3.0 M of hydrogen chloride in water (0.2 mL) was stirred under an atmosphere of hydrogen overnight. The reaction mixture was filtered and washed with MeOH. The solvent was removed under vacuum to give 52 mg of an orange viscous oil. The oil was partitioned between ethyl acetate and sat. NaHCO3. The aqueous phase was extracted with ethyl acetate and THF. The combined organic phases were washed with sat. NaCl. Solvents were removed under vacuum to give 47 mg of an orange solid. 1H NMR (400 MHz, MeOH): δ 7.8 (1H, d); 7.1 (1H, d); 6.6 (1H, d); 6.3 (1H, d); 4.45 (1H, m); 3.7 (1H, m); 3.12 (3H, s); 3.4-1.0 (6H, m); 1.1 (3H, d). MS (M+H)+: 245.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH3:17][Mg]Cl.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1COCC1.O>[CH3:17][C:5]1[C:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[S:8][C:7]=2[CH:15]=[CH:16][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: C[Mg]Cl
Reactant: O=[N+]([O-])c1ccc2sc3ccccc3c2c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1c([N+](=O)[O-])ccc2sc3ccccc3c12
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To a stirred suspension of 2-nitrodibenzothiophene (2.20 g, 9.61 mmol) in dry THF (100 ml) at −15° C. was slowly added methyl magnesium chloride (3 M solution in THF; 9.6 ml, 29 mmol). After stirring at this temperature for 5.5 h, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (6.98 g, 30.75 mmol) was added portion wise, keeping the temperature below −10° C. The mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was diluted with water and extracted into DCM. The organic layers were further washed with water, dried and purified by chromatography (eluent—50% DCM /isohexane) to give the title compound as a yellow solid. NMR: 8.52 (m, 1H), 8.12 (m, 2H), 7.94 (d, 1H), 7.61 (m, 2H), 2.92 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]([C:33]5[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=5)[C:25]([C:27]5([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]5)=[O:26])=[CH:20][C:19]=4[F:40])=[C:11]3[C:10](I)=[N:9]2)=[CH:5][CH:4]=1.[CH3:44][N:45]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]#[CH:53])[CH2:47][CH2:46]1.C(N(CC)CC)C>[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]([C:33]5[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=5)[C:25]([C:27]5([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]5)=[O:26])=[CH:20][C:19]=4[F:40])=[C:11]3[C:10]([C:53]#[C:52][CH2:51][N:48]3[CH2:49][CH2:50][N:45]([CH3:44])[CH2:46][CH2:47]3)=[N:9]2)=[CH:5][CH:4]=1
Reactant: C#CCN1CCN(C)CC1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4F)ccnc32)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(C#CCN3CCN(C)CC3)c3c(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4F)ccnc32)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 39.4 %

Procedure:
A stirred mixture of N-(4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (25 mg, 0.036 mmol), 1-methyl-4-(prop-2-ynyl)piperazine (10 mg, 0.072 mmol; obtained from Example 7, Step D), copper(I)iodide (0.3 mg, 0.002 mmol), triethylamine (0.25 mL, 1.8 mmol), and THF (0.5 mL) was sparged with N2 for 2 minutes, then tetrakis(triphenylphosphine)palladium (2 mg, 0.002 mmol) was added. The sealed reaction was heated to 50° C. for 18 hours. Additional 1-methyl-4-(prop-2-ynyl)piperazine (10 mg, 0.07 mmol), copper(I)iodide (0.3 mg, 0.002 mmol), and tetrakis(triphenylphosphine)palladium (2 mg, 0.002 mmol) were added and heating was continued at 80° C. for 5 hours. After cooling to room temperature, the entire reaction mixture was loaded directly on to a preparative TLC plate, eluting with 10% MeOH (containing 7N NH3) in CHCl3. The product was obtained as a waxy solid (10 mg, 37%). 1H NMR (400 MHz, CDCl3) δ 10.06 (s, 1H), 8.30 (d, J=6 Hz, 1H), 8.25 (s, 1H), 7.77 (m, 1H), 7.45 (m, 2H), 7.34 (d, J=9 Hz, 2H), 7.24 (m, 2H), 7.06 (m, 2H), 6.82 (d, J=9 Hz, 2H), 6.25 (d, J=6 Hz, 1H), 5.60 (s, 2H), 3.76 (s, 3H), 3.55 (s, 2H), 2.68 (m, 4H), 2.39 (m, 4H), 2.23 (s, 3H), 1.81 (m, 2H), 1.62 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18]C(=O)C)=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[N:5][N:4]=1.Cl>>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:6]2[S:7][C:3]([CH2:2][OH:1])=[N:4][N:5]=2)(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2nnc(CO)s2)cc1
Agent: Cl
Product: Nc1ccc(S(=O)(=O)Nc2nnc(CO)s2)cc1
Yield: 68.1 %

Procedure:
Distilled water (3.0 mL) and 10% NaOH (1.5 mL) were added to compound 126 (328 mg, 0.94 mmol) and the mixture was heated under reflux for 2 h. The pH of the solution was then adjusted to 4.0 by addition of 1.0 M HCl and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with water (20 mL) and concentrated to give a crude product which was purified by chromatography on silica gel eluted with CH2Cl2:methanol 4:1 to afford 182 mg (0.64 mmol, 68%) of the product as a solid, mp 89-90° C.; 1H NMR (300 MHz, DMSO-d6) δ 4.54 (s, 2H), 5.91 (br, 1H), 6.55 (d, 2H, J=8.7 Hz), 7.39 (d, 2H, J=9.0 Hz); 13C NMR (75 MHz, DMSO-d6) δ 59.1, 113.2, 128.0, 128.4, 153.2, 161.0, 167.5; MS (LCQ, ESI+) Calcd for C9H11N4O3S2 287.0, found 287.0 (M+H)+; HRMS (ESI+, m/z) Calcd for C9H11N4O3S2 287.0273, found 287.0269 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:12]=[CH:11][C:10]2[CH:9]=[CH:8][C:7]3[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:14][NH:15][C:6]=3[C:5]=2[N:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][CH2:29][N:30]([CH3:32])[CH3:31].O>CN(C)C=O>[CH3:31][N:30]([CH3:32])[CH2:29][CH2:28][N:15]1[C:6]2[C:5]3[N:4]=[C:3]([S:2][CH3:1])[N:12]=[CH:11][C:10]=3[CH:9]=[CH:8][C:7]=2[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:14]1
Reactant: CCOC(=O)c1n[nH]c2c1ccc1cnc(SC)nc12
Reactant: CN(C)CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nn(CCN(C)C)c2c1ccc1cnc(SC)nc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of ethyl 8-(methylsulfanyl)-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (150 mg, 0.52 mmol) in dry dimethylformamide (4 ml) was added cesium carbonate (339 mg 1.04 mmol) followed by 2-bromo-N,N-dimethylethanamine (135 mg 0.88 mmol). The heterogeneous mixture was stirred at room temperature for 24 hours. The mixture was treated with water and extracted with EtOAc. The organic layer washed with brine, dried over Na2SO4 and concentrated. The crude was purified by silica gel chromatography eluting with EtOAc/Ethanol 85/15 to give ethyl 1-[2-(dimethylamino)ethyl]-8-(methylsulfanyl)-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate as the major isomer (60 mg 32%) 1H NMR (401 MHz, DMSO-d6) δ 9.51 (s, 1H), 8.16 (d, J=8.67 Hz, 1H), 7.83 (d, J=8.79 Hz, 1H), 5.29 (t, J=6.59 Hz, 1H), 4.32-4.49 (m, 2H), 2.94 (br. s., 2H), 2.71 (s, 3H), 2.24 (br. s., 6H), 1.41 (t, J=7.08 Hz, 3H); and
Reaction SMILES: [O:1]=[C:2]([CH3:10])[CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[CH3:11][Mg+].[Br-].Cl>C(OCC)C>[OH:1][C:2]([CH3:11])([CH3:10])[CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: CC(=O)CN1CCOCC1
Reactant: C[Mg+]
Agent: Cl
Agent: [Br-]
Solvent: CCOCC
Product: CC(C)(O)CN1CCOCC1
Temperature: 0 °C
Yield: 33 %

Procedure:
A solution of N-(2-oxopropyl)morpholine (82 g, 0.57 mmol) in diethyl ether (400 ml) was added to a solution of 3M CH3MgBr (500 ml, 1.5 ml) in anhydrous diethyl ether (21) and stirred at 0° C. under an argon atmosphere. The mixture was stirred at ambient temperature for 16 hours, treated with 12N HCl (50 ml) and extracted with ethyl acetate. The product was purified by flash column chromatography eluting with ethyl acetate to give N-(2-hydroxy-2-methylpropyl)morpholine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:23])=[C:15]([N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[CH:16]=3)[C:11](=[O:24])[N:10]([O:25]CC3C=CC=CC=3)[C:9]2=[O:33])=[CH:4][CH:3]=1>[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:23])=[C:15]([N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[CH:16]=3)[C:11](=[O:24])[N:10]([OH:25])[C:9]2=[O:33])=[CH:4][CH:3]=1
Reactant: O=c1c2cc(F)c(N3CCCC3)cc2n(-c2ccc(F)cc2)c(=O)n1OCc1ccccc1
Agent: [Pd]
Product: O=c1c2cc(F)c(N3CCCC3)cc2n(-c2ccc(F)cc2)c(=O)n1O
Yield: 77.3 %

Procedure:
Using the General Method 6A, the reaction of 10% Pd/C (0.027 g) with 1-(4-fluorophenyl)-6-fluoro-3-benzyloxy-7-pyrrolidin-1-yl-1H-quinazoline-2,4-dione (Example L-1, 0.08 g, 0.18 mmol) afforded 0.05 g of the title compound as a solid, mp 183-185° C.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:18][C:19]1[CH:38]=[CH:37][C:22]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)[C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:11]=1.ClC1C=CC=C(C(OO)=[O:47])C=1>O1CCCC1>[CH3:1][S:2]([CH2:3][CH2:4][CH2:5][N:6]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][O:24][C:25]2[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:29][CH:30]=2)=[CH:37][CH:38]=1)[C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:11]=1)=[O:47]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)CCc1ccc(OCc2ccc(CN(CCCSC)c3nc(-c4ccccc4)cs3)cc2)cc1
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(OCc2ccc(CN(CCCS(C)=O)c3nc(-c4ccccc4)cs3)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.5 %

Procedure:
A mixture of methyl 3-{4-[(4-{[[3-(methylthio)propyl](4-phenyl-1,3-thiazol-2-yl)amino]methyl}benzyl)oxy]phenyl}-propanoate (280 mg), m-chloroperbenzoic acid (122 mg) and tetrahydrofuran (10 mL) was stirred at room temperature for 3 hr. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19-1:0 in volume ratio) to give the title compound (180 mg, yield 62%) as a yellow oil.