Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][CH:4]=[C:3]1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([O:23][CH2:24][C:25]#[N:26])[CH:17]=[CH:16]2.[Cl-].[NH4+].[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C=O)C>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=[C:3]1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([O:23][CH2:24][C:25]1[NH:31][N:30]=[N:29][N:26]=1)[CH:17]=[CH:16]2
Reactant: Cn1c(-c2ccccc2)ccc1-c1ccc2cc(OCC#N)ccc2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(-c2ccccc2)ccc1-c1ccc2cc(OCc3nnn[nH]3)ccc2c1

Procedure:
In a similar manner as described in step 2 of Example 3, the title compound was prepared from {[6-(1-methyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetonitrile (0.20 g, 0.48 mmol), prepared in the previous step, ammonium chloride (0.077 g, 1.44 mmol) and sodium azide (0.094 g, 1.44 mmol) in DMF (10 mL). The precipitated solids were isolated by vacuum filtration to give 5-({[6-(1-methyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)-1H-tetraazole. as a white solid (0.228 g, 81%), mp 231–233° C. (dec). Elemental Analysis for C23H19N5O.0.34 H2O.0.07 C3H7NO Calc'd: C, 70.99; H, 5.18; N, 18.08. Found: C, 70.84; H, 5.07; N, 18.18.
Reaction SMILES: C([Sn]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)(CCCC)CCCC)CCC.Br[C:21]1[O:22][CH:23]=[CH:24][C:25]=1[Br:26]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Br:26][C:25]1[CH:24]=[CH:23][O:22][C:21]=1[C:18]1[CH:19]=[CH:14][N:15]=[CH:16][CH:17]=1
Reactant: Brc1ccoc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Brc1ccoc1-c1ccncc1
Temperature: 100 °C
Yield: 24.7 %

Procedure:
A solution of tributylstannylpyridine (8.0 g, 21.7 mmol) and 2,3-dibromofuran (5.9 g, 26.1 mmol) in dry toluene (200 ml) was treated with bis(triphenylphosphine)palladium (II) chloride (1.5 g, 2.2 mmol) and heated at 100° C. overnight. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with water, dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate to afford the title compound (1.2 g, 25%); 1H NMR (CDCl3) 8.66 (2H, d, J 11 Hz), 7.84 (2H, d, J 11 Hz), 7.50 (1H, d, J 3 Hz), 6.60 (1H, d, J 3 Hz).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[O:12]1[C:16]2[CH:17]=[CH:18]C=CC=2N=C1>>[O:12]1[CH2:16][CH:17]1[CH2:18][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: c1ccc2ocnc2c1
Reactant: Oc1ccnc2ccccc12
Product: c1ccc2c(OCC3CO3)ccnc2c1

Procedure:
Compound 75 was prepared in the manner of compound 6 substituting 4-hydroxy-quinoline for compound 8 in part C-5 of Example 1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4](=[O:6])[CH3:5].[C:7](OC(=O)C)(=[O:9])[CH3:8]>C(O)(=O)C>[C:7]([O:1][CH2:2][CH2:3][C:4](=[O:6])[CH3:5])(=[O:9])[CH3:8]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)CCO
Solvent: CC(=O)O
Product: CC(=O)CCOC(C)=O

Procedure:
Crude 4-acetoxy-2-butanone was prepared as follows. A mixture of 4-hydroxy-2-butanone (101.48 g) and acetic anhydride (131.05 g) was stirred and heated to about 120° C. for about 40 minutes before the acetic acid by-product was removed by vacuum distillation at about 24 torr and vapor temperatures rising to about 49° C. The distillation residue was about 129.0 g of crude 4-acetoxy-2-butanone.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[Ru:21](Cl)([Cl:23])[Cl:22]>CO>[Ru:21]([Cl:23])[Cl:22].[C:14]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1.[C:14]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1.[C:14]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cl[Ru](Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CO
Product: Cl[Ru]Cl

Procedure:
Using the procedure of Example 1, 50 mls. of methanol, 5.0 gram of triphenylphosphine and 1.0 gram of ruthenium trichloride hydrate are stirred and heated to form tris(triphenylphosphine) ruthenium dichloride as a brown insoluble powder which is recovered by filtration. 1.0 Gram of this powder is dissolved in a mixture containing 50 mls. of tertiary butanol and 1.4 grams of sodium acetate trihydrate. The resulting mixture is heated with stirring at reflux temperature under N2 for 4.5 hours to form an orange powder (0.44 gram) which is identified as the desired bis(acetato)bis(triphenylphosphine) ruthenium.
Reaction SMILES: [CH2:1]=[CH:2][C:3]([N:5]1[CH2:10][C@H:9]([N:11]2[N:15]=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([O:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:20][CH:21]=3)[C:13]3=[C:29]([NH2:33])[N:30]=[CH:31][N:32]=[C:12]23)[CH2:8][CH2:7][CH2:6]1)=[O:4].[C:34]([O:37][CH2:38][O:39][C:40](ON1C(=O)CCC1=O)=[O:41])(=[O:36])[CH3:35].C(N(CC)CC)C>CN(C)C(=O)C>[C:34]([O:37][CH2:38][O:39][C:40](=[O:41])[NH:33][C:29]1[N:30]=[CH:31][N:32]=[C:12]2[N:11]([C@@H:9]3[CH2:8][CH2:7][CH2:6][N:5]([C:3](=[O:4])[CH:2]=[CH2:1])[CH2:10]3)[N:15]=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:20][CH:21]=3)[C:13]=12)(=[O:36])[CH3:35]
Reactant: C=CC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Reactant: CC(=O)OCOC(=O)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: C=CC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(NC(=O)OCOC(C)=O)ncnc32)C1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Alternatively, a mixture of ibrutinib (25 mg, 1.0 eq), (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl acetate (1.5 eq), and triethylamine (3.0 eq) in N,N-dimethylacetamide (DMA) (1.0 mL) was stirred at 20° C. overnight. The reaction was then purified by reverse-phase (C-18) liquid chromatography using water and acetonitrile as eluents to yield compound (1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[C:38]1[N:43]=[CH:42][C:41]([CH2:44][CH3:45])=[CH:40][N:39]=1>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:17][CH2:18][N:19]([C:38]4[N:43]=[CH:42][C:41]([CH2:44][CH3:45])=[CH:40][N:39]=4)[CH2:20][CH2:21]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1
Reactant: CCc1cnc(Cl)nc1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1cnc(N2CCC(c3cc(F)c(Nc4ncc(Cl)c(Nc5cc(C)[nH]n5)n4)cc3C)CC2)nc1
Temperature: 120 °C

Procedure:
To a mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (0.10 mmol) and triethylamine (83 uL, 0.6 mmol) in DMF (1.5 mL), was added 2-chloro-5-ethylpyrimidine (27 mg, 0.20 mmol). The mixture was heated in a microwave at 120° C. for 10 min. The reaction was filtered and the filtrate was purified by preparative RP-HPLC to afford 5-chloro-N2-(4-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-2-fluoro-5-methylphenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as a white solid. ESMS m/z 522.2 (M+H+).
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:10].C1C(=O)N([Cl:18])C(=O)C1>C(#N)C.C(OCC)(=O)C>[Cl:18][C:7]1[CH:8]=[C:9]2[O:1][C:2](=[O:10])[NH:3][C:4]2=[N:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=c1[nH]c2ncccc2o1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=c1[nH]c2ncc(Cl)cc2o1
Temperature: 85 °C

Procedure:
A mixture of 3H-oxazolo[4,5-b]pyridin-2-one (36) (300 mg, 2.2 mmol, 1 equiv) and NCS (352 mg, 2.65 mmol, 1.2 equiv) in 5 mL of acetonitrile was heated at 85° C. overnight. The reaction solution was diluted with ethyl acetate (EtOAc), and washed with water. The organic solution was concentrated and purified by flash chromatography, to provide 6-Chloro-3H-oxazolo[4,5-b]pyridin-2-one (37): LCMS Retention time, 0.69 min; LCMS observed (M+H)+: 171.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[N+:25]([O-:27])=[O:26])=[N:16][N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH2:29]([O:39][C:40]([NH:42][C:43]1[CH:48]=[CH:47][N:46]([CH2:49][C:50](O)=[O:51])[C:45](=[O:53])[N:44]=1)=[O:41])[C:30]1[CH:38]=[CH:37][C:36]2[O:35][CH2:34][O:33][C:32]=2[CH:31]=1>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[N+:25]([O-:27])=[O:26])=[N:16][N:17]=1)(=[O:12])=[O:11])[C:50](=[O:51])[CH2:49][N:46]1[CH:47]=[CH:48][C:43]([NH:42][C:40]([O:39][CH2:29][C:30]2[CH:38]=[CH:37][C:36]3[O:35][CH2:34][O:33][C:32]=3[CH:31]=2)=[O:41])=[N:44][C:45]1=[O:53])[CH3:2]
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2[N+](=O)[O-])s1
Reactant: O=C(O)Cn1ccc(NC(=O)OCc2ccc3c(c2)OCO3)nc1=O
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2[N+](=O)[O-])s1)C(=O)Cn1ccc(NC(=O)OCc2ccc3c(c2)OCO3)nc1=O

Procedure:
The title compound was synthesized by the reaction of N-{2-[5-(4-chloro-2-nitrophenyl)-1,3,4-thiadiazole-2-sulfonylamino]-ethyl}-glycine ethyl ester with [4-N-(piperonyloxycarbonyl)-cytosin-1-yl]-acetic acid as per the procedure of example 13. 1H NMR (500 MHz; DMSO-d6) δ 10.71 (s, 1H), 9.22 (brs, 0.6H), 9.08 (brs, 0.4H), 8.40 (s, 1H), 8.07–7.96 (m, 2H), 7.92 (d, 0.6H), 7.86 (d, 0.4H), 7.02 (d, 0.6H), 7.00 (d, 0.4H), 6.99 (s, 1H), 6.91 (s, 2H), 6.02 (s, 2H), 5.08 (s, 2H), 4.81 (s, 1.2H), 4.64 (s, 0.8H), 4.37 (s, 0.8H), 4.18 (q, 0.8H), 4.08 (s, 1.2H), 4.08 (q, 1.2H), 3.62 (t, 1.2H), 3.47 (t, 1.2H), 3.43 (t, 0.8H), 3.28 (t, 0.8H), 1.24 (t, 1.2H), 1.17 (t, 1.8H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:27]=[CH:26][C:21]4[NH:22][C:23](=[O:25])[S:24][C:20]=4[CH:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.O.[C:29](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]([CH3:29])[C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:27]=[CH:26][C:21]4[NH:22][C:23](=[O:25])[S:24][C:20]=4[CH:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2ccc([C@H]3CC[C@H](NCCCc4ccc(F)cc4)CC3)cc2s1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(CCCc1ccc(F)cc1)[C@H]1CC[C@H](c2ccc3[nH]c(=O)sc3c2)CC1
Reaction time: 3 h

Procedure:
To a stirred solution of 6-{trans-4-[3-(4-fluorophenyl)-propylamino]cyclohexyl}-3H-benzthiazol-2-one (0.24 g, 0.67 mmol) in MeOH (10 mL) containing H2O (0.5 mL) was added p-formaldehyde (0.1 g, 3.3 mmol). The reaction mixture was stirred for 3 hours. Sodium triacetoxyborohydride (0.2 g, 0.9 mmol) was added, and the mixture was stirred overnight. Solid NaOH was added until the solution became clear. The reaction mixture was concentrated under reduced pressure to give a yellow oil. Purification by flash chromatography (eluent 9.5:1:1 CH2Cl2:MeOH:NH4OH) gave 6-(trans-4-{[3-(4-fluorophenyl)-propyl]methylamino}cyclohexyl)-3H-benzthiazol-2-one (55 mg, 15%), as a pale yellow solid: mp 256-261° C.; IR (KBr): 2942, 1683, 1509 cm−1; 1H NMR (500 MHz, DMSO-d6): δ 7.41 (s, 1H), 7.31-7.03 (m, 6H), 3.29 (m, 2H), 3.01 (m, 2H), 2.70 (s, 3H), 2.64 (m, 2H), 2.11 (m, 1H), 2.08 (m, 1H), 1.99 (m, 2H), 1.87 (m, 2H), 1.98-1.61 (m, 4H); API-MS (m/z): 399 [M+H]+; calcd for C23H27FN2OS, 399.1906; found, 399.1909; HPLC: method A, 5.85 minutes (>99%); method B, 11.48 minutes (>99%); Anal. Calcd for C23H27FN2OS.HCl.0.75NaCl: C, 57.69; H, 5.89; N, 5.85. Found: C, 57.72; H, 5.96;N, 5.51.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:12][N:11]([CH3:13])[CH2:10]2)=[CH:4][N:3]=1.[NH2:14][C:15]1[C:16](=[O:23])[N:17]([CH3:22])[CH:18]=[C:19]([Br:21])[CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.O>[Br:21][C:19]1[CH:20]=[C:15]([NH:14][C:2]2[CH:7]=[CH:6][C:5]([O:8][CH:9]3[CH2:12][N:11]([CH3:13])[CH2:10]3)=[CH:4][N:3]=2)[C:16](=[O:23])[N:17]([CH3:22])[CH:18]=1
Reactant: Cn1cc(Br)cc(N)c1=O
Reactant: CN1CC(Oc2ccc(Br)nc2)C1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CN1CC(Oc2ccc(Nc3cc(Br)cn(C)c3=O)nc2)C1
Temperature: 100 °C
Yield: 41.5 %

Procedure:
To a solution of 2-Bromo-5-(1-methyl-azetidin-3-yloxy)-pyridine (0.327 g, 1.32 mmol) and 3-Amino-5-bromo-1-methyl-1H-pyridin-2-one (0.321 g, 1.58 mmol) in dioxane (5.5 mL) add Cs2CO3 (0.645 g, 1.98 mmol), xantphos (0.153 g, 0.264 mmol) and bubbled argon through reaction mixture for 15 min. Add Pd (OAc)2 (0.03 g, 0.132 mmol) in the end. The reaction was heated at 100° C. under argon for 3 h. TLC shows 2-Bromo-5-(1-methyl-azetidin-3-yloxy)-pyridine was gone. The reaction mixture was treated with water (30 mL) and extracted with dichloromethane (3×20 mL). Organic phase was concentrated and loaded onto silica gel column separation. Using 3-5% MeOH in DCM gave 5-bromo-1-methyl-3-[5-(1-methyl-azetidin-3-yloxy)-pyridin-2-ylamino]-1H-pyridin-2-one as green solid (200 mg, 40% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]1[CH2:11][CH:12](OS(C)(=O)=O)[CH2:13][CH2:14][C:8]1=[C:7]2[CH2:20][C:21]([O:23][CH2:24][CH2:25][CH3:26])=[O:22].[N-:27]=[N+:28]=[N-:29].[Na+]>CN(C=O)C>[N:27]([CH:12]1[CH2:11][N:9]2[C:10]3[C:6]([C:7]([CH2:20][C:21]([O:23][CH2:24][CH2:25][CH3:26])=[O:22])=[C:8]2[CH2:14][CH2:13]1)=[CH:5][CH:4]=[CH:3][C:2]=3[F:1])=[N+:28]=[N-:29]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCOC(=O)Cc1c2n(c3c(F)cccc13)CC(OS(C)(=O)=O)CC2
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOC(=O)Cc1c2n(c3c(F)cccc13)CC(N=[N+]=[N-])CC2
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a stirred solution of propyl {4-fluoro-7-[(methylsulfonyl)oxy]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl}acetate (1 eq) in DMF (0.15M) at 0° C. was added sodium azide (1.2 eq). The reaction mixture was stirred at 60° C. for 6 h. The reaction was quenched by addition of water and NH4Cl, extracted with EtOAc, washed with water, brine, dried and evaporated. The residue was purified by column chromatography on silica gel eluting with EtOAc/Hexanes (0 to 50%) to give the desired material as a yellow oil.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=2)[CH:7]=1)C.[C:22]([NH:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)(=[O:24])[CH3:23]>>[C:22]([NH:25][C:26]1[CH:31]=[C:30]([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:8]3[CH:7]=[C:6]([CH2:5][C:4]([OH:3])=[O:21])[CH:11]=[CH:10][CH:9]=3)=[CH:19][CH:18]=2)[CH:29]=[CH:28][CH:27]=1)(=[O:24])[CH3:23]
Reactant: CCOC(=O)Cc1cccc(COc2ccc(I)cc2)c1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Product: CC(=O)Nc1cccc(-c2ccc(OCc3cccc(CC(=O)O)c3)cc2)c1

Procedure:
[3-(3′-Acetylamino-biphenyl-4-yloxymethyl)-phenyl]-acetic acid was prepared using general procedure 5 from [3-(4-iodo-phenoxymethyl)-phenyl]-acetic acid ethyl ester (of intermediate 4) and 3-acetamidobenzeneboronic acid (ASDI Incorporated, Newark, Del.). Mass spectrum MH+=376.
Reaction SMILES: [C:1]([Si:3]([CH3:6])([CH3:5])[CH3:4])#[CH:2].Br[C:8]1[C:9]([C:15]#[N:16])=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1>[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].CN(C=O)C>[Cl:14][C:12]1[CH:13]=[C:8]([C:2]#[C:1][Si:3]([CH3:6])([CH3:5])[CH3:4])[C:9]([C:15]#[N:16])=[N:10][CH:11]=1
Reactant: C#C[Si](C)(C)C
Reactant: N#Cc1ncc(Cl)cc1Br
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cc(Cl)cnc1C#N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 39.9 %

Procedure:
A pressure vessel was charged with TEA (7.65 mL, 55.2 mmol), ethynyltrimethylsilane (2.32 mL, 16.6 mmol), copper (I) iodide (0.263 g, 1.380 mmol), palladium (0) tetrakis(triphenylphosphine) (0.558 g, 0.483 mmol), 3-bromo-5-chloropicolinonitrile (3.0 g, 13.8 mmol), and DMF (50 ml). The vessel was flushed with argon, sealed, stirred at ambient temperature for 15 minutes, and then heated at 50° C. for 4 hours. The solution was diluted with water and extracted with EtOAc. The combined organic layers were concentrated, and the residue was purified by silica-gel chromatography, eluting 0-50% ethyl acetate in hexane, to afford the title compound (1.3 g, 5.5 mmol). MS m/z=235 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:24]=1[N+:25]([O-])=O)[CH2:7][N:8]1[C:12]2[CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=[CH:16][C:11]=2[O:10][C:9]1=[O:21])([O-])=O>C1COCC1.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:24]=1[NH2:25])[CH2:7][N:8]1[C:12]2[CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=[CH:16][C:11]=2[O:10][C:9]1=[O:21]
Reactant: COC(=O)c1ccc2oc(=O)n(Cc3ccc([N+](=O)[O-])c([N+](=O)[O-])c3)c2c1
Agent: [Ni]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2oc(=O)n(Cc3ccc(N)c(N)c3)c2c1
Reaction time: 24 h

Procedure:
1.45 g (3.8 mmol) of methyl 3-(3,4-dinitrobenzyl)-2-oxo-2,3-dihydrobenzoxazole-5-carboxylate are dissolved in 20 ml of THF and hydrogenated under a hydrogen atmosphere using 1 g of Raney nickel (water-wet). After 24 h, the reaction solution is filtered, and the filtrate is evaporated to dryness; product; 1.1 g, ESI: 314 (M+H).
Reaction SMILES: [CH2:1]([NH:3][C@H:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH3:2].[CH3:18][C:19]([CH3:21])=O.C(O)(=O)C.C([BH3-])#N.[Na+]>CCO>[CH2:1]([N:3]([CH:19]([CH3:21])[CH3:18])[C@H:4]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:9])[CH3:10])=[O:6])[CH3:2]
Reactant: CC(C)=O
Reactant: CCN[C@@H](C(=O)OC(C)(C)C)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCN(C(C)C)[C@@H](C(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.5 %

Procedure:
To a solution of product from example 122A (0.098 g, 0.416 mmol) in EtOH (5 mL) was added acetone (0.031 mL, 0.416 mmol), acetic acid (0.024 mL, 0.416 mmol), and sodium cyanoborohydride (0.039 g, 0.625 mmol), and the resulting mixture and stirred at rt for 8 hrs. The mixture was partitioned between CH2Cl2 and saturated aq. NaHCO3, and the organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-1% MeOH in CH2Cl2 to give the title compound (0.0352 g, 31%).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29]>>[C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCOC(=O)Cl
Reactant: CSc1nc(-c2cccc(N)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1
Product: C=CCOC(=O)Nc1cccc(-c2nc(SC)nc3sc(C(=O)NC(C)(C)C)c(N)c23)c1
Reaction time: 0.5 h

Procedure:
The reaction of tert-butyl 5-amino-2-methylthio-4-(3-aminophenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 9e, 100 mg) with allyl chloroformate (274 μl) was performed using the methods described in example 15. The title compound was purified by HPLC using a Luna C-18 column with the following gradient: CH3CN/10% aq. CH3CN=10/90 to 90/10 (v/v) in 30 min. The title compound was then lyophilized from a mixture of 1,4-dioxane and H2O.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:12]=2)[N:7]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[C:6]=1[CH2:26][CH2:27][CH3:28])=[O:4].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=2)[C:5]([C:3](=[O:4])[CH2:2][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[C:6]1[CH2:26][CH2:27][CH3:28]
Reactant: C1COCCN1
Reactant: CCCc1c(C(=O)CCl)c2ccc(C(=O)OC)cc2n1Cc1ccccc1Cl
Product: CCCc1c(C(=O)CN2CCOCC2)c2ccc(C(=O)OC)cc2n1Cc1ccccc1Cl
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
A mixture of methyl 3-chloroacetyl-1-(2-chlorobenzyl)-2-propylindole-6-carboxylate (123 mg) and morpholine (1 ml) was stirred at 50° C. for 2.5 hours. After cooled to 20° C., the reaction mixture was extracted with ethyl acetate. The organic phase was washed with 1N hydrochloric acid and water, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:2) to give methyl 1-(2-chlorobenzyl)-3-morpholineacetyl-2-propylindole-6-carboxylate (94 mg) as colorless amorphous.
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:4]=2[N:3]=1.[H-].[Na+].[N+]([C:20]1[O:24][C:23]([CH:25]=[O:26])=[CH:22][CH:21]=1)([O-])=O>O1CCCC1>[F:12][C:11]([F:14])([F:13])[C:8]1[CH:9]=[CH:10][C:4]2[N:3]=[C:2]([S:1][C:20]3[O:24][C:23]([CH:25]=[O:26])=[CH:22][CH:21]=3)[NH:6][C:5]=2[CH:7]=1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: FC(F)(F)c1ccc2nc(S)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1ccc(Sc2nc3ccc(C(F)(F)F)cc3[nH]2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
Aldehyde intermediate preparation: 2-mercapto-6-trifluoromethyl-1H-benzimidazole (0.65 g, 2.98 mmol) dissolved in 5 ml of anhydrous tetrahydrofuran is added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil, 0.095 g, 3.16 mmol) in anhydrous tetrahydrofuran (2 ml) over a 20 minutes period. The reaction mixture is stirred for 2 hours at room temperature. Then 5-nitro-2-furaldehyde (0.42 g, 2.98 mmol) dissolved in 5 ml of anhydrous tetrahydrofuran is added dropwise over a 15 minutes period and the reaction mixture is stirred at room temperature for an additional 16 hours period. Sodium hydride (67 mg, 2.23 mmol) is then added and the reaction mixture is stirred for an additional 2 hours period at room temperature. The reaction mixture is then concentrated under reduced pressure, dissolved in ethyl acetate (50 ml) and washed with water (2×10 ml). The organic phase is dried over MgSO4, concentrated under reduced pressure and the residue is triturated in diisopropylether, collected by filtration and dried under vacuum to yield 720 mg of 5-(6-trifluoromethyl-1H-benzimidazol-2-ylsulfanyl)-furan-2-carbaldehyde as a beige powder. Yield=77%, Analytical LC/MS (method B): retention time=3.73 min., m/z=313.01 (positive ion mode).