Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]([N:26]([C:35]4[CH:40]=[CH:39][C:38]([S:41]([CH3:44])(=O)=O)=[CH:37][CH:36]=4)C(=O)C4C=CC=CC=4)[CH3:25])[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:4])=[O:3].[Cl:45][C:46]1[CH:47]=[C:48]([S:53](Cl)(=[O:55])=[O:54])[CH:49]=[CH:50][C:51]=1[Cl:52]>N1C=CC=CC=1.C([O-])(O)=O.[Na+]>[Cl:45][C:46]1[CH:47]=[C:48]([S:53]([N:26]([CH:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:16]3[CH:17]=[C:8]([C:5]([S:2]([CH3:1])(=[O:4])=[O:3])([CH3:7])[CH3:6])[CH:9]=[C:10]4[C:15]=3[N:14]=[CH:13][CH:12]=[CH:11]4)[CH:19]=2)[CH3:25])[C:35]2[CH:36]=[CH:37][C:38]([S:41][CH3:44])=[CH:39][CH:40]=2)(=[O:55])=[O:54])[CH:49]=[CH:50][C:51]=1[Cl:52]
Reactant: CC(c1cccc(-c2cc(C(C)(C)S(C)(=O)=O)cc3cccnc23)c1)N(C(=O)c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CSc1ccc(N(C(C)c2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)S(=O)(=O)c2ccc(Cl)c(Cl)c2)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To solution of (1-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-ethyl)-(4-methylsulfanyl-phenyl)-amine from EXAMPLE 44 (Step 1) (1.0 eq) in pyridine (0.38M) was added 3,4-dichloro-benzenesulfonyl chloride (3.2 eq). The resulting mixture was stirred at 80° C. for 12 h, cooled to room temperature, poured in saturated aqueous NaHCO3 and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. Flash chromatography (CH2Cl2:EtOAc; 9:1) afforded the desired compound as a foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:12]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:12]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C1CNCCNC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCCNCC1
Reaction time: 8 h
Yield: 76.2 %

Procedure:
The 1-(4-chlorophenylsulphonyl)homopiperazine was prepared as follows. 4-Chlorophenylsulphonyl chloride (3.74 g) in dichloromethane (100 ml) was added slowly to a solution of homopiperazine (6.73 g) in dichloromethane (100 ml). The reaction was stood at room temperature overnight. The reaction was washed with water, dried (MgSO4) and the solvent removed in vacuo. The residue was triturated with 20% ether in hexane to give 1-(4-chlorophenylsulphonyl)homopiperazine (3.71 g); NMR (DMSOd6): 1.65 (m, 2H), 2.73 (m, 4H), 3.2-3.65 (m 4H), 7.7 (m, 2H), 7.8 (m, 2H).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[CH:5]([CH:7]([CH:13]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH3:14])[C:8](OCC)=O)=[O:6].[O-]CC.[Na+]>C(O)C>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH:13]([C:7]2[C:5](=[O:6])[NH:1][C:2](=[S:3])[NH:4][CH:8]=2)[CH3:14])[CH:16]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(C=O)C(C)c1cccnc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(c1cccnc1)c1c[nH]c(=S)[nH]c1=O
Reaction time: 8 h
Yield: 51 %

Procedure:
Thiourea (1.4 g) and ethyl 2-formyl-3-(3-pyridyl)butyrate (3.4 g) was added to a solution of sodium ethoxide (from 0.78 g sodium) in ethanol (45 ml). The mixture was heated under reflux for 7 hours and evaporated. The residue was taken up in water and extracted with chloroform at pH 13. The pH was adjusted to 7.0 and the mixture allowed to stand at 0° overnight. The solid was filtered off to give 5-[1-(3-pyridyl)ethyl]-2-thiouracil (1.83 g) m.p. 225°-228° (from 2-propanol).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][CH2:5][C@@H:4]2[CH2:8][N:9](C(OCC3C=CC=CC=3)=O)[CH2:10][CH2:11][N:3]12.C(O)=O.C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH2:5]1[C@@H:4]2[CH2:8][NH:9][CH2:10][CH2:11][N:3]2[C:2](=[O:1])[CH2:7][O:6]1
Reactant: O=C(OCc1ccccc1)N1CCN2C(=O)COC[C@@H]2C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O=CO
Solvent: CCO
Product: O=C1COC[C@@H]2CNCCN12
Temperature: 120 °C

Procedure:
Benzyl (9aS)-4-oxohexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (0.19 g, 0.65 mmol was dissolved in ethanol (20 mL). The solution was transferred to a 25 mL vial, which contained 10% palladium on carbon (0.1 g), formic acid (0.1 g, 2.2 mmol) and ammonium formate (0.2 g, 3.17 mmol). The mixture was heated for 5 min at 120° C. using microwave single node heating. The catalyst was filtered off and the solution of crude (9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one was used in the next step without purification and quantification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7](OC)=[C:6]([N+:15]([O-:17])=[O:16])[CH:5]=1.[F:19]C1C([N+]([O-])=O)=CC([N+]([O-])=O)=CC=1C(O)=O>>[F:19][C:5]1[C:6]([N+:15]([O-:17])=[O:16])=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:18]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(OC)c([N+](=O)[O-])c1
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1F
Product: COC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1F

Procedure:
Methyl 2-fluoro-3,5-dinitrobenzoate (D137) was prepared in an analogous manner to Description 25 (D25) from 2-fluoro-3,5-dinitrobenzoic acid (D136).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[N:21][C:20]([NH:23][C:24]4[CH:25]=[N:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=4)=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[OH-].[Li+].Cl>C1COCC1.O>[F:33][C:30]([F:31])([F:32])[C:27]1[N:26]=[CH:25][C:24]([NH:23][C:20]2[N:21]=[CH:22][C:17]([C:14]3[CH:13]=[CH:12][C:11]([CH:8]4[CH2:7][CH2:6][CH:5]([CH2:4][C:3]([OH:34])=[O:2])[CH2:10][CH2:9]4)=[CH:16][CH:15]=3)=[N:18][CH:19]=2)=[CH:29][CH:28]=1
Reactant: COC(=O)CC1CCC(c2ccc(-c3cnc(Nc4ccc(C(F)(F)F)nc4)cn3)cc2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC1CCC(c2ccc(-c3cnc(Nc4ccc(C(F)(F)F)nc4)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (4-{4-[5-(6-trifluoromethyl-pyridin-3-ylamino)-pyrazin-2-yl]-phenyl}-cyclohexyl)-acetic acid methyl ester (0.051 g) in 4 Ml THF/water (1:1) was added solid lithium hydroxide (0.030 g). The reaction was stirred at room temperature for 48 h, then heated to 45° C. for 24 h. The reaction was neutralized with 6 N hydrochloric acid and then purified by reverse-phase preparative HPLC to afford the title compound: 1H NMR (400 MHz, DMSO-D6) δ ppm 1.1 (s, 2 H) 1.3 (s, 1 H) 1.6 (s, 2 H) 1.9 (s, 6 H) 3.5 (s, 6 H) 7.4 (s, 2 H) 7.9 (s, 1 H) 8.0 (s, 2 H) 8.6 (s, 1 H), 8.6 (s, 1 H) 8.9 (s, 1 H) 9.1 (s, 1 H) 10.9 (s, 1 H); (M+H)+ 457.1.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[S:4][C:3]=1[C:8]([O:10]C)=O.Cl[C:13]1[N:18]=[CH:17][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=1>CO>[CH3:7][C:5]1[S:4][C:3]2[C:8](=[O:10])[N:18]3[CH:17]=[C:16]([C:19]([O:21][CH3:22])=[O:20])[CH:15]=[CH:14][C:13]3=[N:1][C:2]=2[CH:6]=1
Reactant: COC(=O)c1sc(C)cc1N
Reactant: COC(=O)c1ccc(Cl)nc1
Solvent: CO
Product: COC(=O)c1ccc2nc3cc(C)sc3c(=O)n2c1
Temperature: 180 °C

Procedure:
A mixture of 5 g (0.0292 mol) of 3-amino-5-methyl-2-thiophene-carboxylic acid, methyl ester (German Patent No. 1055007, Apr. 16, 1959) and 5 g (0.0292 mol) of 6-chloro-3-pyridinecarboxylic acid, methyl ester (Alfred Bader Chemical Company) is heated in an oil bath at 180° C. for thirty minutes. The mixture is cooled, dissolved in hot methanol, cooled and 1.2 g of 2-methyl-10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxylic acid, methyl ester is collected; mp 215°-216° C. after recrystallization from methanol.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[CH:17][N:18]([CH2:19][C:20](=[O:27])[N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:12]2=[N:11][C:10]=1[C:28]1[O:29][C:30]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[CH:31][N:32]=1)C1C=CC=CC=1.[Si](I)(C)(C)C.CO.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(#N)C>[F:40][C:37]1[CH:36]=[CH:35][C:34]([CH2:33][C:30]2[O:29][C:28]([C:10]3[N:11]=[C:12]4[N:18]([CH2:19][C:20](=[O:27])[N:21]5[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]5)[CH:17]=[CH:16][N:13]4[C:14](=[O:15])[C:9]=3[OH:8])=[N:32][CH:31]=2)=[CH:39][CH:38]=1
Reactant: O=C(Cn1ccn2c(=O)c(OCc3ccccc3)c(-c3ncc(Cc4ccc(F)cc4)o3)nc12)N1CCCCC1
Agent: C[Si](C)(C)I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: O=C(Cn1ccn2c(=O)c(O)c(-c3ncc(Cc4ccc(F)cc4)o3)nc12)N1CCCCC1
Reaction time: 8 h
Yield: 24.1 %

Procedure:
To a solution of the product of example 6 (50 mg, 0.092 mmol) in acetonitrile (2 ml) was added TMSI (150 mg, 0.75 mmol) drop-wise at room temperature. The mixture was stirred for 8 hours, after which methanol (0.1 ml) was added to quench the reaction. Then saturated solution of Na2S2O3 was added drop-wise till a yellow solid was precipitated. The resulting solids were collected by filtration, washed with ethyl acetate to give the desired product (10 mg, 24% yield).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][C:12]=3[F:19])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26].NCCC(O)=O>>[O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=[C:24]4[S:20][C:21](=[O:26])[NH:22][C:23]4=[O:25])=[CH:13][C:12]=3[F:19])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc(N2CCC3(CC2)OCCO3)c(F)c1
Agent: NCCC(=O)O
Product: O=C1NC(=O)C(=Cc2ccc(N3CCC4(CC3)OCCO4)c(F)c2)S1

Procedure:
The title compound was prepared from 4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-3-fluoro-benzaldehyde (which was obtained in Example 59), 2,4 thiazolidinedione and β-alanine according to the procedure of Example 33 as an orange solid; mp 159–160° C.; 1H NMR (300 MHz, CDCl3) δ 7.01 (m, 1H), 7.13–7.22 (m, 2H), 7.71–7.77 (m, 1H); MS (ES) m/z: 363.3 (M−H)−.
Reaction SMILES: [CH2:1]([NH:9][CH:10]1[C:18]2[C:13](=[CH:14][C:15]([O:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][N:21]=3)=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C=O.[BH3-][C:32]#N.[Na+]>>[CH3:32][N:9]([CH2:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[CH:10]1[C:18]2[C:13](=[CH:14][C:15]([O:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][N:21]=3)=[CH:16][CH:17]=2)[CH2:12][CH2:11]1
Reactant: [BH3-]C#N
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3NCCc2ccccc2)nc1
Agent: C=O
Agent: [Na+]
Product: CN(CCc1ccccc1)C1CCc2cc(Oc3ccc(C(N)=O)cn3)ccc21
Yield: 91.6 %

Procedure:
Using a method similar to Example 13, using 6-(1-phenethylamino-indan-5-yloxy)-nicotinamide (example 18, 980 mg, 2.62 mmol), paraformaldehyde (1.03 g), and NaBH3CN (494 mg, 7.87 mmol) gives the title compound (930 mg) as a light yellow solid. Mass spectrum (ion spray): m/z=388 (M+1); 1HNMR (CDCl3): 8.59 (s, 1H), 8.16 (d, 1H), 7.30-7.17 (m, 6H), 6.97-6.91 (m, 3H), 5.79 (br. s, 2H), 4.45 (t, 1H), 2.96-2.74 (m, 4H), 2.68 (m, 2H), 2.33 (s, 3H), 2.09 (m, 2H).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]([O:15]C)[C:8]([O:13]C)=[C:9]([CH:12]=1)[C:10]#[N:11])=[O:4].B(Br)(Br)Br.C(=O)([O-])O.[Na+].C(O)(=O)C>C(Cl)Cl>[Br:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]([OH:15])[C:8]([OH:13])=[C:9]([CH:12]=1)[C:10]#[N:11])=[O:4]
Reactant: COc1cc(C(=O)CBr)cc(C#N)c1OC
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: N#Cc1cc(C(=O)CBr)cc(O)c1O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
4.2 g of 5-(bromoacetyl)-2,3-dimethoxybenzonitrile dissolved in 150 ml of methylene chloride are treated with 8.9 ml of boron tribromide. The reaction mixture is stirred at 20° for 18 hours. It is subsequently poured into 220 ml of saturated sodium hydrogen carbonate solution and 100 g of ice, adjusted to pH 6 with glacial acetic acid and extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulfate and evaporated. There is obtained 5-(bromoacetyl)-2,3-dihydroxybenzonitrile as an amorphous solid.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([CH3:34])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[O:29][C:28]([CH3:30])=[N:27][C:26]=1[C:31](O)=[O:32]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:31]([C:26]3[N:27]=[C:28]([CH3:30])[O:29][C:25]=3[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH3:34])=[O:32])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2C)o1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3nc(C)oc3-c3ccccc3C)n2)o1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(o-tolyl)-2-methyl-oxazole-4-carboxylic acid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][C:20]([OH:24])([CH3:23])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:25]([O:28][CH2:29][C:30]1[C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=[CH:32][C:31]=1[N:45]1[N:54]=[CH:53][C:52]2[C:47](=[C:48]([F:59])[CH:49]=[C:50]([C:55]([CH3:58])([CH3:57])[CH3:56])[CH:51]=2)[C:46]1=[O:60])(=[O:27])[CH3:26].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:25]([O:28][CH2:29][C:30]1[C:35]([C:2]2[CH:3]=[C:4]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][C:20]([OH:24])([CH3:23])[CH2:19][CH2:18]4)=[CH:13][N:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=2)=[CH:34][CH:33]=[CH:32][C:31]=1[N:45]1[N:54]=[CH:53][C:52]2[C:47](=[C:48]([F:59])[CH:49]=[C:50]([C:55]([CH3:57])([CH3:56])[CH3:58])[CH:51]=2)[C:46]1=[O:60])(=[O:27])[CH3:26]
Reactant: Cn1nc(Cl)cc(Nc2ccc(N3CCC(C)(O)CC3)cn2)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCC(C)(O)CC4)cn3)c(=O)n(C)n2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 100 °C

Procedure:
This reaction was carried out under similar conditions to those described above instep 7 of preparation of Example 6. A solution of 6-chloro-4-(5-(4-hydroxy-4-methylpiperidin-1-yl)pyridin-2-ylamino)-2-methylpyridazin-3(2H)-one (150 mg, 429 μmol), 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (212 mg, 429 μmol), xPhos (20.4 mg, 42.9 μmol) and potassium phosphate (228 mg, 1.07 mmol) in 10 ml of dioxane/water (9:1) was degassed with nitrogen for 10 minutes and bis(dibenzylideneacetone)palladium (0) (12.3 mg, 21.4 μmol) was added. The reaction mixture was heated to 100° C. for 2 hr. After work up, the product was purified by preparative HPLC on silica gel, using a gradient of 0% to 5% methanol/ethyl acetate. This provided 1:1 ratio of desire compound and 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(5-(4-hydroxy-4-methylpiperidin-1-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzyl acetate. The reaction mixture was dissolved in methanol (4 ml) and to this was added 2 N NaOH (600 μA). The reaction was stirred at room temperature for 2 h. The methanol was removed by evaporation and the resultant solution was acidified with 1N HCl and extracted with DCM. The resultant organic extract was dried over NaSO4, filtered and concentrated in vacuo. The resultant yellow solid was triturated with ether to afford the desired product as an yellow solid (40 mg, 45.8%). (M+H)+=640.4 m/e. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14-1.24 (m, 3H) 1.31-1.48 (m, 12H) 1.64 (br. s., 2H) 2.35-2.68 (m, 2H) 3.31 (br. s., 2H) 3.52-3.62 (m, 1H) 4.41 (d, J=11.29 Hz, 2H) 7.33-7.60 (m, 7H) 7.75 (d, J=13.30 Hz, 1H) 7.87 (s, 1H) 8.44 (br. s., 1H) 8.52 (br. s., 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1.[NH:24]1[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]1>>[O:30]=[S:27]1(=[O:31])[CH2:28][CH2:29][N:24]([C:20]([C:17]2[S:16][C:15](/[CH:14]=[CH:13]/[C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][C:11]=3[CH3:23])=[N:19][CH:18]=2)=[O:22])[CH2:25][CH2:26]1
Reactant: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)O)s1
Reactant: O=S1(=O)CCNCC1
Product: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)N2CCS(=O)(=O)CC2)s1
Yield: 84 %

Procedure:
As described for example 77c, 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-vinyl}-thiazole-5-carboxylic acid (83 mg, 0.25 mmol) was converted, using thiomorpholine 1,1-dioxide instead of 4-aminotetrahydropyran, to the title compound (94 mg, 84%) which was obtained as a light yellow solid after purification by chromatography (silica, 0 to 100% ethyl acetate in heptane). MS: m/e=449.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:15][C:13]=3[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:25]1[C:30]([C:31]([OH:33])=[O:32])=[CH:29][C:28]2[C:34]([O:36][C:37](=O)[C:27]=2[CH:26]=1)=[O:35]>>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:15][C:13]=3[N:14]=2)=[CH:3][C:2]=1[N:1]1[C:34](=[O:35])[C:28]2[C:27](=[CH:26][CH:25]=[C:30]([C:31]([OH:33])=[O:32])[CH:29]=2)[C:37]1=[O:36]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: COc1ccc(-c2nc3cc(-c4ccccc4)ccc3o2)cc1N
Product: COc1ccc(-c2nc3cc(-c4ccccc4)ccc3o2)cc1N1C(=O)c2ccc(C(=O)O)cc2C1=O

Procedure:
Prepared by the method described in Example 1b), from 2-(3-amino-4-methoxyphenyl)-5-phenylbenzoxazole (73 mg, 0.23 mmol) and 1,2,4-benzenetricarboxylic anhydride (50 mg, 0.26 mmol) the title compound was obtained, 50 mg (44%). 1H NMR (DMSO) δ 8.46(dd, 1H), 8.35(m, 3H), 8.13(d, 1H), 8.03(d, 1H), 7.84(d, 1H), 7.73(m, 3H), 7.49(m, 3H), 7.39(t, 1H), 3.90(s, 3H). MS 489 m/z (M−H)−.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C@H:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:3]1[NH:19][C:20](=[O:33])[C@H:21]([CH3:32])[NH:22][C:23](=[O:31])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[F:34]C1C=CC=CC=1CC(O)=O>>[F:34][C:30]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:24][C:23]([NH:22][C@H:21]([C:20]([NH:19][C@@H:3]1[C:2](=[O:1])[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C@@H:4]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:33])[CH3:32])=[O:31]
Reactant: O=C(O)Cc1ccccc1F
Reactant: C[C@H](NC(=O)Cc1ccccc1)C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1
Product: C[C@H](NC(=O)Cc1ccccc1F)C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1

Procedure:
A method similar to the one described for (113) was used except that 2-fluorophenylacetic acid (77 mg) was used instead of phenylacetic acid to afford the title compound as a 1:1 mixture with the 2S,3R diastereomer (150 mg), white solid, m.p. 115-135° C. 1H NMR (300 MHz, CDCl3) δ 0.97 (d, 1.5H, J=5 Hz), 1.25 (d, 1.5H, J=5 Hz), 3.49 (m, 2H), 4.63 (p, 0.5H, J=7 Hz), 4.75 (p, 0.5H, J=7 Hz), 4.85 (t, 1H, J=6 Hz), 5.11 (t, 1H, J=6 Hz), 5.80 (dd, 1H, J=7 Hz, J=10 Hz), 6.08 (d, 0.5H, J=8 Hz), 6.27 (d, 0.5 Hz, J=8 Hz), 6.38 (d, 0.5H, J=6 Hz), 6.66 (d, 0.5H, J=7 Hz), 6.78-7.34 (m, 13H), 8.02 (s, 1H). MS APCI, m/z=484 (M+Na). LC/MS: 2.09 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]2[NH:9][N:10]=[CH:11][C:3]=12.Cl[CH2:13][C:14]1[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:17]2[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=2[N:15]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]2[N:9]([CH2:13][C:14]3[N:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:17]4[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=4[N:15]=3)[N:10]=[CH:11][C:3]=12
Reactant: Nc1nc(Cl)c2cn[nH]c2n1
Reactant: ClCc1nc2ccccc2n1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1nc(Cl)c2cnn(Cc3nc4ccccc4n3-c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
A mixture of 4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (1.0 g, 5.9 mmol), 2-(chloromethyl)-1-phenyl-1H-benzo[d]imidazole (1.4 g, 5.9 mmol) and K2CO3 (0.86 g, 6.2 mmol) in DMSO (20 mL) was stirred at room temperature overnight. Then the mixture was added H2O (50 mL) and extracted with CH2Cl2 (20 mL×3). The combined organic layers were concentrated in vacuo to give 4-chloro-1-(1-phenyl-1H-benzoimidazol-2-ylmethyl)-1H-Pyrazolo[3,4-d]pyrimidin-6-ylamine (1.5 g, yield 68%) as orange solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH2:9][OH:10])[N:3]=1.Br[CH2:12][CH:13]1[CH2:15][CH2:14]1>>[Cl:1][C:2]1[N:3]=[C:4]([CH2:9][OH:10])[CH:5]=[CH:6][C:7]=1[O:8][CH2:12][CH:13]1[CH2:15][CH2:14]1
Reactant: BrCC1CC1
Reactant: OCc1ccc(O)c(Cl)n1
Product: OCc1ccc(OCC2CC2)c(Cl)n1

Procedure:
Using 2-chloro-6-(hydroxymethyl)pyridin-3-ol and (bromomethyl)cyclopropane, and in the same manner as in Example 5, the title compound was obtained.
Reaction SMILES: C(OC([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]([NH:24][C:25]([NH:27][CH2:28][C:29]([O:31]CC)=[O:30])=[O:26])[C:20](OC)=[O:21])=[CH:15][CH:14]=1)=O)C1C=CC=CC=1.[ClH:34]>>[ClH:34].[NH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C@H:19]2[NH:24][C:25](=[O:26])[N:27]([CH2:28][C:29]([OH:31])=[O:30])[C:20]2=[O:21])=[CH:15][CH:14]=1
Reactant: CCOC(=O)CNC(=O)N[C@@H](C(=O)OC)c1ccc(CNC(=O)OCc2ccccc2)cc1
Agent: Cl
Product: NCc1ccc([C@H]2NC(=O)N(CC(=O)O)C2=O)cc1

Procedure:
280 mg of N-(1-(R)-(4-benzyloxycarbonylaminomethylphenyl-1-methoxycarbonylmethyl),N'-ethoxycarbonylmethylurea are boiled under reflux for 45 min in 4 ml of 6N HCl and the mixture is then concentrated and dried over KOH.
Reaction SMILES: C([NH:8][OH:9])(OC(C)(C)C)=O.[H-].[Na+].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1.Cl>C1COCC1.C(OCC)C>[NH2:8][O:9][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)NO
Reactant: COc1ccc(CCl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(CON)cc1
Reaction time: 8 h
Yield: 39 %

Procedure:
A solution was made of Boc hydroxylamine (2.0 g, 17.1 mmol) in dry THF (60 ml). Sodium hydride (1.1 g of a 60% suspension in paraffin oil, 25.7 mmol) was then added and the suspension stirred. A catalytic amount of KI was then added to the reaction prior to the cautious addition of 4-methoxybenzyl chloride (3.2 g, 20.4 mmol). The reaction was then allowed to stir overnight before removal of solvent in vacuo. The residue was taken up with diethyl ether (100 ml) and HCl gas bubbled in for 20 minutes, causing the start of precipitation of the product. The flask was stoppered and left to stand overnight. The product was then filtered off as a off-white wax (39–52% yield according to varying batches).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[CH:9][CH:8]=1.[OH-].[Na+:27]>CCO>[Na+:27].[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([NH-:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH3:15])=[CH:11][CH:12]=1
Reactant: CCOc1ccc(-c2c(Cl)ncn2-c2ccc(S(N)(=O)=O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1ccc(-c2c(Cl)ncn2-c2ccc(S([NH-])(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-[4-chloro-5-(4-ethoxyphenyl)imidazol-1-yl]benzenesulfonamide (1 g, 2.89 mmol) (obtained as described in WO 00/23426) in EtOH (55 mL), NaOH powder (115 mg, 2.89 mmol) was added under argon atmosphere, and the resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated to dryness and a crude product was obtained, which was directly used in the following reaction.