Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2](=[NH:7])(OCC)[CH3:3].C(N(CC)CC)C.Cl.[CH2:16]([O:18][C:19]([NH:21][C:22]1([CH2:28][N:29]2[CH2:34][CH2:33][N:32]([S:35]([C:38]3[CH:47]=[CH:46][C:45]4[C:40](=[CH:41][CH:42]=[C:43]([Cl:48])[CH:44]=4)[CH:39]=3)(=[O:37])=[O:36])[CH2:31][C:30]2=[O:49])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:20])[CH3:17]>CO>[ClH:48].[C:2]([N:25]1[CH2:26][CH2:27][C:22]([CH2:28][N:29]2[CH2:34][CH2:33][N:32]([S:35]([C:38]3[CH:47]=[CH:46][C:45]4[C:40](=[CH:41][CH:42]=[C:43]([Cl:48])[CH:44]=4)[CH:39]=3)(=[O:36])=[O:37])[CH2:31][C:30]2=[O:49])([NH:21][C:19]([O:18][CH2:16][CH3:17])=[O:20])[CH2:23][CH2:24]1)(=[NH:7])[CH3:3]
Reactant: CCOC(=O)NC1(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CCNCC1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOC(=O)NC1(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CCN(C(C)=N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 162.1 %

Procedure:
A 4N hydrochloric acid solution in ethyl acetate (30 ml) and ethanol (6 ml) were added to 1-[1-(tert-butoxycarbonyl)-4-ethoxycarbonylamino-4-piperidylmethyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone (5.21 g), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, the precipitated crystals were filtered, washed with ethyl acetate-ethanol, and dried to obtain 1-[4-ethoxycarbonylamino-4-piperidinylmethyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone hydrochloride (3.71 g). Ethyl acetimidate hydrochloride(148 mg) and triethylamine (0.337 ml) were added to a solution of 1-[4-ethoxycarbonylamino-4-piperidinylmethyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone hydrochloride (218 mg) in methanol (10 ml) under ice-cooling, and the mixture was stirred at room temperature overnight. After distillation of the solvent, purification by CHP20 column chromatography (water:acetonitrile:1N hydrochloric acid=100:0:0→60:40:0.5) afforded the colorless amorphous title compound (190 mg).
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[Br:21]Br.OS([O-])=O.[Na+]>CC([O-])=O.[Na+]>[I:1][C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[C:7]([Br:21])[N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11]
Reactant: BrBr
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: CC(=O)[O-]
Agent: O=S([O-])O
Agent: [Na+]
Product: Nc1nc(I)nc2c1nc(Br)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Iodoadenosine (1, 2.93 g, 7.45 mmol) was dissolved in NaOAc buffer (1.0 M, pH 4, 50 ml) at 50° C. The solution was cooled to room temperature and bromine (0.46 mL, 8.94 mmol) was added. After stirring overnight at room temperature, adding NaHSO3 destroyed the excess of bromine and the pH of the solution was adjusted to 7 with NaOH solution (5 M). The reaction mixture was kept at 4° C. for 5 hr and the precipitate was filtered. The white solid was washed with water and dried. Yield 2.43 mg (5.14 mmol, 69%), Rƒ 0.69 (10% MeOH in EtOAc); 1H NMR (DMSO-d6) δ 7.91 (s, 2H, NH2), 5.77 (d, 1H, J=6.52 Hz, H-1′), 5.47 (d, 1H, J=5.84 Hz, OH-2′), 5.24 (d, 1H, J=4.80 Hz, OH-5′), 5.03–4.84 (m, 2H, OH-3′, H-2′), 4.20–4.09 (m, 1H, H-3′), 3.97–3.88 (m, 1H, H-4′), 3.71–3.42 (m, 2H, H-5′) ppm.
Reaction SMILES: Cl.CO[C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:29])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH2:17]CCN2CCSCC2)=[C:12]([N+:26]([O-:28])=[O:27])[CH:11]=1)=O.[C:30]([O:33][CH2:34]C)(=[O:32])[CH3:31].C(O)C>>[CH3:34][O:33][C:30]([CH:31]1[CH2:4][CH2:6][CH2:7][N:8]1[C:9](=[O:29])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH3:17])=[C:12]([N+:26]([O-:28])=[O:27])[CH:11]=1)=[O:32]
Reactant: COC(=O)CCNC(=O)c1ccc(NCCCN2CCSCC2)c([N+](=O)[O-])c1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CCO
Product: CNc1ccc(C(=O)N2CCCC2C(=O)OC)cc1[N+](=O)[O-]

Procedure:
The same procedure is used as in (1). Rf value: 0.57 (silica gel; ethyl acetate/ethanol=9:1)
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:8]2)[O:4][N:3]=1.[O-:31][CH2:32][CH3:33].[Na+]>C(O)C>[CH2:32]([O:31][C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:8]2)[O:4][N:3]=1)[CH3:33]
Reactant: CC[O-]
Reactant: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(Cl)no2)C1
Agent: [Na+]
Solvent: CCO
Product: CCOc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1
Temperature: 40 °C
Reaction time: 48 h

Procedure:
To a solution of 150 mg (0.337 mmol) of the oxadiazole from Example 23A in 6.25 ml of ethanol were added 229 mg (3.37 mmol) of sodium ethoxide, and then the reaction mixture was stirred at RT for 3 days and at 40° C. for 2 days. The solvent was removed under reduced pressure and the crude product was purified by means of preparative HPLC. Yield: 16.8 mg (11% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][N:14]3[C:22]([C:25](=[O:30])C(Cl)(Cl)Cl)=[CH:23][CH:24]=[C:13]3[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CS(C)=O.[NH2:35][CH2:36][C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][N:14]3[C:22]([C:25]([NH:35][CH2:36][C:37]4[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=4)=[O:30])=[CH:23][CH:24]=[C:13]3[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NCc1cccnc1
Reactant: O=C(c1ccc2n1Cc1ccccc1N(S(=O)(=O)c1ccc(Br)cc1)C2)C(Cl)(Cl)Cl
Solvent: CS(C)=O
Solvent: CC#N
Product: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(S(=O)(=O)c1ccc(Br)cc1)C2
Yield: 90.9 %

Procedure:
To a solution of 1-{10-[(4-bromophenyl)sulfonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}-2,2,2-trichloroethanone of Step B (1.80 g, 3.297 mmol) and dimethyl sulfoxide (1.17 mL, 16.487 mmol) in dry acetonitrile (30 mL) at room temperature under nitrogen was added 3-(aminomethyl)pyridine (0.67 mL, 6.595 mmol) and the reaction mixture heated to reflux for 20 hours. The cooled reaction mixture was concentrated in vacuo, the oily residue dissolved in ethyl acetate (100 mL), washed with 1M sodium hydroxide (2×100 mL), water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a yellow foam. Purification by flash chromatography using a solvent gradient of 0 to 3% methanol in dichloromethane gave the title compound (1.61 g, 91%) as a yellow foam.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].Cl[C:11]([F:16])([F:15])C([O-])=O.[Na+].[OH-].[Na+].C(OCC)(=O)C>CN(C=O)C>[F:15][CH:11]([F:16])[O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: O=C([O-])C(F)(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(OC(F)F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 40.8 %

Procedure:
4-Cyanophenol (0.50 g, 4.2 mmol, Aldrich), sodium chlorodifluoroacetate (0.77 g, 5 mmol, Alfa Products), and sodium hydroxide (0.20 g, 5 mmol) were combined in dry DMF (2 mL) under an atmosphere of argon. After stirring at 125°-130° C. for 5 h, the mixture was cooled to RT, ethyl acetate (50 mL) was added and the organic layer was washed twice with brine. The organic extract was dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography (silica gel, 25% ethyl acetate/hexanes) to provide a white solid. The solid was sublimed (1 mm Hg, 23° C.) to provide the title compound as colorless crystals (0.29 g, 41%). mp 33°-35° C.
Reaction SMILES: BrC1C(N2CCN(CC3C=NC=CC=3)CC2)=C2N=C(C3C=CC(CN)=CC=3)NC2=NC=1.[Br:32][C:33]1[C:34]([N:51]2[CH2:56][CH2:55][N:54]([CH2:57][C:58]3[CH:59]=[N:60][CH:61]=[CH:62][CH:63]=3)[CH2:53][CH2:52]2)=[C:35]2[N:41]=[C:40]([CH2:42][NH:43]C(=O)OC(C)(C)C)[NH:39][C:36]2=[N:37][CH:38]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:32][C:33]1[C:34]([N:51]2[CH2:52][CH2:53][N:54]([CH2:57][C:58]3[CH:59]=[N:60][CH:61]=[CH:62][CH:63]=3)[CH2:55][CH2:56]2)=[C:35]2[N:41]=[C:40]([CH2:42][NH2:43])[NH:39][C:36]2=[N:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)NCc1nc2c(N3CCN(Cc4cccnc4)CC3)c(Br)cnc2[nH]1
Agent: NCc1ccc(-c2nc3c(N4CCN(Cc5cccnc5)CC4)c(Br)cnc3[nH]2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1nc2c(N3CCN(Cc4cccnc4)CC3)c(Br)cnc2[nH]1
Yield: 87 %

Procedure:
This was prepared using the same procedure as for (4-(6-bromo-7-(4-(pyridin-3-ylmethyl)piperazin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)phenyl)methanamine, but here using tert-butyl (6-bromo-7-(4-(pyridin-3-ylmethyl)piperazin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)methylcarbamate (10 mg, 0.020 mmol), TFA (0.2 mL) and CH2Cl2 (1 mL). The same purification procedure gave the desired product (7 mg, 88%) as a colourless solid; δH (500 MHz, DMSO-d6) 2.60 (s, br, 4H, piperazine N(CH2)2), 3.57 (s, br, 4H, piperazine N(CH2)2), 3.62 (s, 2H, NCH2Ar), 4.04 (s, br, 2H, CH2NH2), 7.38 (dd, J=7.7, 4.7 Hz, 1H, pyridine H-5), 7.77 (dt, J=7.8, 1.7 Hz, 1H, pyridine H-4), 8.24 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.50 (dd, J=4.7, 1.5 Hz, 1H, pyridine H-6), 8.56 (d, J=1.6 Hz, 1H, pyridine H-2);
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[C:9]([CH:11]=[CH:12][C:13]3[N:17]([CH2:18][C:19]([F:22])([F:21])[F:20])[N:16]=[C:15]([N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[N:14]=3)[N:10]=[C:6]2[C:5]([CH3:28])=[N:4][CH:3]=1>C(OCC)(=O)C.CO>[CH3:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][CH2:12][C:13]3[N:17]([CH2:18][C:19]([F:21])([F:20])[F:22])[N:16]=[C:15]([N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[N:14]=3)[N:10]=[C:6]2[C:5]([CH3:28])=[N:4][CH:3]=1
Reactant: Cc1ncc(C)n2nc(C=Cc3nc(N4CCCC4)nn3CC(F)(F)F)nc12
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ncc(C)n2nc(CCc3nc(N4CCCC4)nn3CC(F)(F)F)nc12
Yield: 54.7 %

Procedure:
Was prepared in the same manner as described in General Procedure Example 2 using 5,8-dimethyl-2-(2-(3-(pyrrolidin-1-yl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)vinyl)-[1,2,4]triazolo[1,5-a]pyrazine (20 mg, 51.0 μmol, Eq: 1.00) as starting material. The crude material was applied on a 5 g silicagel column using ethyl acetate/methanol 0-10% as eluent affording 5,8-dimethyl-2-{2-[5-pyrrolidin-1-yl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-ethyl}-[1,2,4]triazolo[1,5-a]pyrazine (11 mg/52.4%) as a white solid. MS: m/e=395.8 (M+H+)
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH:9]=[CH:10][C:11](=[O:24])[C:12]2[S:13][C:14]([CH3:23])=[C:15]3[CH2:20][C:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][C:16]=23)[CH:6]=[C:5]([CH3:25])[C:4]=1[CH:26]=[CH:27][C:28]([OH:30])=[O:29])[CH3:2].CCN(C(C)C)C(C)C>C(O)C.[Pd]>[CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11](=[O:24])[C:12]2[S:13][C:14]([CH3:23])=[C:15]3[CH2:20][C:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][C:16]=23)[CH:6]=[C:5]([CH3:25])[C:4]=1[CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH3:2]
Reactant: CCc1cc(C=CC(=O)c2sc(C)c3c2CCC(C)(C)C3)cc(C)c1C=CC(=O)O
Agent: [Pd]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(CCC(=O)c2sc(C)c3c2CCC(C)(C)C3)cc(C)c1CCC(=O)O
Temperature: 50 °C
Reaction time: 72 h
Yield: 44.8 %

Procedure:
To a solution of 3-{2-ethyl-6-methyl-4-[3-oxo-3-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propenyl]-phenyl}-acrylic acid (340 mg, 0.805 mmol) and DIPEA (182 mg, 1.41 mmol) in ethanol, Pd/C (340 mg, 10% Pd, moistened with 50% water) is added and the resulting slurry is stirred at 50° C. for 72 h under 10 bar of H2. Another portion of Pd/C is added and stirring is continued for 16 h at 50° C. under 10 bar of H2. The reaction mixture is filtered and the filtrate is evaporated. The crude product is purified by prep. HPLC (Grom-Sil 120 ODS-4-HE, 30×75 mm, 10 μm, acetonitrile/water (0.5% HCOOH), 20% to 95% acetonitrile) to give 3-{2-ethyl-6-methyl-4-[3-oxo-3-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propyl]-phenyl}-propionic acid (154 mg) as a colourless foam; LC-MS: tR=1.15 min, [M+1]=427.30.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14]CC=C)=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].[C:19]1(OC2C=CC=CC=2)[CH:24]=CC=C[CH:20]=1>>[CH3:18][C:2]([CH3:1])([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[C:12]([CH2:24][CH:19]=[CH2:20])[CH:13]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: C=CCOc1ccc(CC(C)(C)C(=O)OC)cc1
Product: C=CCc1cc(CC(C)(C)C(=O)OC)ccc1O
Temperature: 25 °C

Procedure:
A solution of methyl 2,2-dimethyl-3-(4-allyloxyphenyl)propionate (1.56 g) in diphenyl ether was heated at reflux for 15 minutes. The reaction mixture was cooled to ambient temperature and the reaction mixture was filtered through a silica gel pad. Elution with a 4:1 (v/v) mixture of hexane and ethyl acetate gave methyl 2,2-dimethyl-3-(3-allyl-4-hydroxyphenyl)propionate (1.53 g) as a yellow oil; microanalysis, found: C, 72.2; H, 7.80%; C15H20O3 requires: C, 72.6; H, 8.12%; NMR(CDCl3): 1.15(6H,s), 2.73(2H,s), 3.35(2H,m), 3.63(3H,s), 4.87(1H,s), 5.10(2H,m), 5.95(1H,m), 6.67(1H,m) and 6.83(2H,m); m/z 249 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:44]=[CH:43][C:7]([CH2:8][O:9][C:10](=[O:42])[CH:11]([N:15]2[CH:18]([S:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:17]([NH:30][C:31](=[O:40])[CH2:32][O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:16]2=[O:41])[C:12](=[CH2:14])C)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(O)[O-:46].[Na+]>C(OC)(=O)C.O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:44]=[CH:43][C:7]([CH2:8][O:9][C:10](=[O:42])/[C:11](/[N:15]2[CH:18]([S:19][S:20]([C:23]3[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)(=[O:21])=[O:22])[CH:17]([NH:30][C:31](=[O:40])[CH2:32][O:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:16]2=[O:41])=[C:12](\[OH:46])/[CH3:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=S([O-])O
Reactant: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Solvent: COC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: C/C(O)=C(/C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1

Procedure:
(di) The crude 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylenebutyric acid p-nitrobenzyl ester, obtained according to Example 1cvii), is dissolved in 20 ml of methyl acetate and ozonised at -70° C. until no further starting material is present, according to a thin layer chromatogram. A stream of nitrogen is then passed through the solution and the latter is warmed to 0°-5° C. A solution of 300 mg of sodium bisulphite in 5 ml of water is added and the mixture is stirred for about 5 minutes until no further ozonide can be detected with potassium iodide/starch paper. The mixture is diluted with ethyl acetate, the aqueous phase is separated off, and the organic phase is washed with water, dried over magnesium sulphate and freed from solvent in vacuo. The crude product is dissolved in 3 ml of methylene chloride and 15 ml of toluene are added. The precipitate is filtered off and the filtrate is evaporated in vacuo. The residue is recrystallised from mthanol and gives 2 -[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxycrotonic acid p-nitrobenzyl ester of melting point 159°-160° C.
Reaction SMILES: [H-].[Na+].O[C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[C:5]1=[O:14])[CH2:11]2.C(Br)C.C1C[O:21][CH2:20][CH2:19]1>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-]>[CH2:20]([O:21][C:10]12[CH2:12][CH:6]3[CH2:7][CH:8]([CH2:13][CH:4]([C:5]3=[O:14])[CH2:11]1)[CH2:9]2)[CH3:19]
Reactant: C1CCOC1
Reactant: O=C1C2CC3CC(C2)CC1(O)C3
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CCBr
Product: CCOC12CC3CC(C1)C(=O)C(C3)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a suspension of NaH (60% dispersed in nujol, 0.96 g, 24 mmol) in THF (40 mL) cooled to ice bath temperature was added hydroxyadamantanone (3.32 g, 20 mmol) dissolved in THF (40 mL) via a syringe over a period of 15 minutes. The reaction mixture was stirred for 30 min then n-Bu4NI (0.74 g, 2 mmol) and ethyl bromide (1.6 mL, 22 mmol) were added. The reaction mixture was warmed to room temperature and stirred for 16 h. After cooling the reaction mixture to 0° C., the excess NaH was quenched by adding sat. aq. NH4Cl solution. The two layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and the solvent was evaporated under reduced pressure to obtain a crude reaction mass, which was purified by column chromatography to yield 5-ethoxyadamantan-2-one (3.0 g) in 77% yield. m/z (M+1) 195; 1H NMR (CDCl3) 300 MHz δ 3.47 (q, J=7.0 Hz, 2H), 2.67-2.60 (m, 2H), 2.38-2.30 (m, 1H), 2.13-1.78 (m, 10H), 1.17 (t, J=7.0 Hz, 3H).
Reaction SMILES: Cl[CH2:2][N:3]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][C:9]([O:20][CH3:21])=[C:10]([O:18][CH3:19])[C:11]=2[CH2:15][CH2:16][CH3:17])[S:4]1(=[O:6])=[O:5].[Na].[C:23]1([N:29]2[C:33]([SH:34])=[N:32][N:31]=[N:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(OCC)(=O)C.CCCCCC.CCCCCC>CN(C)C=O>[C:23]1([N:29]2[C:33]([S:34][CH2:2][N:3]3[C:13](=[O:14])[C:12]4[C:7](=[CH:8][C:9]([O:20][CH3:21])=[C:10]([O:18][CH3:19])[C:11]=4[CH2:15][CH2:16][CH3:17])[S:4]3(=[O:6])=[O:5])=[N:32][N:31]=[N:30]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Sc1nnnn1-c1ccccc1
Reactant: CCCc1c(OC)c(OC)cc2c1C(=O)N(CCl)S2(=O)=O
Agent: [Na]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OC)c(OC)cc2c1C(=O)N(CSc1nnnn1-c1ccccc1)S2(=O)=O
Yield: 76 %

Procedure:
By the method of Example 44 condensation of 2-chloromethyl-4-propyl-5,6-dimethoxysaccharin (0.6 g) and 1-phenyltetrazol-5-thiol sodium salt (0.36 g) in dimethylformamide (5 mL) and purification of the product by column chromatography on silica gel using ethyl acetate-hexane (3:7) as eluant followed by trituration with hexane afforded 2-(1-phenyltetrazol-5-yl)thiomethyl-4-propyl-5,6-dimethoxysaccharin, 0.65 g, 76% yield, mp 145°-146° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]([C:16]#[N:17])[CH2:13][C@@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1C[C@H](CN)C[C@H]1C(O)=O)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:15][C@@H:14]([CH2:16][NH2:17])[CH2:13][C@@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](C#N)C[C@@H]1C(=O)O
Agent: CC(C)(C)OC(=O)N1C[C@H](CN)C[C@H]1C(=O)O
Product: CC(C)(C)OC(=O)N1C[C@@H](CN)C[C@@H]1C(=O)O
Yield: 95 %

Procedure:
Cyano acid 28 (650 mg, 2.7 mmol) was hydrogenated as for the synthesis of 12, and the produce was crystallized from water/ethanol/ether to give 630 mg (95% yield), m.p.=187°-189° C. (decomposition). 1H NMR (D2O) δ 1.40/1.44 (2s, 9H), 1.62 (m, 1H). 2.55 (m, 2H), 3.13 (m, 2H), 3.75 (m, 2H), 4.10 (m, 1H). Anal. (C11H20N2O4).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2].Cl[C:14]1[N:19]=[C:18]([S:20][CH3:21])[N:17]=[C:16]([NH:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=2)[CH:15]=1>>[CH3:34][O:33][C:27]1[CH:26]=[C:25]([CH2:24][CH2:23][NH:22][C:16]2[N:17]=[C:18]([S:20][CH3:21])[N:19]=[C:14]([C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:1]([OH:3])=[O:2])[CH:15]=2)[CH:30]=[CH:29][C:28]=1[O:31][CH3:32]
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: COc1ccc(CCNc2cc(Cl)nc(SC)n2)cc1OC
Product: COc1ccc(CCNc2cc(-c3cccc(C(=O)O)c3)nc(SC)n2)cc1OC

Procedure:
By proceeding in a similar manner to Example 16(a) above but using commercially available 3-carboxy-phenyl-boronic acid, and (6-chloro-2-methylsulfanyl-pyrimidin-4-yl)-[2-(3,4-dimethoxy-phenyl)-ethyl]-amine (0.57 g) in Step 2, and extracting the reaction mixture (adjusted to pH 2) with EtOAc followed by evaporation of the organic extract, there is prepared 3-{6-[2-(3,4-dimethoxy-phenyl)-ethylamino]-2-methylsulfanyl-pyrimidin-4-yl}-benzoic acid [0.48 g, Example 16(b)]. LCMS: RT=2.75 minutes, MS: 426 (M+H). IC50=243 nM
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]([NH:12][C:13]2[CH:22]=[C:21]3[NH:23][N:24]=[C:19]4[C:20]3=[C:15]([CH2:16][CH2:17][NH:18]4)[N:14]=2)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)Cl>[C:32]([N:18]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]([NH:12][C:10]([NH:9][C@@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH3:8])=[O:11])[CH:22]=[C:21]3[NH:23][N:24]=[C:19]1[C:20]=23)(=[O:34])[CH3:33]
Reactant: C[C@@H](NC(=O)Nc1cc2[nH]nc3c2c(n1)CCN3)c1ccccc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2nc(NC(=O)N[C@H](C)c3ccccc3)cc3[nH]nc1c23
Reaction time: 1 h

Procedure:
(R)-1-(1-phenylethyl)-3-(1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridin-7-yl)urea (Example 136; 13 mg, 0.040 mmol) and triethylamine (50 mg, 0.494 mmol) were taken in DCM (0.15 mL) and added acetyl chloride (20 mg, 0.255 mmol) and stirred for 1 hour. The reaction mixture was diluted with DCM, washed with aqueous sodium bicarbonate, brine, dried with sodium sulfate and concentrated. Purification of the residue by flash column (0-15% MeOH-DCM) gave (R)-1-(3 acetyl-1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridin-7-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. for C19H20N6O2 [M+H]+ 365. found 365. 1H NMR (ppm, 500 MHz, DMSO-d6) δ 12.35 (s, 1H), 9.13-9.05 (m, 1H), 8.05-7.86 (m, 1H), 7.39-7.28 (m, 6H), 7.27-7.18 (m, 1H), 3.06-2.96 (m, 2H), 1.38 (t, J=9.1, 3H), 1.25-1.18 (m, 2H).
Reaction SMILES: [I:1][C:2]1[C:10]2[O:9][C:8](=[O:11])[NH:7][C:6]=2[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:24][Si:25]([CH3:32])([CH3:31])[CH2:26][CH2:27][O:28][CH2:29]Cl>CN(C)C=O.C(OCC)(=O)C>[I:1][C:2]1[C:10]2[O:9][C:8](=[O:11])[N:7]([CH2:29][O:28][CH2:27][CH2:26][Si:25]([CH3:32])([CH3:31])[CH3:24])[C:6]=2[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: O=c1[nH]c2cc([N+](=O)[O-])cc(I)c2o1
Reactant: C[Si](C)(C)CCOCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1c(=O)oc2c(I)cc([N+](=O)[O-])cc21
Temperature: 20 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
A solution of 7-iodo-5-nitro-1,3-benzoxazol-2(3H)-one (0.76 g, 2.5 mmol) in N,N-dimethylformamide (5 mL) at 0° C. was treated with N,N-diisopropylethylamine (0.65 mL, 3.7 mmol) followed by [β-(trimethylsilyl)ethoxy]methyl chloride (0.61 mL, 3.5 mmol) dropwise and stirred at 20° C. for 1 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with 0.5 M HCl (50 mL), brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to a crude oil. This material was purified by flash column chromatography to give the desired product (0.93 g, 86%) as a yellow oil.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[C:11]([O:13]CC)=[O:12])[CH:2]=1.O1CCOCC1>[OH-].[Na+].O>[C:1]1([CH3:19])[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[C:11]([OH:13])=[O:12])[CH:2]=1
Reactant: CCOC(=O)c1cccc(Oc2cccc(C)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(Oc2cccc(C(=O)O)c2)c1

Procedure:
A mixture of ethyl 3-(m-tolyloxy)benzoate (0.084 g, 0.326 mmol) in NaOH 1M in water (2 mL) and dioxane (2 mL) was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue washed with dichloromethane, acidified to pH 2 with a 6N solution of hydrochloric acid in water, and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure to yield quantitatively the title compound which was used without further purifications.