Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:22])[NH:9]2)(=[O:3])[CH3:2].I([Cl:26])(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>ClC(Cl)C.CO>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:4]([C:1](=[O:3])[CH2:2][Cl:26])=[C:5]2[C:10]=1[NH:9][C:8](=[O:22])[CH:7]=[CH:6]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=I(=O)Cl
Reactant: CC(=O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: CO
Solvent: CC(Cl)Cl
Product: O=C(CCl)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reaction time: 8 h

Procedure:
25.2 g (86 mmol) 5-acetyl-8-benzyloxy-1H-quinolin-2-one (European Journal of Medicianl Chemistry 1984, 19(4), 341) and 50 g (142 mmol) benzyltrimethylammonium dichloriodate in 500 mL dichloroethane and 300 mL methanol are stirred overnight at reflux temperature. The reaction mixture is evaporated down and the residue is stirred overnight in THF and 1 N hydrochloric acid. After the THF has been distilled off the precipitated solid is suction filtered, washed with diethyl ether and dried.
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[S:23](=[O:35])(=[O:34])[NH:24][C:25](=[O:33])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])=[CH:13][CH:12]=2)=[C:8]([C:36]([O:38]CC)=[O:37])[N:7]([C:41]2[CH:46]=[C:45]([NH:47][C:48](=[O:53])[CH2:49][CH2:50][CH2:51][CH3:52])[CH:44]=[CH:43][C:42]=2[Cl:54])[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].CO.Cl>O>[CH2:1]([C:5]1[C:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[S:23](=[O:35])(=[O:34])[NH:24][C:25](=[O:33])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])=[CH:13][CH:12]=2)=[C:8]([C:36]([OH:38])=[O:37])[N:7]([C:41]2[CH:46]=[C:45]([NH:47][C:48](=[O:53])[CH2:49][CH2:50][CH2:51][CH3:52])[CH:44]=[CH:43][C:42]=2[Cl:54])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(=O)Nc1ccc(Cl)c(-n2nc(CCCC)c(Cc3ccc(-c4ccccc4S(=O)(=O)NC(=O)c4ccccc4Cl)cc3)c2C(=O)OCC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCC(=O)Nc1ccc(Cl)c(-n2nc(CCCC)c(Cc3ccc(-c4ccccc4S(=O)(=O)NC(=O)c4ccccc4Cl)cc3)c2C(=O)O)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
A mixture of 39.5 mg (0.05 mmol) of ethyl 3-n-butyl-4-[[2'-[N-(2-chlorobenzoyl)sulfamoyl]biphenyl-4-yl]methyl]-1-[2-chloro-5-(valerylamino)phenyl]-1H-pyrazole-5-carboxylate (from Example 1), 200 μL (0.5 mmol) of 2.5N NaOH, and 600 μL of methanol was stirred under N2 at 60° C. for 2 hours. The solution was cooled, diluted with 5 mL of H2O, and adjusted to approximately pH 2 by gradual addition of 2N HCl, resulting in precipitation. The precipitate was collected on a filter and dried to yield 37.8 mg (97%) of the title compound as a nearly white solid, mp>110° C. (gradual); homogeneous by TLC in 9:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 761 (M+1)+. 400 MHz 1H NMR (DMSO-d6) δ0.80 (t, J=7.3 Hz, 3H), 0.88, (t, J=7.3 Hz, 3H), 1.24, 1.31 (overlapping m, each 2H), 1.47 (m, 2H), 1.57 (m, 2H), 2.31 (t, J=7.4 Hz, 2H), 2.48 (t, 2H, partially obscured by DMSO peak), 4.18 (br, 2H), 7.09 (d, J=7.4 Hz, 1H), 7.21 (d, J=8.3 Hz, 2H), 7.27-7.74 (m, 10H), 7.87 (d, J=2.5 Hz, 1H), 8.17 (dd, J=8.0, 1.3 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]2[N:10]=[C:11]([N:14]=[C:15]([NH2:17])[NH2:16])[S:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=1.[CH3:18][S:19][C:20](SC)=[N:21][C:22]#[N:23]>C(O)C>[NH2:16][C:15](=[N:14][C:11]1[S:12][CH:13]=[C:9]([C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][NH:1][C:20](=[N:21][C:22]#[N:23])[S:19][CH3:18])[N:8]=2)[N:10]=1)[NH2:17]
Reactant: NCc1cccc(-c2csc(N=C(N)N)n2)n1
Reactant: CSC(=NC#N)SC
Solvent: CCO
Product: CSC(=NC#N)NCc1cccc(-c2csc(N=C(N)N)n2)n1

Procedure:
A mixture of 4-(6-aminomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole (0.50 g) and dimethyl N-cyanodithioiminocarbonate [(CH3S)2C=N--CN] (0.29 g) in ethanol (10 ml) was refluxed for one hour to give 2-(diaminomethyleneamino)-4-[6-(3-cyano-2-methylisothioureido)methylpyridin-2-yl]thiazole of a crude product. After being concentrated to dry the above product, 40 weight % methanolic methylamine (1.6 ml) and N,N-dimethylformamide (10 ml) was added and the mixture was stirred at 60° C. for 5 hours. The solvent was evaporated in vacuo and the residue was mixed with water. The resulting precipitate was collected by filtration and recrystallized from aqueous N,N-dimethylformamide to give 4-[6-(2-cyano-3-methylguanidino)methylpyridin-2-yl]-2-(diaminomethyleneamino)thiazole (0.42 g).
Reaction SMILES: [H-].[Na+].[C:3]1([CH3:31])[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:30][CH2:29][CH2:28][C@H:13]2[C:14]([NH:16][C@H:17]([C:25]([NH2:27])=[O:26])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>C1COCC1>[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38]([NH:27][C:25](=[O:26])[C@H:17]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:16][C:14](=[O:15])[C@@H:13]2[CH2:28][CH2:29][CH2:30][N:12]2[S:9]([C:6]2[CH:7]=[CH:8][C:3]([CH3:31])=[CH:4][CH:5]=2)(=[O:11])=[O:10])(=[O:40])=[O:39])=[CH:34][CH:33]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](Cc2ccccc2)C(N)=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@@H]2CCCN2S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
N-(Toluene-4-sulfonyl)-L-proline was reacted with L-phenylalanine amide using the procedure described in Method 12 to yield N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine amide. To a solution of NaH (60% mineral oil—prewashed with THF) in THF at 0° C. was added N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine amide and the reaction was stirred at 0° C. for 45 minutes. Toluene-4-sulfonyl chloride was added and the reaction was stirred for 16 hours at room temperature. The reaction mixture was extracted with EtOAc (3×50 mL) and 0.2 N HCl (50 mL), and the combined organic layers were washed successively with sat. NaHCO (50 mL), and sat. NaCl (2×50 mL), dried over MgSO4, filtered, and concentrated to yield the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](=[O:24])[NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[CH:11]=[C:10]([C:25](O)=[O:26])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:28][NH:29][C@@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:28][N:29]([C@@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)[C:25]([C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:13]=[C:12]([C:14]([NH:15][CH2:16][C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[O:24])[CH:11]=1)=[O:26]
Reactant: CN[C@@H]1CCNC1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)NCc3ccc(C)nc3)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(C(=O)N(C)[C@@H]3CCNC3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-((6-methylpyridin-3-yl)methylcarbamoyl)biphenyl-3-carboxylic acid (50 mg, 0.14 mmol) in N,N-dimethylformamide (1 mL) were added (R)—N-methylpyrrolidin-3-amine (50 mg, 0.50 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (120 mg, 0.32 mmol) and N,N-diisopropylethylamine (120 μL, 0.69 mmol). The reaction mixture was stirred for 16 hours at 25° C. The reaction solution was purified by preparative HPLC to afford the final product as a light color solid.
Reaction SMILES: [OH-].[Na+].[P:3]([O:7][CH2:8][C@@H:9]([OH:18])[C@H:10]([OH:17])[C@H:11]([OH:16])[C@@H:12]([OH:15])[CH:13]=[O:14])([O-:6])([O-:5])=[O:4].[Ba+2].[N+]([O-])(O)=O>O>[P:3]([O:7][CH2:8][C@@H:9]([OH:18])[C@H:10]([OH:17])[C@H:11]([OH:16])[C@@H:12]([OH:15])[CH:13]=[O:14])([OH:5])([OH:6])=[O:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)COP(=O)([O-])[O-]
Agent: [Ba+2]
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: O
Product: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)COP(=O)(O)O
Reaction time: 504 h

Procedure:
The pH of an 11.3-ml aqueous solution of 0.67 M cis-[Pt(NH3)2 (H2O)2 ](NO3)2 was adjusted with sodium hydroxide to 4. Then, 3.0 grams of barium D-galactose-6-phosphate dissolved in 30 ml water were added. The pH of the resulting solution was adjusted to 5.0 with 2 M nitric acid. After stoppering the solution with a porous plug and stirring for 21 days, the above-identified complex which had formed during that time period was recovered as a water-insoluble blue precipitate by the method described in Example 5.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([NH2:17])=[N:13][NH:14]3)=[CH:10][CH:9]=2)[CH:5]=[C:4](S(C)(=O)=O)[N:3]=1.[CH3:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][NH2:31].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[NH2:17][C:12]1[C:11]2[C:15](=[CH:16][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:31][CH2:30][CH2:29][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[CH3:22])[CH:5]=3)=[CH:9][CH:10]=2)[NH:14][N:13]=1
Reactant: Cc1ccccc1CCN
Reactant: CS(=O)(=O)c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1CCNc1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 160 °C
Yield: 42.2 %

Procedure:
A mixture of 6-[2-amino-6-(methylsulfonyl)-4-pyrimidinyl]-1H-indazol-3-amine (300 mg, 0.99 mmol), 2-(2-methylphenyl)ethanamine (300 mg, 2.22 mmol), and Hunig's base (2 mL) in NMP (3 mL) was heated for 2 hours at 160° C. in a BiotageInitiator® microwave synthesizer. Upon cooling, the mixture was decanted to remove the solids, and the resulting solution was concentrated to dryness. The crude material was purified by RPHPLC to afford the title compound (150 mg) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 2.33 (s, 3H), 2.82-2.86 (m, 2H), 3.50-3.45 (m, 2H), 5.36 (s, 2H), 5.98 (s, 2H), 6.29 (s, 1H), 6.97 (s, 1H), 7.09-7.22 (m, 4H), 7.43 (d, J=8.0 Hz, 1H), 7.85 (s, 1H), 11.51 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@:15]([NH:30][C:31](=O)[O:32]C(C)=C)([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1.[NH2:37][C:38]1[S:39][CH:40]=[CH:41][N:42]=1.CN1CCCC1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@:15]([NH:30][C:31]([NH:37][C:38]2[S:39][CH:40]=[CH:41][N:42]=2)=[O:32])([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:5]=[C:6]([O:8][C:9]([F:13])([F:14])[CH:10]([F:12])[F:11])[CH:7]=1
Reactant: Nc1nccs1
Reactant: C=C(C)OC(=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Agent: CN1CCCC1
Solvent: C1CCOC1
Product: O=C(Nc1nccs1)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Temperature: 150 °C
Yield: 40.6 %

Procedure:
(R)-prop-1-en-2-yl 1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylcarbamate (15 mg, 0.029 mmol) and 2-aminothiazole (8.2 mg, 0.082 mmol, 2.8 eq), and N-methylpyrrolidine (0.9 μl, 0.3 eq) were stirred in THF (0.3 mL) in a microwave vial. The reaction mixture was heated at 150° C. for 20 min under microwave irradiation. After cooling, the solvent was evaporated. The residue was purified by reverse phase HPLC (20-90% CH3CN in H2O with 0.1% TFA) to give pure (R)-1-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(thiazol-2-yl)urea as white solids (6.5 mg, yield: 40.6%). 1H NMR (400 MHz, CDCl3-D) δ ppm 7.29 (m, 1H), 7.23-7.18 (m, 3H), 7.16 (t, J=8.0 Hz, 2H), 7.02 (t, J=8.5 Hz, 2H), 6.94-6.89 (m, 4H), 6.71 (d, J=6.82 Hz, 2H), 5.86 (tt, J=47.1, 2.9 Hz, 1H), 3.84-3.75 (m, 2H); LC-MS (ESI) 552.28 (M+H), retention time=4.12 min (10-90% MeOH in H2O with 0.1% TFA in a 4-min run).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)/[C:8]([OH:10])=[O:9])[N:6]=1.[Cl:32]N1C(=O)CCC1=O.O>CN(C=O)C>[NH2:1][C:2]1[S:3][C:4]([Cl:32])=[C:5](/[C:7](=[N:11]/[O:12][C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)O)cs1
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)O)c(Cl)s1
Yield: 70.9 %

Procedure:
To a solution of (Z)-2-(2-aminothiazol-4-yl)-2-(triphenylmethoxyimino)acetic acid (5.81 g, 13.47 mmol) in DMF (30 mL) at room temperature (1 mL) was added N-chlorosuccinimide (1.80 g, 13.47 mmol). After overnight reaction the reaction mixture was poured into water (about 500 mL) and the resulting precipitate was filtered, washed with water and then with ethyl acetate and dried in vacuum to afford 4.43 g (71%) of the title compound. 13C NMR (CDCl3) δ 108.5, 125.6, 126.2, 126.6, 12.3, 134.7, 141.8, 146.5, 162.1, 163.3.
Reaction SMILES: NC1N=C(N)C2C(CN(C3C=CC=CC=3)C3C=CC=CC=3)=CSC=2N=1.[NH2:26][C:27]1[N:28]=[C:29]([NH2:37])[C:30]2[C:35]([CH3:36])=[CH:34][S:33][C:31]=2[N:32]=1.[CH:38]1[C:48]2[CH:47]=[CH:46][C:45]3[CH:49]=[CH:50][CH:51]=[CH:52][C:44]=3[NH:43][C:42]=2[CH:41]=[CH:40][CH:39]=1>>[NH2:26][C:27]1[N:28]=[C:29]([NH2:37])[C:30]2[C:35]([CH2:36][C:49]3[C:45]4[CH:46]=[CH:47][C:48]5[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=5[NH:43][C:44]=4[CH:52]=[CH:51][CH:50]=3)=[CH:34][S:33][C:31]=2[N:32]=1
Reactant: Cc1csc2nc(N)nc(N)c12
Reactant: C1=Cc2ccccc2Nc2ccccc21
Agent: Nc1nc(N)c2c(CN(c3ccccc3)c3ccccc3)csc2n1
Product: Nc1nc(N)c2c(Cc3cccc4c3C=Cc3ccccc3N4)csc2n1

Procedure:
9-[(2,4-Diaminothieno[2,3-d]pyrimidin-5-yl)methyl]dibenz[b,f]azepine (Formula I: Ar=2,4-diaminothieno[2,3-d]pyrimidin-5-yl; W=CH2; X=N; Z=CH═CH; m=n=0) is prepared similarly to N-[(2,4-diaminothieno[2,3-d]pyrimidin-5-yl)methyl]-N,N-diphenylamine as disclosed above by using 2,4-diamino-5-methylthieno[2,3-d]pyrimidine (1.3 g, 7.4 mmol) in Step 1 and dibenz[b,f]azepine (154 mg, 0.8 mmol) in Step 3. The final product and its intermediates can be purified by chromatography.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[SH:12])[NH:5][C:6](=[O:8])[CH3:7].[CH2:13](OC=C(C#N)C#N)C>CC(O)=O>[C:6]([NH:5][C:4]1[CH:9]=[CH:10][C:11]2[S:12][CH:13]=[N:1][C:2]=2[CH:3]=1)(=[O:8])[CH3:7]
Reactant: CCOC=C(C#N)C#N
Reactant: CC(=O)Nc1ccc(S)c(N)c1
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc2scnc2c1
Temperature: 125 °C
Yield: 17 %

Procedure:
To a solution of intermediate 3′-amino-4′-mercaptoacetanilide in HOAc (50 mL) was added ethoxymethylene malononitrile (1.95 g, 16 mmol) and the resulting mixture was refluxed at 125° C. for 5 h. After cooling, the product mixture was concentrated under reduced pressure, and the residue was partitioned between saturated aqueous NaHCO3 and EtOAc. The aqueous phase was extracted with EtOAc, and the combined extracts were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography on silica gel, eluting with EtOAc-Hex (0:100 to 50:50) to give the title compound (508 mg, 17%) as a yellow solid. 1H-NMR (DMSO-d6): δ 9.35 (1H, s), 8.53 (1H, s), 8.10 (1H, d), 7.63 (1H, d), 2.15 (3H, s).
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[C:15]([C:16]([OH:19])([CH3:18])[CH3:17])=[N:14][C:13]2[C:8]1=[N:9][C:10](Cl)=[N:11][C:12]=2[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)(=O)C.[CH3:27][C:28]1[C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=[C:30]([NH2:43])[N:29]=1>>[NH2:43][C:30]1[N:29]=[C:28]([CH3:27])[C:33]([C:10]2[N:9]=[C:8]3[C:13]([N:14]=[C:15]([C:16]([OH:19])([CH3:17])[CH3:18])[N:7]3[CH2:6][CH2:5][OH:4])=[C:12]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:11]=2)=[CH:32][N:31]=1
Reactant: Cc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(=O)OCCn1c(C(C)(C)O)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2nc(C(C)(C)O)n(CCO)c2n1

Procedure:
2-(2-Chloro-8-(2-hydroxypropan-2-yl)-6-morpholino-9H-purin-9-yl)ethyl acetate (300 mg) was treated with 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure A and was purified via reverse phase HPLC to give 107 mg of 102 as a white solid. MS (Q1) 415.2 (M)+
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[SH:10])([O-:3])=[O:2].Cl[CH2:12][CH:13]([OH:15])[CH3:14].[OH-].[Na+]>O>[OH:15][CH:13]([CH3:14])[CH2:12][S:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1S
Reactant: CC(O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(O)CSc1ccccc1[N+](=O)[O-]
Yield: 94.8 %

Procedure:
In accordance with Reaction I of Example 1, 15.5 g. (0.1 mole) of 2-nitrothiophenol, 11.34 g. (0.12 mole) of 1-chloro-2-propanol, 4.0 g. (0.1 mole) of sodium hydroxide and 150 ml. of water were used for the reaction and an oily product was extracted with benzene after the reaction and benzene was distilled off after a dehydration to obtain 20.2 g. of blackish brawn liquid 2-(β-hydroxypropylthio)nitrobenzene (yield of 94.8%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][CH:36]=1)[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH2:17][CH2:18][NH:19][CH3:20])=[CH:13][CH:14]=2)[C:9]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[C:8]1[C:29]([O:31][CH2:32][CH3:33])=[O:30].C(N(C(C)C)CC)(C)C.Cl[C:47]1[O:48][C:49]2[CH:55]=[CH:54][CH:53]=[CH:52][C:50]=2[N:51]=1>CN(C)C=O.C(=O)(O)[O-].[Na+]>[O:48]1[C:49]2[CH:55]=[CH:54][CH:53]=[CH:52][C:50]=2[N:51]=[C:47]1[N:19]([CH3:20])[CH2:18][CH2:17][O:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:5]1[CH:34]=[CH:35][CH:36]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:8]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:9]2[C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1c(-c2ccc(OC)cc2)c2cc(OCCNC)ccc2n1Cc1cccc(OC)c1
Reactant: Clc1nc2ccccc2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1c(-c2ccc(OC)cc2)c2cc(OCCN(C)c3nc4ccccc4o3)ccc2n1Cc1cccc(OC)c1
Temperature: 120 °C
Yield: 97 %

Procedure:
To a solution of Ethyl 1-(3-methoxybenzyl)-3-(4-methoxyphenyl)-5-[2-(methylamino)ethoxy]-1H-indole-2-carboxylate (Example 156, 100 mg, 0.2028 mmol) in N,N-dimethylformamide (1.5 ml) was added diisopropylethylamine (0.09 ml, 0.5167 mmol, 2.5 eq.) and 2-chlorobenzoxazole (0.03 ml, 0.2636 mmol, 1.3 eq.). The reaction mixture was heated at 120° C. for 4 hr. After cooling the reaction was diluted with saturated aqueous sodium bicarbonate and then extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash column (silica gel, dichloromethane to dichloromethane:methanol 95:5). The desired product was obtained as a light yellow oil in 97% yield (119 mg), MS (M+H)=606.3, Rf=0.69 (dichloromethane/methanol 95:5).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:22]3[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[S:14][C:13]=3[C:12]([O:23]C(=O)OC(C)(C)C)=[CH:11][CH:10]=2)O1.Cl[C:33]1[O:34][C:35]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)=[CH:36][C:37](=[O:39])[CH:38]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[OH:23][C:12]1[C:13]2[S:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:21][C:22]=2[C:9]([C:33]2[O:34][C:35]([N:40]3[CH2:41][CH2:42][O:43][CH2:44][CH2:45]3)=[CH:36][C:37](=[O:39])[CH:38]=2)=[CH:10][CH:11]=1
Reactant: O=c1cc(Cl)oc(N2CCOCC2)c1
Reactant: CC(C)(C)OC(=O)Oc1ccc(B2OC(C)(C)C(C)(C)O2)c2c1Sc1ccccc1C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=c1cc(-c2ccc(O)c3c2Cc2ccccc2S3)oc(N2CCOCC2)c1
Temperature: 90 °C
Yield: 18.9 %

Procedure:
Carbonic acid tert-butyl ester 1-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-9H-thioxanthen-4-yl ester (3.00 g, 6.81 mmol), 2-chloro-6-morpholin-4-yl-pyran-4-one (1.22 g, 5.67 mmol) and potassium carbonate (2.07 g, 14.98 mmol) were suspended in anhydrous dioxane (6 ml) under nitrogen atmosphere. The solution was degassed for 15 minutes. To the solution tetrakis(triphenylphosphino) palladium (291 mg, 5% eq.) was added. The mixture was degassed for a further 5 minutes. The reaction was heated at 90° C. under nitrogen atmosphere for 24 hours. The solvent was evaporated in vacuo and the crude mixture was purified by column chromatography (9:1, ethyl acetate/ethanol), to yield the title compound (421 mg, 16%) as a light yellow amorphous solid. 1H NMR (300 MHz, DMSO-d6): δH=3.33 (4H, t), 3.67 (4H, t), 3.88 (2H, s), 5.45 (1H, d), 6.05 (1H, d), 6.87 (1H, d), 7.24–7.65 (5H, m), 10.62 (1H, bs); m/z (LC-MS, ESP), RT=3.96 min, (M++1)=394.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH:21]1[N:25]=[C:24]([NH2:26])[S:23][CH:22]=1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:26][C:24]2[S:23][CH:22]=[CH:21][N:25]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: Nc1nccs1
Product: O=C(Nc1nccs1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (150 mg, 0.43 mmol) and aminothiazole (51.2 mg, 0.51 mmol). The title compound was obtained as a brown solid (77.0 mg, 42% yield). 1H NMR (400 MHz, d6-DMSO) δ: 13.12 (1H, br), 9.02 (2H, s), 7.73 (1H, m), 7.24 (1H, m). MS m/z: 431.20, 433.13 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.[S:14](N)([NH2:17])(=[O:16])=[O:15]>O1CCOCC1>[C:9]([O:8][C:7](=[O:13])[NH:6][C@@H:3]1[CH2:4][CH2:5][N:1]([S:14]([NH2:17])(=[O:16])=[O:15])[CH2:2]1)([CH3:10])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(S(N)(=O)=O)C1
Temperature: 110 °C

Procedure:
To a solution of tert-butyl (3R)-pyrrolidin-3-ylcarbamate (1.3 g) in dioxane (50 ml) was added sulfamide (1.55 g) and the reaction was heated at 110° C. for 18 h. The reaction mixture was then partitioned between DCM (100 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with DCM (2×100 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a pale yellow solid. Yield: 1.69 g
Reaction SMILES: [ClH:1].Cl.[C:3]1([NH:9][C:10]2([C:23]([OH:25])=[O:24])[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[CH2:31](O)[CH3:32]>>[ClH:1].[ClH:1].[C:3]1([NH:9][C:10]2([C:23]([O:25][CH2:31][CH3:32])=[O:24])[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:14][CH2:15]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)C1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Reactant: CCO
Agent: Cl
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1(Nc2ccccc2)CCN(Cc2ccccc2)CC1

Procedure:
A mixture of 19 parts of 4-(phenylamino)-1-(phenylmethyl)-4-piperidinecarboxylic acid dihydrochloride, 14.4 parts of sulfuric acid and 64 parts of ethanol is stirred and refluxed for 16 hours. The solvent is decanted. The residue is dissolved in water. The aqueous solution is alkalized with ammonium hydroxide and extracted with a mixture of methylbenzene and 2,2'-oxybispropane. The combined organic layers are dried over mangnesium sulfate, filtered and evaporated. The oily residue is dissolved in 200 parts of 2,2'-oxybispropane and gaseous hydrogen chloride is introduced into the solution. The precipitated hydrochloride is filtered off, washed with 2-propanol, filtered off again and dried, yielding 11.5 parts of ethyl 4-(phenylamino)-1-(phenylmethyl)-4-piperidinecarboxylate dihydrochloride; mp. 212°-214° C.