Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]#[CH:15])[O:7][C@H:6]1[N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2ON1C2C=CC=CC=2N=N1)(=[O:3])[CH3:2].[F:35][C:36]1[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:37]=1[NH2:38]>>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]#[CH:15])[O:7][C@H:6]1[N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2[NH:38][C:37]1[CH:39]=[CH:40][C:41]([Cl:43])=[CH:42][C:36]=1[F:35])(=[O:3])[CH3:2]
Reactant: C#C[C@H]1O[C@@H](n2cnc3c(On4nnc5ccccc54)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Nc1ccc(Cl)cc1F
Product: C#C[C@H]1O[C@@H](n2cnc3c(Nc4ccc(Cl)cc4F)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 60 °C

Procedure:
(2R,3R,4R,5R)4-(acetyloxy)-2-[6-(1H-1,2,3-benzotriazol-1-yloxy)-9H-purin-9-yl]-5-ethynyltetrahydrofuran-3-yl acetate was treated with 2-fluoro-4-chloroaniline (0.63 ml), and the mixture was heated at 60° C. for 22.5 h. The mixture was purified by chromatography on silica gel (Varian Bondelut cartridge), eluting with ethyl acetate:cyclohexane 10:90-60:40, to give the title compound (55 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH2:6])=[O:5].[CH:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)([CH3:14])[CH3:13].CC1C=CC(S(O)(=O)=O)=CC=1.OS([O-])=O.[Na+]>CC(N(C)C)=O.C(Cl)Cl>[Cl:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:25]([C:24]1[CH:23]=[CH:22][C:21]([N:18]3[CH2:17][CH2:16][N:15]([CH:12]([CH3:14])[CH3:13])[CH2:20][CH2:19]3)=[CH:28][CH:27]=1)=[N:1]2
Reactant: CC(C)N1CCN(c2ccc(C=O)cc2)CC1
Reactant: NC(=O)c1c(N)cccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CC(C)N1CCN(c2ccc(-c3nc4cccc(Cl)c4c(=O)[nH]3)cc2)CC1
Temperature: 140 °C

Procedure:
A solution of 2-amino-6-chlorobenzamide (0.314 g, 1.85 mmol) and 4-(4-isopropylpiperazin-1-yl)benzaldehyde (0.430 g, 1.85 mmol) in DMA (25 mL) were treated with p-TsOH (0.035 g, 0.185 mmol) and NaHSO3 (0.212 g, 2.04 mmol), and the mixture was heated at 140° C. for 18 hours. Then, the mixture was cooled, diluted with CH2Cl2 (200 mL), and washed with saturated NaHCO3 (100 mL). The organic phase was dried over anhydrous MgSO4, filtered, concentrated, and purified by silica gel chromatography, eluting with 1:1 CH2Cl2/92:7:1 CHCl3/MeOH/concentrated NH4OH to 100% 92:7:1 CHCl3/MeOH/concentrated NH4OH to 100% 6:3:1 CHCl3/MeOH/concentrated NH4OH. The resulting solids were rechromatographed with 9:1 CH2Cl2/MeOH to afford the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 12.24 (br s, 1H), 8.11 (d, J=8.8 Hz, 2H), 7.66-7.71 (m, 1H), 7.59 (d, J=7.9 Hz, 1H), 7.42 (d, J=7.4 Hz, 1H), 7.03 (d, J=8.6 Hz, 2H), 3.28-3.34 (m, 4H), 2.64-2.73 (m, 1H), 2.55-2.59 (m, 4H), 1.01 (d, J=6.4 Hz, 6H). ESI MS m/z 383 [M+H]+.
Reaction SMILES: [NH2:1][C:2](SC)=[C:3]([N:9]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([NH:32][C:33]([NH:35][CH2:36]CC)=O)(=[O:31])=[O:30])=[CH:19][CH:18]=1)[C:10](=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14])[C:4]([O:6][CH2:7][CH3:8])=[O:5].O.[CH3:42]OC>C(O)CO.S(=O)(=O)(O)O>[C:2]([CH:3]([N:9]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([N:32]=[CH:33][N:35]([CH3:36])[CH3:42])(=[O:30])=[O:31])=[CH:21][CH:22]=1)[C:10](=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:1]
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)NCCC)cc1)C(C(=O)OCC)=C(N)SC
Reactant: COC
Agent: O=S(=O)(O)O
Solvent: OCCO
Solvent: O
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2S(=O)(=O)N=CN(C)C)cc1)C(C#N)C(=O)OCC
Reaction time: 1 h

Procedure:
200 mg of the product of Stage C of Example 3 were dissolved in 5 ml of dimethyl ether of ethylene glycol and 1 ml of concentrated sulfuric acid was added at ambient temperature. After stirring for one hour, water was added while cooling in an ice bath. Extraction was carried out with dichloromethane and the organic phases .were washed and dried. The solvent was evaporated under reduced pressure to obtain 180 mg of crude product which was crystallized from ethyl acetate to obtain 140 mg of the expected product melting at 130°-132° C.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:41])[CH2:13][NH:14][C:15](=[O:40])[CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH:27]1[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]1)[N:22]=[CH:21]2>C(OC(C)=O)C.Cl>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:41])[CH2:13][NH:14][C:15](=[O:40])[CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[N:22]=[CH:21]2
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3cc(OCC(=O)NCC(O)CN4CCc5ccccc5C4)ccc32)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(COc1ccc2c(cnn2C2CCNCC2)c1)NCC(O)CN1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To tert-butyl 4-(5-(2-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)amino)-2-oxoethoxy)-1H-indazol-1-yl)piperidine-1-carboxylate (110 mg, 0.195 mmol) was added EtOAc.HCl (10 mL), the solution was stirred at 25° C. for 2 h, concentrated under reduced pressure, and purified by prep-HPLC to give N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-((1-(piperidin-4-yl)-1H-indazol-5-yl)oxy)acetamide (85 mg, yield 94%) as a colorless oil. 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.47 (br. s., 2H), 8.00 (s, 1H), 7.70 (d, J=8.78 Hz, 1H), 7.29-7.19 (m, 3H), 7.18-7.11 (m, 2H), 6.93 (dd, J=8.85, 1.95 Hz, 1H), 5.12 (s, 2H), 4.86-4.81 (m, 1H), 4.17 (s, 3H), 3.49-3.35 (m, 4H), 3.32-3.20 (m, 4H), 3.13-2.92 (m, 4H), 2.28-2.04 (m, 4H). LCMS (m/z): 464.2 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH:7]=[O:8].C(N(CC)CC)C.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>CN(C)C=O.O.CO>[CH3:1][C:2]1[N:6]([S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[CH:5]=[N:4][C:3]=1[CH:7]=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1[nH]cnc1C=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cnc(C=O)c2C)cc1
Yield: 83.9 %

Procedure:
To a suspension of 5-methyl-1H-imidazole-4-carbaldehyde (20 g) in N,N-dimethylformamide (100 ml) was added triethylamine (20.5 g) and p-toluenesulfonyl chloride (38 g). The mixture was stirred under ice-cooling for two hours. The reaction mixture was diluted with water (600 ml) and separated organic layer was filtered. The residue obtained was suspended in methanol (100 ml). After being stirred at ambient temperature for two hours, the mixture was cooled and filtered to give 5-methyl-1-tosyl-1H-imidazole-4-carbaldehyde (40.3 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]([C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1)[CH2:6][CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH3:2].[C:24]([O:28][C:29](=[O:42])[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH:37][C:38](=[O:41])[CH:39]=[CH2:40])([CH3:27])([CH3:26])[CH3:25]>>[CH2:1]([O:3][C:4](=[O:23])[CH:5]([C:16]1[CH:21]=[CH:20][C:19](/[CH:40]=[CH:39]/[C:38](=[O:41])[NH:37][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[NH:30][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:42])=[CH:18][CH:17]=1)[CH2:6][CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH3:2]
Reactant: C=CC(=O)Nc1ccccc1NC(=O)OC(C)(C)C
Reactant: CCOC(=O)C(CCO[Si](C)(C)C(C)(C)C)c1ccc(Br)cc1
Product: CCOC(=O)C(CCO[Si](C)(C)C(C)(C)C)c1ccc(/C=C/C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1

Procedure:
Key building block (E)-2-{4-[2-(2-tert-butoxycarbonylamino-phenylcarbamoyl)-vinyl]-phenyl}-4-(tert-butyl-dimethyl-silanyloxy)-butyric acid ethyl ester (II) can be prepared according to Scheme 6. Starting with commercially available 2-bromo-ethanol (XXIX), silylation with tert-butyldimethylsilyl chloride provides (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (XXX). Alkylation of the potassium enolate of (4-bromo-phenyl)-acetic acid ethyl ester with XXX furnishes 2-(4-bromo-phenyl)-4-(tert-butyl-dimethyl-silanyloxy)-butyric acid ethyl ester (XXXI). Heck reaction of XXXI with (2-acryloylamino-phenyl)-carbamic acid tert-butyl ester gives key building block 2-{4-[2-(2-tert-butoxycarbonylamino-phenylcarbamoyl)-vinyl]-phenyl}-4-hydroxy-butyric acid ethyl ester (II).
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]([NH:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:14]C)=[O:5].[CH2:16]([O:19]C1C=C(C)C(=C(C)C=1)N)[CH2:17][CH3:18].C(O)(=O)C.O.O.O.C([O-])(=O)C.[Na+]>O>[Br:1][CH2:2][CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:14])=[CH:9][C:10]([O:19][CH2:16][CH2:17][CH3:18])=[CH:11][C:12]=1[CH3:13])=[O:5]
Reactant: CCCOc1cc(C)c(N)c(C)c1
Reactant: CCc1cccc(C)c1NC(=O)CCBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCOc1cc(C)c(NC(=O)CCBr)c(C)c1
Yield: 93 %

Procedure:
This compound was prepared analogously to 3-bromo-2'-ethyl-6'-methylpropionanilide of Example 11A from 20 g 4-propoxy-2, 6-xylidine, 95 ml glacial acetic acid, 37 g sodium acetate trihydrate, 150 ml water 21.2 g 3-bromopropionyl bromide. The yield was 93% of recrystallized (methanol:water) material melting at 121.5°-122.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH:19][CH3:20])[N:13]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl.CN.[CH2:24]([N:26](CC)CC)C>CCO>[CH3:20][NH:19][C:14]1[N:13]=[C:12]([NH:11][S:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)(=[O:10])=[O:9])[CH:17]=[C:16]([NH:26][CH3:24])[N:15]=1
Reactant: CCN(CC)CC
Reactant: CNc1nc(Cl)cc(NS(=O)(=O)c2cccc(Cl)c2)n1
Agent: CN
Agent: Cl
Solvent: CCO
Product: CNc1cc(NS(=O)(=O)c2cccc(Cl)c2)nc(NC)n1
Temperature: 145 °C
Reaction time: 17 h
Yield: 40.7 %

Procedure:
0.10 g (0.00030 mol) of 3-chloro-N-(6-chloro-2-methylamino-pyrimidin-4-yl)-benzenesulfonamide was dissolved in 5 ml of EtOH, treated with 0.27 g (0.004 mol) of methylamine hydrochloride and 1 ml (0.007 mol) of triethylamine and stirred in an autoclave at 145° C. for 17 hours. The entire reaction mixture was partitioned in ethyl acetate/water and extracted. The residue was recrystallized from MeOH. There was obtained 0.04 g (41%) of N-(2,6-bis-methylamino-pyrimidin-4-yl)-3-chloro-benzenesulfonamide as white crystals; m.p. 167-168° C.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]([Br:11])=[C:8]([Br:10])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:14][Si:15]([CH2:18][CH2:19][O:20][CH2:21]Cl)([CH3:17])[CH3:16].O>C1COCC1.CCOC(C)=O>[Br:11][C:7]1[N:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[N:9]([CH2:21][O:20][CH2:19][CH2:18][Si:15]([CH3:17])([CH3:16])[CH3:14])[C:8]=1[Br:10]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(C)(C)c1nc(Br)c(Br)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1nc(Br)c(Br)n1COCC[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 101.9 %

Procedure:
To a cooled solution of 2-t-butyl-4,5-dibromoimidazole (1.4 grams, 5.0 mmol; Example 5, Step 2) in dry THF (10 mL) at 0° C. was added sodium hydride (95%, 0.15 grams, 6.0 mmol) portion wise. The reaction mixture was stirred for 10 minutes at 0° C., at room temperature for 40 minutes. The reaction was re-cooled to 0° C. and SEM-chloride (0.97 ml, 5.5 mmol) was added in dropwise. The reaction mixture was stirred overnight allowing the ice bath to expire and poured into a mixture of water (30 mL) and EtOAc (50 mL). The resulting layers were partitioned and separated. The organic portion was washed with brine, then water, dried (Na2SO4), and concentrated. The remaining residue was purified by flash chromatography (SiO2, 0-10% EtOAc in hexanes) to provide 2.1 g of 4,5-dibromo-2-tert-butyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole: LCMS(m/z): 412.9 (MH+), tR=1.320 minutes; 1H NMR (400 MHz, CDCl3) δ 8.75 (dd, 1H,), 7.92 (dd, 1H,), 5.90 (s, 2H), 3.51 (m, 2H), 1.55 (s, 9H), 0.82 (m, 2H), 0.08 (s, 9H).
Reaction SMILES: [CH:1]1([CH2:5][C:6]2[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([CH3:16])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1.[I:17]I.S(=O)(=O)(O)O>CC(O)=O>[CH:1]1([CH2:5][C:6]2[C:15]([I:17])=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([CH3:16])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: II
Reactant: COC(=O)c1ccc(CC2CCC2)cc1C
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COC(=O)c1cc(I)c(CC2CCC2)cc1C
Temperature: 60 °C
Reaction time: 12 h
Yield: 60.4 %

Procedure:
To a round-bottom flask was added a solution of methyl 4-(cyclobutylmethyl)-2-methylbenzoate (compound 189.1, 8.40 g, 38.5 mmol, 1.00 equiv) in AcOH (150 mL). NaIO4 (5.00 g, 23.4 mmol, 0.50 equiv), iodine (10.0 g, 39.4 mmol, 1.00 equiv), and sulfuric acid (0.3 mL) were added to the reaction mixture. The resulting solution was stirred at 60° C. for 12 h. After cooling to room temperature, the reaction was quenched with 200 mL of NaHSO3 (aq). The mixture was extracted with 2×200 mL of ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (20:1) as eluent to furnish 8.00 g (60%) of methyl 4-(cyclobutylmethyl)-5-iodo-2-methylbenzoate as a white solid.
Reaction SMILES: [C:1]1([S:7][CH2:8]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][SiH:11]([Cl:13])[Cl:12]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC>[CH3:10][Si:11]([CH2:8][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([Cl:13])[Cl:12]
Reactant: C[SiH](Cl)Cl
Reactant: ClCSc1ccccc1
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: C[Si](Cl)(Cl)CSc1ccccc1
Reaction time: 12 h
Yield: 36.7 %

Procedure:
As in Example 1, phenylthiomethyl chloride (3.31 g, 0.0209 mol), methyldichlorosilane (7.23 g, 0.0628 mol) and tetrabutylphosphonium chloride (0.615 g, 0.00209 mol) were put in a 50 mL stainless steel tube under nitrogen atmosphere. The reaction chamber was closed with a cover and the reaction was carried out at 120° C. for 12 hours. This reaction mixture was distilled under low pressure to give 1.82 g of methyl(phenylthiomethyl)dichlorosilane in 36.9% yield.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].ClCCl.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C@H:17]2[NH:21][C@@H:20]([C@@H:22]([OH:24])[CH3:23])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1.N1C=CC=CC=1>O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C@H:17]2[N:21]3[C@@H:20]([C@H:22]([CH3:23])[O:24][C:1](=[O:5])[C:2]3=[O:3])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1
Reactant: C[C@H](O)[C@H]1CC[C@@H](c2ccc(F)cc2)N1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: C[C@@H]1OC(=O)C(=O)N2[C@@H]1CC[C@H]2c1ccc(F)cc1
Reaction time: 1 h

Procedure:
Under ice-cooling, oxalyl chloride (392 μL) was added dropwise into a dichloromethane (4 mL) solution containing (S)-1-[(2R,5S)-5-(4-fluorophenyl)pyrrolidine-2-yl]ethanol (479 mg) and pyridine (1 mL). Stirring was continued for 1 hour at the same temperature and for 1 hour at room temperature. Water was added, and the organic layer was partitioned, and the resultant was dried over anhydrous magnesium sulfate. The solvent was removed under a vacuum, and the residue was purified by silica gel column chromatography (heptane/ethyl acetate→ethyl acetate), and the title compound (130 mg) was obtained. The physical property values are as follows.
Reaction SMILES: [Na].[C:2](O)(=O)C.C[N:7]1[CH:13]2[CH2:14][C:15](=[N:17]O)[CH2:16][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12]2>>[CH3:2][NH:17][CH:15]1[CH2:14][CH:13]2[NH:7][CH:8]([CH2:9][CH2:10][CH2:11][CH2:12]2)[CH2:16]1
Reactant: CC(=O)O
Reactant: CN1C2CCCCC1CC(=NO)C2
Agent: [Na]
Product: CNC1CC2CCCCC(C1)N2

Procedure:
15 g of sodium are reacted in analogous manner to that disclosed below in Example (j) with 9.69 g 10-methyl-10-azabicyclo[4.3.1]decan-8-one oxime acetate [m.pt. 253°-253.5° C. prepared in analogous manner to that disclosed in Example A-lb] giving an oil bpt 105°/0.9 mm working up in conventional manner.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([C:13]#[CH:14])[CH:3]=1.Br[C:16]1[CH:31]=[CH:30][C:19]2[C:20](=[O:29])[N:21]([C:25]([CH3:28])([CH3:27])[CH3:26])[S:22](=[O:24])(=[O:23])[C:18]=2[CH:17]=1.C(N(CC)CC)C.CCOC(C)=O>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:25]([N:21]1[C:20](=[O:29])[C:19]2[CH:30]=[CH:31][C:16]([C:14]#[C:13][C:4]3[CH:3]=[C:2]([Cl:1])[CH:12]=[CH:11][C:5]=3[O:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:17][C:18]=2[S:22]1(=[O:23])=[O:24])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)N1C(=O)c2ccc(Br)cc2S1(=O)=O
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)N1C(=O)c2ccc(C#Cc3cc(Cl)ccc3OCC(=O)O)cc2S1(=O)=O
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A mixture of (4-chloro-2-ethynylphenoxy)acetic acid (Intermediate 238; 211 mg; 1.00 mmol), 6-bromo-2-tert-butyl-1,2-benzisothiazol-3(2H)-one-1,1-dioxide (prepared as described in Tetrahedron, 2006, 62, 7902-7910, 382 mg; 1.20 mmol), dichlorobis(triphenylphosphine)palladium(II) (70 mg; 0.10 mmol) and cuprous iodide (9.5 mg; 0.05 mmol) in anhydrous THF (4 ml) was degassed for 10 minutes then treated with triethylamine (1.00 ml; 7.21 mmol) and the mixture stirred at 60° C. for 16 h. EtOAc was added and the organic phase washed with a sat. NH4Cl solution then brine. The organic phase was dried on MgSO4, filtered and concentrated under reduced pressure to give a residue which was purified by preparative HPLC to afford the title compound as a white solid.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[Cl:9][C:10]1[CH:15]=[C:14]([O:16]C)[CH:13]=[CH:12][C:11]=1[O:18][CH3:19].Cl>C(Cl)Cl>[Cl:9][C:10]1[C:11]([O:18][CH3:19])=[CH:12][C:13]([C:5](=[O:7])[CH3:6])=[C:14]([OH:16])[CH:15]=1
Reactant: COc1ccc(OC)c(Cl)c1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(C(C)=O)c(O)cc1Cl
Temperature: 25 °C
Yield: 527.3 %

Procedure:
To a mixture of AlCl3 (8.89 g, 59 mmol) in CH2Cl2 at −10° C. was added acetyl chloride (4.1 ml, 58 mmol) drop-wise while maintaining the internal temperature below 0° C. After 20 min 2-Chloro-1,4-dimethoxybenzene (10.0 g, 8.3 mmol) was dissolved in 8 ml CH2Cl2 and added to the above solution drop-wise while maintaining the internal temperature below 0° C. After 20 min the mixture was warmed to room temperature for 1 hour then warmed to reflux. After 21 h the solution was cooled, poured over a mixture of ice and concentrated HCl and extracted with dichloromethane. The combined organics were concentrated in vacuo and recrytsallized from H2O/EtOH to afford 1-(4-chloro-2-hydroxy-5-methoxy-phenyl)-ethanone (8.78 g, 85%) as a solid.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH3:8])[C:3](Cl)=[O:4].[C:9]1([S:15][CH3:16])[CH:14]=[CH:13][CH:12]=CC=1>>[CH3:1][CH:2]([CH2:6][CH2:7][CH3:8])[C:3]([C:9]1[S:15][CH:16]=[C:13]([CH3:12])[CH:14]=1)=[O:4]
Reactant: CSc1ccccc1
Reactant: CCCC(C)C(=O)Cl
Product: CCCC(C)C(=O)c1cc(C)cs1

Procedure:
Following the procedure described for Example 1, Step 1, the title compound was prepared from 2-methyvaleryl chloride and thioanisole.
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([OH:16])=O)=[CH:6]1.C(N(CC)CC)C.CCCP(O)(O)=O.Cl.[F:37][CH2:38][CH2:39][NH2:40]>C(Cl)Cl>[CH3:1][C:2]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([NH:40][CH2:39][CH2:38][F:37])=[O:16])=[CH:6]1
Reactant: NCCF
Reactant: Cc1ccc(Cn2cc(C(=O)O)c3ncccc32)c(C)c1
Agent: CCCP(=O)(O)O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(Cn2cc(C(=O)NCCF)c3ncccc32)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.6 %

Procedure:
See FIG. 24(b). 1-(2,4-dimethylbenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (200 mg, 0.71 mmol) was taken in a 100 ml single necked flask equipped with an air condenser connected to nitrogen source. Added CH2Cl2 (10 mL) to get a clear solution. Triethylamine (5 mL, 35.87 mmol) was added followed by the addition of 1-Propylphosphonic acid cyclic anhydride (2 mL, 1.43 mmol) and 2-Fluoroethylamine hydrochloride (142 mg, 1.43 mmol). The reaction mass was stirred at RT for overnight. This crude compound was subjected for reverse phase purification to obtain 1-(2,4-dimethylbenzyl)-N-(2-fluoroethyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (50.00 mg, 22%) as a off white solid. ES+MS m/z: 326 (M+1). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.21 (s, 3 H ) 2.24 (s, 3 H ) 3.57-3.86 (m, 2 H ) 4.50 (t, J=4.99 Hz, 1 H ) 4.66 (t, J=4.99 Hz, 1 H ) 5.41-5.60 (m, 2 H ) 6.72 (d, J=7.72 Hz, 1 H ) 6.94 (d, J=7.54 Hz, 1 H ) 7.05 (s, 1 H ) 7.28 (dd, J=8.29, 4.71 Hz, 1 H ) 7.98 (dd, J=8.38, 1.04 Hz, 1 H ) 8.13 (s, 1 H ) 8.51 (dd, J=4.62, 1.04 Hz, 1 H ) 8.94 (t, J=5.84 Hz, 1 H ).
Reaction SMILES: [C:1]([CH:6]=[CH:7][CH:8]=[CH:9][C:10]1[C:11](=[O:25])[NH:12][C:13](=[O:24])[N:14]([CH:23]=1)[C@@H:15]1[O:22][C@H:19]([CH2:20][OH:21])[C@@H:17]([OH:18])[CH2:16]1)([O:3]CC)=[O:2]>[OH-].[Na+]>[C:1]([CH:6]=[CH:7][CH:8]=[CH:9][C:10]1[C:11](=[O:25])[NH:12][C:13](=[O:24])[N:14]([CH:23]=1)[C@@H:15]1[O:22][C@H:19]([CH2:20][OH:21])[C@@H:17]([OH:18])[CH2:16]1)([OH:3])=[O:2]
Reactant: CCOC(=O)C=CC=Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C=CC=Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Yield: 54.2 %

Procedure:
5-(4-Carbethoxy-1,3-butadienyl)-2′-deoxyuridine (V, from Example 1) (0.449 g, 1.28 mmol) was dissolved in 2N NaOH (3 mL) and stirred at 25° C. After 20 mm, a precipitate was formed and TLC showed that the starting material was completely consumed. The mixture was cooled to 0° C. and acidified to pH 1 with 2N HCl. The resulting off-white solid was filtered off, washed with water and dried in vacuo to give 0.225 g (54%) product.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:13][C:12](=[O:14])[C:11]1(Cl)Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)C>C(O)(=O)C.[Zn]>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:13][C:12](=[O:14])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(COCc2ccccc2)C1(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C1CC(COCc2ccccc2)C1
Temperature: 60 °C

Procedure:
Zinc dust (93.5 g, 1.44 mol) was added to a solution of 3-(benzyloxymethyl)-2,2-dichlorocyclobutanone (124 g, 0.48 mol) in glacial acetic acid (800 ml) at room temperature. The reactants were heated at 60° C. for 1 hr, after which time dry diethyl ether was added to the cooled products, which were then filtered. The residue was washed with diethyl ether and the combined filtrate and washings were concentrated under reduced pressure. The residue was dissolved in dichloromethane, which was washed with saturated NaHCO3 twice and water once. The organic phase was dried over MgSO4 and the solvent was evaporated to give an oily product, which was purified by column chromatography (Hexane: EtOAc=6:1).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][CH2:10][C:11]([O:13]CC)=[O:12])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[OH-].[Na+].O.P(=O)(O)(O)O>CCCCCCC.O1CCCC1>[Br:1][C:2]1[C:3]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1
Reactant: CCOC(=O)CNc1ncc(Br)nc1Br
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CNc1ncc(Br)nc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 2-(3,5-dibromopyrazin-2-ylamino)acetate (1 equiv), tetrahydrofuran and sodium hydroxide in water (1.1 equiv) were combined and stirred at room temperature overnight. The reaction mixture was treated with dilute phosphoric acid (1.9 equiv) and heptane. The organic layer was concentrated to about 75% of its original volume and further distilled with addition of heptane until the reaction mixture was 80° C. The solution was treated with seed and distillation with addition of heptane was continued until reaching 85° C. The slurry was cooled and filtered, and the solids washed with heptane and dried to obtain 2-((3,5-dibromopyrazin-2-yl)amino)acetic acid as a solid. MS (ESI) m/z 309.9 [M+1].