Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[NH:9][CH:8]=1)=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]1[C:29]([F:30])=[C:28]([F:31])[CH:27]=[CH:26][C:25]=1[O:32][CH3:33]>CN(C=O)C>[F:30][C:29]1[C:28]([F:31])=[CH:27][CH:26]=[C:25]([O:32][CH3:33])[C:24]=1[CH2:23][N:9]1[C:10]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[C:7]([C:5]([NH:4][CH2:3][CH2:2][F:1])=[O:6])=[CH:8]1
Reactant: O=C(NCCF)c1c[nH]c2cccnc12
Reactant: COc1ccc(F)c(F)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(F)c(F)c1Cn1cc(C(=O)NCCF)c2ncccc21
Temperature: 0 °C
Reaction time: 4 h
Yield: 34.4 %

Procedure:
See FIG. 17(a). In a 50 mL round-bottomed flask N-(2-fluoroethyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (0.1 g, 0.48 mmol) was DMF (10 mL) to give a colourless suspension. the reaction mixture was cooled to 0° C. and potassium carbonate (0.200 g, 1.45 mmol) and 2-(bromomethyl)-3,4-difluoro-1-methoxybenzene (0.114 g, 0.48 mmol) was added then the RM was stirred at 80° C. for 4 h. The reaction was monitored by LCMS. DMF was concentrated under vacuao, added water and extracted with DCM. The combined organic layer was washed with brine, dried over sodium sulphate, filtered and evaporated to give crude product. The crude material was purified on reverse phase preparative HPLC system to get 1-(2,3-difluoro-6-methoxybenzyl)-N-(2-fluoroethyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (0.060 g, 34.2%). ES+MS m/z: 364 (M+1) 1H NMR (DMSO-d6, 300 MHZ): δ ppm 8.90 (br. s., 1 H ), 8.50 (d, J=4.3 Hz, 1 H ), 8.02-8.15 (m, 2 H ), 7.30-7.52 (m, 2 H ), 6.92 (d, J=8.7 Hz, 1 H ), 5.53 (s, 2 H ), 4.63 (t, J=4.4 Hz, 1 H ), 4.47 (t, J=4.8 Hz, 1 H ), 3.86 (s, 3 H ), 3.74 (d, J=5.3 Hz, 1 H ), 3.65 (d, J=5.3 Hz, 1 H ).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11](OCC)=[O:12])[C:6]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:5]=2[S:4][C@H:3]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[NH3:27]>CO>[NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([NH2:27])=[O:12])[C:6]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:5]=2[S:4][C@H:3]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)CN1C(=O)[C@@H](N)[C@H](c2ccccc2)Sc2cc(Cl)ccc21
Reactant: N
Solvent: CO
Product: NC(=O)CN1C(=O)[C@@H](N)[C@H](c2ccccc2)Sc2cc(Cl)ccc21
Reaction time: 8 h

Procedure:
In the same manner as in (iv) of Example 23, 1.7 g of ethyl trans-3-amino-8-chloro-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate is dissolved in 50 ml of methanol, into which ammonia gas is blown to the level of saturation under ice-cooling. The reaction temperature is slowly elevated to room temperature, and the mixture is allowed to stand still overnight. Then, the reaction mixture is concentrated under reduced pressure. The separated crystals are collected by filtration to give 1.4 g of trans-3-amino-8-chloro-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide, m.p. 225°-228° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.OO.[NH3:11].C[O-].[Na+]>CO>[CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[CH3:1][CH:2]1[CH2:7][CH2:6][NH:11][C:5](=[O:8])[CH2:4][CH2:3]1
Reactant: N
Agent: CC1CCC(=O)CC1
Agent: C[O-]
Agent: OO
Solvent: CO
Product: CC1CCNC(=O)CC1

Procedure:
4,4' -Dimethyl-1,1'-peroxydicyclohexylamine (5 g.) derived from the reaction of 4-methylcyclohexanone, hydrogen peroxide and ammonia) was added to a solution of sodium methoxide in methanol (1 g. of sodium in 20 c.c. methanol) and the mixture heated under reflux for 2 hours when very little peroxide remained unreacted. The product was worked up as in Example 17 to give, on distillation, 4-methylcyclohexanone (2.2 g.), 4-methyl-caprolactam (2.2 g.), b.p. 145°-150°/15 mm, and residue (0.3 g.). The structure of the lactam was confirmed by I.R. and N.M.R. spectra.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])=[O:4].[Br:15][CH2:16][C:17](Br)=[O:18].[Al+3].[Cl-].[Cl-].[Cl-]>C(=S)=S>[Br:15][CH2:16][C:17]([C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[C:2]([F:13])([F:14])[F:1])=[C:7]([CH3:12])[CH:8]=1)=[O:18]
Reactant: Cc1ccccc1NC(=O)C(F)(F)F
Reactant: O=C(Br)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: Cc1cc(C(=O)CBr)ccc1NC(=O)C(F)(F)F
Yield: 37.6 %

Procedure:
2,2,2-trifluoro-N-o-tolylacetamide (5.0 g; 24.6 mmol) was dissolved in 20 mL CS2. The mixture was cooled below 10° C. Bromoacetic bromide (10.1 g; 50.0 mmol) was added dropwise. AlCl3 (10.0 g; 75.0 mmol) was added in portions, with drying tube attached to the reaction flask. The reaction mixture was refluxed overnight. After the reaction is complete as monitored by TLC, the upper CS2 layer was removed. The lower layer was added into 7.0 mL ice water mixed with HCl. The product was extracted into CH2Cl2, and dried over MgSO4. The solvent was removed, and the solid was dried to afford 5.0 g of crude product, which was purified by silica gel column chromatography, to afford 3.0 g (yield 38%) of product as yellow solid. 1H NMR (300 MHz; CDCl3), δ 8.40 (s, 1H, Ar—H), 7.87 (brs+d, 3JHH=8.0 Hz, 2H, Ar—H), 7.43 (d, 3JHH=8.0 Hz, 1H, Ar—H), 4.46 (s, 2H, COCH2Br), 2.41 (s, 3H, CH3).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[OH:5][C:6]1[CH:17]=[CH:16][C:9]([O:10][CH2:11][C:12](OC)=[O:13])=[CH:8][CH:7]=1>CO>[CH2:1]([NH:4][C:12](=[O:13])[CH2:11][O:10][C:9]1[CH:16]=[CH:17][C:6]([OH:5])=[CH:7][CH:8]=1)[CH2:2][CH3:3]
Reactant: COC(=O)COc1ccc(O)cc1
Reactant: CCCN
Solvent: CO
Product: CCCNC(=O)COc1ccc(O)cc1
Reaction time: 72 h

Procedure:
A solution of 1-propylamine (4.1 ml) and methyl 4-hydroxyphenoxyacetate (3.64 g) in methanol (50 ml) was left to stand for 72 hours at ambient temperature. The solvent was evaporated in vacuo and the residue taken up in ethyl acetate. The solution was washed sequentially with 1M HCl (2×25 ml) and brine (30 ml), then dried (MgSO4) and the solvent evaporated to give N-(1-propyl)-4-hydroxyphenoxyacetamide as a red oil, NMR: 0.95 (t, 3H, CH3), 1.55 (m, 2H, CH2) 3.3 (q 2H, CH2N), 4.4 (s, 2H, CH2O) 6.5-6.7 (broad s, 1H, OH), 6.8 (s, 4H, phenyl-H); m/e 227 (M+NH4)+, 210 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:21]([S:30]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[F:29])=[CH:4][C:5]([N:8]([CH2:10][CH2:11][N:12](C)[C:13](=O)OC(C)(C)C)[CH3:9])=[N:6][CH:7]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH:21]([S:30]([C:33]2[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=2)(=[O:32])=[O:31])[C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[F:29])=[CH:4][C:5]([N:8]([CH3:9])[CH2:10][CH2:11][NH:12][CH3:13])=[N:6][CH:7]=1
Reactant: CN(CCN(C)c1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CNCCN(C)c1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Reaction time: 1 h
Yield: 42 %

Procedure:
In methylene chloride (2.0 ml) was dissolved t-butyl 2-[N-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]-N-methylamino]ethylmethylcarbamate (61 mg, 0.10 mmol). To the resulting solution were added anisole (40 μl) and trifluoroacetic acid (200 μl) at room temperature and the resulting mixture was stirred for 1 hour. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by silica gel chromatography (3% methanol/chloroform 3%→methanol, 3% t-butylamine/chloroform) to give the title compound (21 mg, 41%) as an oil.
Reaction SMILES: [C:1]([N:14]([CH2:16][C:17]([OH:19])=[O:18])[CH3:15])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].S(=O)(=O)(O)O>C(O)CCC>[CH2:1]([O:18][C:17](=[O:19])[CH2:16][N:14]([C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:15])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCCCCCC(=O)N(C)CC(=O)O
Agent: O=S(=O)(O)O
Solvent: CCCCO
Product: CCCCCCCCCCCC(=O)N(C)CC(=O)OCCCC

Procedure:
One hundred and thirty-five point five(135.5) grams of N-lauroylsarcosine (ex. Kawaken Fine Chemicals Co., Ltd.) and 200 ml of 1-butanol were charged into a 500-milliliter flask. Further, 4.99 g of conc. sulfuric acid were added as the catalyst. The mixture was heated under reflux for reaction for 6 hours.
Reaction SMILES: [ClH:1].[CH2:2]([N:6]1[CH2:11][CH2:10][C@@H:9]([C:12]2[CH:17]=[CH:16][C:15]([N:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)[C@H:8]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26](C(F)(F)F)=[CH:25][CH:24]=2)[CH2:7]1)[CH2:3][CH2:4][CH3:5].C(N1CCC(C2C=CC(N(C)C)=CC=2)C(CO)C1)CCC.FC1C=CC=CC=1[C:61]([F:64])([F:63])[F:62].[H-].[Na+]>CN(C=O)C>[ClH:1].[CH2:2]([N:6]1[CH2:11][CH2:10][C@@H:9]([C:12]2[CH:13]=[CH:14][C:15]([N:18]([CH3:20])[CH3:19])=[CH:16][CH:17]=2)[C@H:8]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:61]([F:64])([F:63])[F:62])[CH2:7]1)[CH2:3][CH2:4][CH3:5]
Reactant: Fc1ccccc1C(F)(F)F
Reactant: CCCCN1CC[C@@H](c2ccc(N(C)C)cc2)[C@H](COc2ccc(C(F)(F)F)cc2)C1
Agent: CCCCN1CCC(c2ccc(N(C)C)cc2)C(CO)C1
Agent: Cl
Agent: [H-]
Solvent: CN(C)C=O
Product: CCCCN1CC[C@@H](c2ccc(N(C)C)cc2)[C@H](COc2ccccc2C(F)(F)F)C1

Procedure:
Preparation as described for compound (11) using 1 g of compound (12), 2-fluorobenzotrifluoride (1.2 g) and NaH (0.174 g) in DMF (100 ml). The crude product was precipitated as the hydrochloride from acetone-ether giving 0.4 g of crystals. M.p. 213.9°-214.9° C.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:18]=[CH:17][C:16]([C:19]([OH:21])=O)=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].S(Cl)(Cl)=O.C(C1C=CC(C2N=CC(C(Cl)=O)=C[N:39]=2)=CC=1)CCCCC.N>O1CCOCC1>[CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:18]=[CH:17][C:16]([C:19]([NH2:39])=[O:21])=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(-c2ncc(C(=O)O)cn2)cc1
Reactant: CCCCCCc1ccc(-c2ncc(C(=O)Cl)cn2)cc1
Agent: N
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Product: CCCCCCc1ccc(-c2ncc(C(N)=O)cn2)cc1

Procedure:
12.0 G. of 2-(p-n-hexylphenyl)-5-pyrimidinecarboxylic acid are reacted with 80 ml. of thionyl chloride with the exclusion of moisture and worked up in a manner analogous to that described in Example 7. The remaining 2-(p-n-hexylphenyl)-5-pyrimidinecarboxylic acid chloride is dissolved in 120 ml. of absolute dioxane while warming and added with stirring to a solution of 200 ml. of absolute dioxane saturated with ammonia at room temperature and treated further in a manner analogous to that described in Example 7. A sample of the obtained crude 2-(p-n-hexylphenyl)-5-pyrimidinecarboxamide is sublimed at 180° C. in a high vacuum for purification; melting point 250.2°-258.3° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:9]1[CH2:12][CH:11]([NH:13][C:14](=[O:31])[CH2:15][NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH2:10]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:1][CH:2]1[CH2:7][CH2:6][CH:5]([N:9]2[CH2:10][CH:11]([NH:13][C:14](=[O:31])[CH2:15][NH:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]([F:28])([F:30])[F:29])[CH:25]=4)[N:20]=[CH:19][N:18]=3)[CH2:12]2)[CH2:4][CH2:3]1
Reactant: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: CC1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC1CCC(N2CC(NC(=O)CNc3ncnc4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
Reaction of 4-methylcyclohexanone with N-(azetidin-3-yl)-2-((6-(trifluoromethyl)quinazolin-4-yl)amino)acetamide (as prepared in Example 1 Step G) in the presence of TEA and NaBH(OAc)3 as described in Example 1, Step H afforded the product. 1H NMR (CHLOROFORM-d) δ: 8.61 (s, 1 H), 8.11 (s, 1 H), 8.04 (t, J=4.9 Hz, 1 H), 7.71-7.82 (m, 2 H), 6.80 (d, J=7.3 Hz, 1 H), 4.59 (sxt, J=6.4 Hz, 1 H), 4.27 (d, J=5.3 Hz, 2 H), 3.60 (t, J=7.3 Hz, 2 H), 2.95 (t, J=6.6 Hz, 2 H), 2.15 (br. s., 1 H), 1.49-1.61 (m, 1 H), 1.27-1.49 (m, 8H), 0.91 (d, J=6.8 Hz, 3 H); ESI-MS (m/z): Calcd. For C21H26F3N5O: 421.21. found: 422 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][N:13]3[C:17]4[N:18]=[C:19](SC)[N:20]([CH3:23])[C:21](=[O:22])[C:16]=4[CH:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C(O)(=O)C>COCCOC.C(O)C.[Ni]>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][N:13]3[C:17]4[N:18]=[CH:19][N:20]([CH3:23])[C:21](=[O:22])[C:16]=4[CH:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CSc1nc2c(ccn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c(=O)n1C
Agent: [Ni]
Solvent: COCCOC
Solvent: CC(=O)O
Solvent: CCO
Product: Cn1cnc2c(ccn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1=O
Temperature: 40 °C
Yield: 75.6 %

Procedure:
In a mixture of DME (15 ml) and ethanol (1.5 ml) was dissolved 7-[4-(4-chlorobenzoyl)benzyl]-3-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4-one (221 mg) followed by addition of acetic acid (185 mg), and the mixture was warmed to 40° C. Then, Raney nickel was added until disappearance of the starting compound could be verified by thin-layer chromatography (TLC). The catalyst was then filtered off and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution in the order mentioned, and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was allowed to stand, whereupon crystals separated out. This crystal crop was harvested by filtration, rinsed with ethanol and hexane, and dried to provide the title compound (149 mg).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:18]=[C:17]2[N:8]([C:9](SC)=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=32)[N:7]=1.[CH2:21]([NH2:23])[CH3:22]>C(O)C>[CH2:21]([N:23]=[C:9]1[N:8]2[N:7]=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[N:18]=[C:17]2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:10]1)[CH3:22]
Reactant: CCN
Reactant: CSc1nc2ccccc2c2nc(-c3ccco3)nn12
Solvent: CCO
Product: CCN=c1[nH]c2ccccc2c2nc(-c3ccco3)nn12

Procedure:
2-(2-Furyl)-5-methylthio-[1,2,4]triazolo[1,5-c]quinazoline (1.41 g) is placed in a stainless steel pressure vessel with ethanol (200 ml) and 70% aqueous ethylamine (100 ml) and heated to an outside temperature of 150°. It reaches a pressure of 100 p.s.i. and is maintained at that pressure and temperature for 16 hours. It is cooled and the material concentrated to dryness at reduced pressure The residual solid is recrystallized from methanol to afford pure 5-ethylimino-2-(2-furyl)-5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazoline, mp 133°-135°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][O:11][CH3:12])=[CH:4][C:3]=1[CH3:13].C1C(=O)N([Br:21])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:21][CH2:13][C:3]1[CH:4]=[C:5]([O:8][CH2:9][CH2:10][O:11][CH3:12])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: COCCOc1ccc(Cl)c(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COCCOc1ccc(Cl)c(CBr)c1

Procedure:
A mixture of 1-chloro-4-(2-methoxyethoxy)-2-methylbenzene (1 eq.) from the previous step, NBS (1.1 eq.) and benzoyl peroxide (0.05 eq.) in CCl4 (0.2 M) was refluxed for 2 h. The volatiles were then removed in vacuo and the resulting residue was suspended in hexanes. The insolubles were removed via filtration and washed further with hexanes. The filtrate was concentrated in vacuo to afford the title compound as a colorless oil.
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][CH2:21][CH:22]([CH3:42])[CH:23]([C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1[F:41])[S:24]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)(=[O:26])=[O:25])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([S:24]([CH:23]([C:34]2[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=2[F:41])[CH:22]([CH3:42])[CH2:21][CH2:20][CH2:19][OH:18])(=[O:26])=[O:25])=[CH:32][CH:31]=1
Reactant: CC(CCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(CCCO)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 101.4 %

Procedure:
The 2-[5-(t-butyldiphenylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]-2-methylpentyl]-1,4-difluorobenzene (isomer mixture) (1.40 g, 2.23 mmol) obtained in Example 38 was dissolved in tetrahydrofuran (30 ml), followed by the addition of a tetrahydrofuran solution (1.0M, 5.0 ml, 5.0 mmol) of tetrabutylammonium fluoride under ice cooling. The resulting mixture was stirred at room temperature for 14 hours. After addition of water (3 ml), the residue obtained by concentrating the resulting mixture under reduced pressure was subjected to flash silica gel chromatography. The fraction obtained from the hexane:ethyl acetate=2:1 eluate was concentrated under reduced pressure, whereby 5-[(4-chlorophenyl)sulfonyl]-5-(2,5-difluorophenyl)-4-methyl-1-pentanol (isomer mixture) (879 mg, quant.) was obtained as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[N+:13]([O-:15])=[O:14].NCC(O)[CH2:19][OH:20].C(CN)O>>[OH:1][CH:2]([CH2:19][OH:20])[CH2:3][NH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[N+:13]([O-:15])=[O:14]
Reactant: NCC(O)CO
Reactant: N#Cc1ccc(NCCO)c([N+](=O)[O-])c1
Solvent: NCCO
Product: N#Cc1ccc(NCC(O)CO)c([N+](=O)[O-])c1

Procedure:
Preparation is similar to the synthesis in (a) above, except that 3-amino-1,2-propanediol is used in lieu of monoethanolamine.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]#[N:11])=[C:8]([F:12])[C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][CH:5]=1)[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]1[C:9]([C:10]#[N:11])=[C:8]([F:12])[C:7]([C:32]2[N:28]=[CH:29][NH:30][CH:31]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1C#N
Reactant: c1c[nH]cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOc1ccc(-c2c[nH]cn2)c(F)c1C#N
Temperature: 85 °C
Yield: 46.1 %

Procedure:
To a sealed tube was added the above tert-butyl ester intermediate (25.5 mg, 0.103 mmol), 6-ethoxy-2-fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile (60 mg, 0.206 mmol) and tetrakis(triphenylphosphine)palladium(0) (23.85 mg, 0.0206 mmol) in 1 mL of dimethoxyethane, followed by the addition of 0.5 mL of 20% Na2CO3. The mixture was heated at 85° C. for 4 h. LCMS showed both de-boc and boc-protected imidazole compounds formed. The reaction mixture was filtered, concentrated and the residue was purified by silica gel chromatography eluting with 2-5% MeOH/CH2Cl2. The boc-protected intermediate was not found during the column process, the de-boc intermediate was found and the fractions were collected and concentrated to afford 11 mg (46.1%) of 6-ethoxy-2-fluoro-3-(1H-imidazol-4-yl)-benzonitrile.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10]/[C:9]/2=[N:14]\[C:15](=[O:17])[CH3:16])=[CH:4][CH:3]=1.[Cl:18][C:19]1[S:23][C:22]([C:24]([NH:26][CH2:27][C:28]2[N:29]=[CH:30][NH:31][CH:32]=2)=[O:25])=[CH:21][CH:20]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[C:15](/[N:14]=[C:9]1/[N:8]([C:5]2[CH:6]=[CH:7][C:2]([N:31]3[CH:32]=[C:28]([CH2:27][NH:26][C:24]([C:22]4[S:23][C:19]([Cl:18])=[CH:20][CH:21]=4)=[O:25])[N:29]=[CH:30]3)=[CH:3][CH:4]=2)[CH:13]=[CH:12][CH:11]=[CH:10]/1)(=[O:17])[CH3:16]
Reactant: O=C(NCc1c[nH]cn1)c1ccc(Cl)s1
Reactant: CC(=O)/N=c1\ccccn1-c1ccc(I)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: CC(=O)/N=c1\ccccn1-c1ccc(-n2cnc(CNC(=O)c3ccc(Cl)s3)c2)cc1
Temperature: 130 °C
Yield: 6.6 %

Procedure:
A mixture of (E)-N-(1-(4-iodophenyl)pyridin-2(1H)-ylidene)acetamide (120 mg, 0.27 mmol), 5-Chloro-N-((1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 3-1 (109 mg, 0.30 mmol), 8-hydroxyquinoline (15 mg, 0.10 mmol) and K2CO3 (100 mg, 0.72 mmol) in DMSO (2 mL) was degassed with Ar before being charged with CuI (24 mg, 0.12 mmol). The mixture in a sealed tube was heated at 130° C. for 5 h. It was then purified by HPLC to give the titled compound (8 mg). MS 452.0 and 454.0 (M+H, Cl pattern).
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:31])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:30])[C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1.Cl.[NH2:33][OH:34]>N1C=CC=CC=1>[OH:34][N:33]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:31])[C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21](=[O:30])[C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)=[CH:18][CH:19]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: O=C(Nc1ccc(C(=O)N2CCCC(=O)c3ccccc32)cc1)c1cc(Cl)cc(Cl)c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C(=O)N2CCCC(=NO)c3ccccc32)cc1)c1cc(Cl)cc(Cl)c1
Yield: 48.4 %

Procedure:
To a mixture of 5-oxo-1-[4-(3,5-dichlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (4 g) and pyridine (50 ml) is added hydroxylamine hydrochloride (1.84 g) and the mixture is refluxed for 2.5 hours. The reaction solution is concentrated and water is added to the resulting residue. The precipitated crystal is collected by filtration, and recrystallized from dioxane/water to give 5-hydroxyimino-1-[4-(3,5-dichlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (2 g) as white powder, m.p. 272°-273° C.
Reaction SMILES: [C:1]([O:4][CH:5]([CH:26]1[CH2:28][CH2:27]1)[C@H:6]1[O:10][C@@H:9]([N:11]2[C:15]3[N:16]=[C:17]([NH2:20])[N:18]=[CH:19][C:14]=3[S:13][C:12]2=[O:21])[C@@H:8](CC([O-])=O)[CH2:7]1)(=[O:3])[CH3:2].C(OC([C@H]1O[C@@H](N2C3N=C(N)N=CC=3SC2=O)[C@@H](CC([O-])=O)C1)CC)(=[O:31])C>>[NH2:20][C:17]1[N:18]=[CH:19][C:14]2[S:13][C:12](=[O:21])[N:11]([C@@H:9]3[O:10][C@H:6]([C@@H:5]([O:4][C:1](=[O:3])[CH3:2])[CH:26]4[CH2:27][CH2:28]4)[CH2:7][C@H:8]3[OH:31])[C:15]=2[N:16]=1
Reactant: CCC(OC(C)=O)[C@@H]1C[C@H](CC(=O)[O-])[C@H](n2c(=O)sc3cnc(N)nc32)O1
Reactant: CC(=O)OC(C1CC1)[C@@H]1C[C@H](CC(=O)[O-])[C@H](n2c(=O)sc3cnc(N)nc32)O1
Product: CC(=O)O[C@@H](C1CC1)[C@@H]1C[C@@H](O)[C@H](n2c(=O)sc3cnc(N)nc32)O1

Procedure:
The title compound was prepared in analogy to Example 4, by using [(2R,3R,5S)-5-[acetoxy(cyclopropyl)methyl]-2-(5-amino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-3-yl] acetate (compound 16a) instead of [(2R,3R,5S)-5-(1-acetoxypropyl)-2-(5-amino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-3-yl]acetate (compound 2a). Example 16 was purified and separated by preparative HPLC to afford Example 16-A and Example 16-B as white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]3[CH2:20][CH2:21][CH2:22][O:23][C:12]=23)=[O:10])[CH2:3][CH2:2]1.C(N(CC)CC)C.[O:31]([CH2:38][CH2:39][CH2:40]Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(#N)C.CN(C)C=O>[O:31]([CH2:38][CH2:39][CH2:40][N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]3[CH2:20][CH2:21][CH2:22][O:23][C:12]=23)=[O:10])[CH2:3][CH2:2]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(NCC1CCNCC1)c1c2n(c3ccccc13)CCCO2
Reactant: BrCCCOc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCC1CCN(CCCOc2ccccc2)CC1)c1c2n(c3ccccc13)CCCO2

Procedure:
A stirred solution of N-(4-piperidinylmethyl) 3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide (E21) (250 mg, 0.80 mmole) and triethylamine (0.25 ml, 1.8 mmole) in a mixture of acetonitrile (15 ml) and N,N-dimethylformamide (10 ml) was treated with 3-phenoxypropyl bromide (0.13 ml, 0.88 mmole) and the solution heated under reflux for 48 h. The mixture was allowed to cool, then concentrated in vacuo and the residue dissolved in ethyl acetate (25 ml) and washed with water (20 ml). The organic solution was dried (MgSO4), concentrated in vacuo and the residue purified by flash chromatography on silica gel eluting with 0-20% methanol/ethyl acetate to afford the title compound as a pale pink solid after trituation with ether (44mg) mp 120-126° C.