Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:3]=1[C:4]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[N:14][NH:15][C:9]=2[C:8]2[S:16][CH:17]=[CH:18][C:7]1=2)=[O:5].[CH3:24][C:25]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:26]=1[C:27](Cl)=[O:28].[OH-].[Na+].Cl>C(Cl)Cl.CO.O1CCCC1.O.C(N(CC)CC)C>[NH:15]1[C:9]2[C:8]3[S:16][CH:17]=[CH:18][C:7]=3[N:6]([C:4]([C:3]3[CH:19]=[CH:20][C:21]([NH:23][C:27](=[O:28])[C:26]4[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:25]=4[CH3:24])=[CH:22][C:2]=3[Cl:1])=[O:5])[CH2:12][CH2:11][C:10]=2[CH:13]=[N:14]1
Reactant: Nc1ccc(C(=O)N2CCc3cn[nH]c3-c3sccc32)c(Cl)c1
Reactant: Cc1ccc(F)cc1C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2CCc3cn[nH]c3-c3sccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.1 %

Procedure:
To an ice bath cooled mixture of 345 mg of 6(2-chloro-4-aminobenzoyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]thieno[3,2-b]azepine in 3.5 ml of methylene chloride is added 417 μl of triethylamine is added a solution of 432 mg of 2-methyl-5-fluorobenzoyl chloride in 1.5 ml of methylene chloride. The reaction mixture is stirred at room temperature for 18 hours under argon. An additional 40 ml of methylene chloride is added followed by 20 ml of water. The organic layer is washed with 20 ml each of 2N citric acid, 1M NaHCO3 and brine. The organic layer is dried (Na2SO4), filtered through hydrous magnesium silicate and the filtrate evaporated in vacuo to give a foam residue. To a solution of 800 mg of the preceding compound in 4 ml methanol and 4 ml of tetrahydrofuran is added 2.7 ml of 1N NaOH. The reactants are stirred at room temperature for 1.5 hours. The reaction mixture is neutralized with 1N HCl and evaporated in vacuo to a residue which is diluted with 50 ml of methylene chloride and water and then filtered. The collected solid is dried at 60° C. to give 275 mg of the desired product as an off-white solid, m.p. 310°-312° C.
Reaction SMILES: COC1C=CC(C[N:8]2[C:26](=[O:27])[N:25]3[CH:21]([CH2:22][CH:23]([O:28][C:29]4[C:38]5[C:33](=[C:34]([CH3:41])[C:35]([O:39][CH3:40])=[CH:36][CH:37]=5)[N:32]=[C:31]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[N:30]=4)[CH2:24]3)[C:20](=[O:48])[NH:19][C:18]3([C:49]([NH:51][S:52]([CH:55]4[CH2:57][CH2:56]4)(=[O:54])=[O:53])=[O:50])[CH:16]([CH2:17]3)[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=CC=1>ClCCl.FC(F)(F)C(O)=O>[CH3:40][O:39][C:35]1[C:34]([CH3:41])=[C:33]2[C:38]([C:29]([O:28][CH:23]3[CH2:22][CH:21]4[N:25]([C:26](=[O:27])[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH:15][CH:16]5[C:18]([C:49]([NH:51][S:52]([CH:55]6[CH2:57][CH2:56]6)(=[O:54])=[O:53])=[O:50])([NH:19][C:20]4=[O:48])[CH2:17]5)[CH2:24]3)=[N:30][C:31]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[N:32]2)=[CH:37][CH:36]=1
Reactant: COc1ccc(CN2CCCCCC=CC3CC3(C(=O)NS(=O)(=O)C3CC3)NC(=O)C3CC(Oc4nc(-c5ccccc5)nc5c(C)c(OC)ccc45)CN3C2=O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCNC(=O)N4C3)nc(-c3ccccc3)nc2c1C
Yield: 64 %

Procedure:
Compound 173 (150 mg, 0.18 mmol) was stirred for 30 min in a mixture of dichloromethane-trifluoroacetic acid; 2:1. Evaporation and purification by column chromatography (5% methanol in ether) gave the title compound (81 mg, 62%). MS (M−H)+ 703
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][C:6]([Cl:16])=[C:7]([C:9](=[O:15])[C:10]([O:12]CC)=[O:11])[N:8]=1)=[O:2].[OH-].[Na+].Cl>O>[CH:1]([NH:3][C:4]1[S:5][C:6]([Cl:16])=[C:7]([C:9](=[O:15])[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2]
Reactant: CCOC(=O)C(=O)c1nc(NC=O)sc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=CNc1nc(C(=O)C(=O)O)c(Cl)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the intermediate from Step 1 (3.6 g, 13.7 mmol) was added 1M NaOH (30 mL, 30 mmol). The resulting suspension was stirred at room temperature for 2 hours (at which time the solution was clear) and 1M HCl (30 mL, 30 mmol) was then added, followed by 100 mL of water. After vigorous stirring, the resulting precipitate was filtered, washed with a minimum amount of cold water and air dried to afford the title intermediate as an off-white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1)[CH3:2].[OH-].[K+]>ClCCl.O.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[K+].[K+].[K+].[Fe+3]>[CH2:22]([N:3]([CH2:1][CH3:2])[C:4](=[O:21])[CH:5]=[C:6]1[CH:11]=[C:10]([C:12]([CH3:14])([CH3:15])[CH3:13])[C:9](=[O:16])[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:7]1)[CH3:23]
Reactant: CCN(CC)C(=O)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Fe+3]
Agent: [C-]#N
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCN(CC)C(=O)C=C1C=C(C(C)(C)C)C(=O)C(C(C)(C)C)=C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
4.80 g (0.015 Mol) of N,N-diethyl-2-(3,5-di-tert-butyl-4-hydroxy-phenyl)acetamide are dissolved in 60 ml of dichloromethane. To this solution a solution of 15 g (0.046 mol) of potassium hexacyanoferrate (III) and 6.0 g (0.11 mol) of potassium hydroxide in 120 ml of water is added, and the mixture is stirred one hour at room temperature under nitrogen. The organic layer is separated, washed with water and evaporated in vacuo. The solid residue is recrystallized from acetonitrile to give 3.6 g of the title compound as yellow needles, melting at 109°-110° C.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([Sn](CCCC)(CCCC)CCCC)[CH:4]=[N:3][CH:2]=1.Br[C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[C:24]2[CH2:30][C@H:31]1[CH2:35][CH2:34][CH2:33][N:32]1[CH2:36][CH:37]1[CH2:39][CH2:38]1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>>[CH:37]1([CH2:36][N:32]2[CH2:33][CH2:34][CH2:35][C@@H:31]2[CH2:30][C:24]2[C:23]3[C:27](=[CH:28][CH:29]=[C:21]([C:5]4[CH:4]=[N:3][CH:2]=[N:1][CH:6]=4)[CH:22]=3)[NH:26][CH:25]=2)[CH2:39][CH2:38]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncnc1
Reactant: Brc1ccc2[nH]cc(C[C@H]3CCCN3CC3CC3)c2c1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Product: c1ncc(-c2ccc3[nH]cc(C[C@H]4CCCN4CC4CC4)c3c2)cn1

Procedure:
(5-Pyrimidinyl)tri-n-butylstannane (see Preparation 45) and 5-bromo-3-(1-cyclopropylmethylpyrrolidin-2(R)-ylmethyl)-1H-indole (see Preparation 56) were reacted together in the presence of palladium (II) acetate Pd(OAc)2 !, tri-o-tolylphosphine (o-TI)3P! and triethylamine (C2H5)3N! using a procedure similar to that described in Example 1. This yielded the title compound. Found: C,73.72; H,7.53; N,15.84; C21H24N4.1/8CH2Cl2.1/8H2O requires: C,73.47; H,7.15; N,16.23%.
Reaction SMILES: C(OC([NH:8][C@@:9]1([C:33]([O:35]C(C)(C)C)=[O:34])[C@H:14]([CH2:15][S:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=2)[C@@H:13]([OH:25])[C@@H:12]2[C@H:10]1[C@H:11]2[C:26]([O:28]C(C)(C)C)=[O:27])=O)(C)(C)C.[ClH:40]>ClCCl>[ClH:40].[NH2:8][C@@:9]1([C:33]([OH:35])=[O:34])[C@H:14]([CH2:15][S:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=2)[C@@H:13]([OH:25])[C@@H:12]2[C@H:10]1[C@H:11]2[C:26]([OH:28])=[O:27]
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@H](O)[C@H]1CSc1ccc(F)c(F)c1
Agent: Cl
Solvent: ClCCl
Product: N[C@]1(C(=O)O)[C@@H]2[C@@H](C(=O)O)[C@@H]2[C@H](O)[C@H]1CSc1ccc(F)c(F)c1
Temperature: 70 °C

Procedure:
Di-tert-butyl (1S,2R,3S,4S,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-{[(3,4-difluorophenyl)sulfanyl]methyl}-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylate (4.11 g, 7.19 mmol) is weighed into a one liter round bottom with a stirring bar. Hydrogen chloride (4N in dioxane, 120 mL, 480.0 mmol) is added. The mixture is warmed to 70° C. for 2 hours and then allowed to cool to ambient temperature. The solvent is removed under reduced pressure to give a residue. The residue is dissolve in dichloromethane (200 mL) and the solvent is removed under reduced pressure to give a residue. This is repeated two more times to give (1S,2R,3S,4S,5R,6R)-2-amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid hydrochloride. This material is taken up in tetrahydrofuran (100 mL) as a suspension. To this suspension is added triethylamine (40.08 mL, 287.57 mmol). The suspension is stirred for 10 minutes and then methanol (50 ml) is added. To the reaction is added di-t-butyldicarbonate (4.71 g, 21.57 mmol) and the mixture is heated to 80° C. for 2 hours. The mixture is allowed to come to ambient temperature and the solvent is removed under reduced pressure to give a residue. The residue is dissolved in acetonitrile (50 ml), transferred to a separatory funnel and washed with hexanes. The acetonitrile layer is separated and removed under reduced pressure to give a residue. The residue is suspended in diethyl ether, transferred to a separatory funnel, washed with 1 N aqueous HCl, dried over magnesium sulfate, filtered, and concentrated under reduced pressure giving the title compound (3 g, 6.53 mmol, 90.82% yield). MS (m/z): 457.8 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=3)=[CH:16][CH:17]=2)=[CH:11][C:10]([C:28](Cl)=[O:29])=[N:9]1.C(N(CC)C(C)C)(C)C.[NH:40]1[CH2:49][CH2:48][CH:43]([C:44]([O:46][CH3:47])=[O:45])[CH2:42][CH2:41]1>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=3)=[CH:16][CH:17]=2)=[CH:11][C:10]([C:28]([N:40]2[CH2:49][CH2:48][CH:43]([C:44]([O:46][CH3:47])=[O:45])[CH2:42][CH2:41]2)=[O:29])=[N:9]1
Reactant: COC(=O)C1CCNCC1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(=O)Cl)nn3-c3ccccc3Cl)s2)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)c2cc(-c3ccc(-c4cccc(S(C)(=O)=O)c4)s3)n(-c3ccccc3Cl)n2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 8.2 %

Procedure:
To a solution of 1-(2-chlorophenyl)-5-(5-(3-(methylsulfonyl)phenyl)thiophen-2-yl)-1H-pyrazole-3-carbonyl chloride (0.23 mmol crude from previous step) in CDCl3 (12 ml) was added N,N-diisopropylethylamine (150 μL, 0.86 mmol) and a small amount of DMAP. The resulting mixture was treated with methyl isonipecotate (62 μL, 0.46 mmol). After stirring for 3 hours at ambient temperature the reaction was quenched by dilution with H2O, and dilution with CH2Cl2. The layers were separated and the basic aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude product. This material was purified by flash column chromatography eluting with a gradient from 0% to 16% MeCN in CH2Cl2 to afford methyl 1-{[1-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]carbonyl}piperidine-4-carboxylate (11 mg, 8% yield) as a white powder. MS(ES): 584 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:12])=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1.[CH:13]([N:16]=[C:17]=S)([CH3:15])[CH3:14].CC1C=CC(S([O-])(=O)=O)=CC=1.C[N+]1(CCN=C=NC2CCCCC2)CCOCC1>N1C=CC=CC=1>[CH:13]([NH:16][C:17]1[N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=2[N:12]=1)([CH3:15])[CH3:14]
Reactant: CC(C)N=C=S
Reactant: CNc1ccc([N+](=O)[O-])cc1N
Agent: C[N+]1(CCN=C=NC2CCCCC2)CCOCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: c1ccncc1
Product: CC(C)Nc1nc2cc([N+](=O)[O-])ccc2n1C
Temperature: 90 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a solution of N1-methyl-4-nitro-benzene-1,2-diamine (2.0 g, 12.0 mmol) in pyridine (20 ml) was added isopropyl isothiocyanate (1.41 g, 13.2 mmol) and the mixture was heated to 90° C. After 1 h, 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (6.6 g, 15.6 mmol) was added and the mixture was heated at 90° C. After 16 h, the reaction mixture was cooled to rt, filtered and concentrated to a red residue. This was dissolved in EtOAc and washed with water (4×125 ml). The organic layer was dried over MgSO4 and concentrated to an orange solid. MeOH was added, and the solid was filtered and dried to give the title compound as an orange solid (2.4 g, 85%). 1H NMR (300 MHz, d6-DMSO) δ7.88 (dd, J=8.7 and 2.4 Hz), 7.30 (d, J=8.7 Hz, 1H), 6.89 (d, J=7.5 Hz, 1H), 4.08 (m, 1H), 3.56 (s, 3), 1.25 (d, J=6.6 Hz, 6H). MS (ESI) m/z=235 [M+H]+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH:10]1([SH:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[CH3:8][C:6]1[CH:7]=[C:2]([S:16][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:3]=[C:4]([CH3:9])[CH:5]=1
Reactant: SC1CCCCC1
Reactant: Cc1cc(C)cc(I)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: Cc1cc(C)cc(SC2CCCCC2)c1
Yield: 70.8 %

Procedure:
The general procedure in example 39 was followed. 5-Iodo-m-xylene (144 μL, 1.0 mmol), cyclohexylmercaptan (122 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-propanol (1.0 mL) were used to obtain the cyclohexyl 3,5-dimethylphenyl sulfide (156 mg, 71% yield) as colorless oil. Column chromatographic solvent (hexane). Rf=0.4 (hexane). 1H NMR (CDCl3, 300 MHz) δ 6.99 (s, 2 H), 6.82 (s, 1 H), 3.02-3.10 (m, 1 H), 2.28 (s, 6 H), 1.96-2.00 (m, 2 H), 1.74-1.77 (m, 2 H), 1.56-1.63 (m, 1 H), 1.21-1.42 (m, 4 H). 13C NMR (CDCl3, 75 MHz) δ 138.4, 134.7, 129.7, 128.7, 46.8, 33.8, 26.5, 26.2, 21.6. IR (neat, cm−1) 3088, 3060, 3012, 2962, 2867. MS (EI) m/z (relative intensity) 220 (40), 138 (100), 105 (30). Anal Cald for C14H20S, Cald. C, 76.30; H, 9.15. Found C, 76.30; H, 9.17.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[OH:9])[CH2:4][CH2:3]1.BrCC1C=C[C:26]([C:29]2[N:30]=[N:31][N:32]([CH3:34])[N:33]=2)=CC=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH3:34][N:32]1[N:31]=[N:30][C:29]([CH2:26][N:2]2[CH2:7][CH2:6][CH:5]([CH:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:18])([F:19])[F:20])=[CH:12][CH:11]=3)[OH:9])[CH2:4][CH2:3]2)=[N:33]1
Reactant: Cn1nnc(-c2ccc(CBr)cc2)n1
Reactant: OC(c1ccc(OC(F)(F)F)cc1)C1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cn1nnc(CN2CCC(C(O)c3ccc(OC(F)(F)F)cc3)CC2)n1

Procedure:
This compound was prepared in a manner analogous to that of Step E of Example 3, using 7.0 grams (0.026 mole) of 4-piperidyl[4-(trifluoromethoxy)phenyl]methanol, hydrochloride, 6.8 grams (0.026 mole) of 5-[4-(bromomethyl)phenyl]-2-methyl-1,2,3,4-tetraazole (prepared in a manner analogous to that of Steps A–C of Example 4), and 9.9 grams (0.077 mole) of N,N-diisopropylethylamine in about 40 mL of DMSO. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:17][C:16]3[C:18]4[CH2:19][CH2:20][CH2:21][C:22]=4[CH:23]=[C:24]([Cl:25])[C:15]=3[CH2:14]2)(=O)=O)=CC=1.[N-:26]=[N+:27]=[N-:28].[Na+]>>[Cl:25][C:24]1[C:15]2[CH2:14][CH:13]([CH2:12][N:26]=[N+:27]=[N-:28])[O:17][C:16]=2[C:18]2[CH2:19][CH2:20][CH2:21][C:22]=2[CH:23]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3c(Cl)cc4c(c3O2)CCC4)cc1
Agent: [Na+]
Product: [N-]=[N+]=NCC1Cc2c(Cl)cc3c(c2O1)CCC3

Procedure:
Treatment of (±)-(4-chloro-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methyl 4-methylbenzenesulfonate (4.0 g, 10.6 mmol) with sodium azide (2.75 g, 42.2 mmol) generally according to the procedure described for Intermediate 24 gave (±)-(4-chloro-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methyl azide. Treatment of the azide with sulfided platinum on carbon (5 wt. %, 0.63 g) followed by hydrogen chloride (3 mL, 4 M in isopropanol) generally according to the procedure described for Example 2 provided 2.1 g (76%) of (±)-1-(4-chloro-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methanamine as a white solid, hydrochloride salt. mp 251-254° C.; Anal. calcd. for C12H14ClNOHCl: C, 55.40; H, 5.81; N, 5.38. Found: C, 55.10; H, 5.68; N, 5.29.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][CH:19]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:20][C:21]([NH2:24])=[N:22][OH:23])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1.[C:29](C1NC=CN=1)(C1NC=CN=1)=[O:30].C(N(CC)C(C)C)(C)C.[Cl-].[NH4+]>C1COCC1.ClCCl>[F:1][C:2]1[C:3]([NH:18][CH:19]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:20][C:21]2[NH:22][O:23][C:29](=[O:30])[N:24]=2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CC(C)(C)C(CC(N)=NO)Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C(Cc1nc(=O)o[nH]1)Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of racemic 3-[[5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]-N′-hydroxy-4,4-dimethyl-pentanamidine, 125a, (0.034 g, 0.087 mmol) and carbonyl diimidazole (0.014 g, 0.087 mmol) in THF (1 mL) was added N,N-diisopropylethylamine (0.045 mL, 0.260 mmol). The reaction mixture was stirred at room temperature for 48 hours. Aqueous ammonium chloride and dichloromethane were added and the layers were separated with a phase separator. The residue was purified on a C18 column (acetonitrile/0.1% formic acid) to afford the final product: 1H NMR (400 MHz, Acetone) δ 11.23 (s, 1H), 8.54 (dd, J=9.8, 2.8 Hz, 1H), 8.36 (s, 1H), 8.20 (s, 1H), 8.13 (d, J=3.7 Hz, 1H), 6.81 (s, 1H), 5.00 (d, J=11.2 Hz, 1H), 3.15 (d, J=14.8 Hz, 3H), 2.94 (dd, J=14.4, 11.9 Hz, 2H), 1.16 (s, 8H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=1.58 minutes (M+H) 390.06.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=4)=[N:15][N:14]([CH2:25][O:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[C:11]3=[N:12][CH:13]=2)=[CH:4][C:3]=1[C:33](=[O:37])[N:34]([CH3:36])[CH3:35].[N:38]1([C:44](Cl)=[O:45])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[Cl:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][C:16]1[C:10]2[C:11](=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:44]([N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[O:45])=[C:3]([C:33](=[O:37])[N:34]([CH3:36])[CH3:35])[CH:4]=3)[CH:9]=2)[N:14]([CH2:25][O:26][C:27](=[O:32])[C:28]([CH3:29])([CH3:30])[CH3:31])[N:15]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CN(C)C(=O)c1cc(-c2cnc3c(c2)c(Cc2cccc(Cl)c2)nn3COC(=O)C(C)(C)C)ccc1N
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1cc(-c2cnc3c(c2)c(Cc2cccc(Cl)c2)nn3COC(=O)C(C)(C)C)ccc1NC(=O)N1CCOCC1
Temperature: 50 °C
Reaction time: 48 h
Yield: 49.3 %

Procedure:
2,2-Dimethyl-propionic acid 5-(4-amino-3-dimethylcarbamoyl-phenyl)-3-(3-chloro-benzyl)-pyrazolo[3,4-b]pyridin-1-ylmethyl ester (300 mg, 0.577 mmol), chloroform (50 ml), 4-morpholinecarbonyl chloride (1.2 ml, 10.45 mmol), and di-iso-propyl ethyl amine (2.4 ml, 13.78 mmol) were combined and stirred for 48 hours at 50° C. The reaction was quenched with sodium bicarbonate solution and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (0 to 100% [10% methanol in ethyl acetate] in hexanes) to give 180 mg (49%) of 2,2-dimethyl-propionic acid 3-(3-chloro-benzyl)-5-{3-dimethylcarbamoyl-4-[(morpholine-4-carbonyl)-amino]-phenyl}-pyrazolo[3,4-b]pyridin-1-ylmethyl ester. MS: m/z 633.5 (M+H+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C:5]([NH2:8])([CH3:7])[CH3:6].[C:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)(=[O:12])[CH3:11].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:9])[C:5]([NH:8][S:19]([C:16]1[CH:15]=[CH:14][C:13]([C:10](=[O:12])[CH3:11])=[CH:18][CH:17]=1)(=[O:21])=[O:20])([CH3:7])[CH3:6]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)C(C)(C)N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(C)(C)NS(=O)(=O)c1ccc(C(C)=O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.2 %

Procedure:
methyl-2-amino-2-methylpropanoate hydrochloride (2 g, 13.07 mmol) was dissolved in CH2Cl2 (50 ml), and added with 4-acetylbenzene-1-sulfonyl chloride (2.86 g, 13.07 mmol) and triethylamine (7.2 ml, 52.27 mmol), followed by stirring at room temperature for 12 hours. The resultant solution was added with H2O, extracted with CH2Cl2 (×2), dried with MgSO4, and filtered. Through vacuum distillation, the solvent was removed. The resultant mixture was purified with column chromatography so as to obtain methyl-2-(4-acetylphenylsulfonamido)-2-methylpropanoate (2.55 g, 8.52 mmol, 56%).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[C:20](C)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[O:24][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[Cl:32]C1C=C2C(=CC=1)C(O)=CC(C)=C2>>[C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:32])[CH:18]=2)[C:13]=1[O:24][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(O)c2ccc(Cl)cc2c1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C)c2ccccc2c1OS(=O)(=O)C(F)(F)F
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2cc(Cl)ccc2c1OS(=O)(=O)C(F)(F)F

Procedure:
(S)-ethyl 2-tert-butoxy-2-(6-chloro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate was prepared in a similar way as (S)-ethyl 2-tert-butoxy-2-(3,4-dimethyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate in Example 1 except using 6-chloro-3-methylnaphthalen-1-ol instead of 3,4-dimethylnaphthalen-1-ol. 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J=9.1 Hz, 1H), 7.78 (s, 1H), 7.58 (s, 1H), 7.51 (dd, J=9.0, 1.8 Hz, 1H), 5.70 (s, 1H), 4.17 (dqd, J=14.2, 7.1, 3.2 Hz, 2H), 2.55 (s, 3H), 1.20 (s, J=6.5 Hz, 9H), 1.17 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[OH:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].C1C=CC(N[S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22])=CC=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[O:13][S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Reactant: CCOC(=O)c1ccc(O)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl 3-chloro-4-hydroxybenzoate (available from Aldrich) (5.00 g, 25.0 mmol), N-phenyltriflamide (9.30 g, 26.0 mmol) and TEA (4.2 mL, 30.0 mmol) in DCM (40 mL) with a catalytic amount of DMAP, was stirred at ambient temperature overnight. DCM (150 mL) was added, and the reaction mixture was washed with brine (30×3 mL), dried over MgSO4, and the solvent was removed under reduced pressure. The product B.5 was used in the next step without further purification. MS ESI (pos.) m/e: 335.0 (M+Na)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:11]([Br:15])[CH2:12][CH2:13]Br>CN(C)C=O>[Br:15][CH:11]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1)[CH2:12][CH2:13][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: BrCCCBr
Reactant: Oc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cccc(OCCC(Br)Oc2ccccc2)c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
In a stream of nitrogen, 100 ml of a dimethylformamide (to be referred to as DMF hereinafter) solution containing 20.03 g (115.8 mmol) of 3-bromophenol was cooled to 5° C. and mixed with 4.9 g (122 mmol) of 60% sodium hydride. After 1 hour of stirring at room temperature, this was mixed with 25 ml of a DMF solution containing 11.5 g (57 mmol) of trimethylene dibromide and stirred at 70° C. for 20 hours. The reaction solution was extracted with 800 ml of ethyl acetate and washed with water (200 ml, 5 times) and saturated brine (100 ml, twice). The organic layer was dried with anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. By purifying the residue by a silica gel column chromatography, 13.70 g (yield 62%) of the title compound was obtained as a colorless oil.