Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([OH:14])[C:6]([OH:13])=[N:7]2.O.[CH:16]([CH:18]=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>[OH-].[Na+]>[OH:14][C:5]1[C:6]([OH:13])=[N:7][C:8]2[C:3]([N:4]=1)=[C:2]1[C:11](=[CH:10][CH:9]=2)[N:12]=[CH:18][CH:16]=[N:1]1
Reactant: Nc1ccc2nc(O)c(O)nc2c1N
Reactant: O=CC=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1nc2ccc3nccnc3c2nc1O
Temperature: 50 °C
Yield: 35.9 %

Procedure:
A mixture of 0,5 g (2,6 mmol) 5,6-diamino-2,3-dihydroxyquinoxaline and 20 ml water was added 0,6 ml (3,9 mmol) 40% aqueous glyoxal and 0,41 g (3,9 mmol) sodium carbonate. The reaction mixture was stirred at 50° C. for 1,5 h. After cooling to 25° C., the precipitate was filtered off and washed with water. to give 0,49 g. The crude product was dissolved in 2N sodium hydroxide and reprecipitated with 2N hydrochloric acid to pH 6-7 to give 0,2 g (36%) 2,3-dihydroxypyrazino(2,3-f)quinoxaline, m.p. >300° C. NMR (DMSO-d6): 8.30 (1H,d), 8.20 (1H,d), 7.27 (1H,d), 7.0 (1H,d).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13]([OH:15])=O)[CH2:8][CH2:7][CH2:6]2.[CH3:16][N:17]([CH3:35])[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1>>[CH3:16][N:17]([CH3:35])[C:18]1[CH:19]=[CH:20][C:21]([CH2:24][N:25]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:33])[CH3:34])=[CH:28][CH:27]=2)[C:13]([CH:9]2[C:10]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=3)[CH2:6][CH2:7][CH2:8]2)=[O:15])=[CH:22][CH:23]=1
Reactant: COc1ccc2c(c1)CCCC2C(=O)O
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Product: COc1ccc2c(c1)CCCC2C(=O)N(Cc1ccc(N(C)C)cc1)c1ccc(C(C)C)cc1
Yield: 30.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 6-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.54 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.7 g) as starting materials, N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-6-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.36 g) was obtained.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@:15]([CH2:25][O:26]S(C)(=O)=O)([CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:14][C@H:11]([O:12][CH3:13])[C@@H:10]1O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>CN(C=O)C>[CH2:1]([O:8][C@H:9]1[C@H:10]2[O:26][CH2:25][C@:15]1([CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[O:14][C@H:11]2[O:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@H]1O[C@@](COCc2ccccc2)(COS(C)(=O)=O)[C@@H](OCc2ccccc2)[C@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@@H]1O[C@@]2(COCc3ccccc3)CO[C@@H]1[C@@H]2OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 201 (3.32 g, 7.34 mmol) in anhydrous DMF (25 mL) was stirred at 0° C. and a 60% oil dispersion of sodium hydride (700 mg, 16.9 mmol) was added. The mixture was stirred at room temperature for 90 min, quenched with water (300 mL) and extracted with diethyl ether (2×300 mL). The combined extract was washed with water (200 mL) and dried (MgSO4). The solvent was removed under reduced pressure and the residue was purified by chromatography over silica gel with dichloromethane as eluent to give the two products 202 and 203 as clear oils (1.571 g, 60% and 0.777 g, 30% respectively). (1S,3R,4R,7S)-7-Benzyloxy-1-benzyloxymethyl-3-methoxy-2,5-dioxabicyclo[2.2.1]heptane (202). 1H NMR (CDCl3): δ 7.36-7.26 (10 H, m, Bn), 4.81 (1 H, s, H-1), 4.65 (1 H, d, J 11.9 Hz, Bn), 4.61 (2 H, s, Bn), 4.56 (1 H, d, J 11.9 Hz, Bn), 4.11 (1 H, s, H-2), 4.09 (1 H, s, H-3), 4.01 (1 H, d, J 7.5 Hz, H-5′), 3.80-3.77 (3 H, m, H-5′, H-5), 3.39 (3 H, s, OCH3); 13C NMR (CDCl3): δ 138.05, 137.36, 128.47, 128.44, 127.88, 127.73, 127.63 (Bn), 104.97 (C-1), 85.13 (C-4), 79.16 (C-3), 77.18 (C-2), 73.64 (Bn), 72.26, 72.10 (Bn, C-5′), 66.50 (C-5), 55.34 (OCH3); MS FAB: 379 (M+Na, 28%). Found: C, 70.55; H, 6.97; C21H24O5 requires C, 70.77; H, 6.79%. (7S,3R,4R,7S)-7-Benzyloxy-1-benzyloxymethyl-3-methoxy-2,5-dioxabicyclo[2.2.1]heptane (203). 1H NMR (CDCl3): δ 7.36-7.26 (10 H, m, Bn), 5.00 (1 H, s, H-1), 4.67-4.54 (4 H, m, Bn), 4.18 (1 H, s, H-2), 3.99 (1 H, s, H-3), 3.99-3.90 (2 H, m, H-5′), 3.75-3.68 (2 H, m, H-5), 3.49 (3 H, s, OCH3); 13C NMR (CDCl3): δ 137.83, 137.53, 128.51, 128.48, 127.96, 127.82, 127.71, 127.62 (Bn), 104.05 (C-1), 88.44 (C-4), 79.54 (C-3), 77.16 (C-2), 73.68 (Bn), 72.61 (C-5′), 72.24 (Bn), 65.73 (C-5), 56.20 (OCH3); MS FAB: 379 (M+Na, 100%).
Reaction SMILES: CS([C:5]1[N:6]=[N:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1)(=O)=O.[NH3:17].C1COCC1>>[C:11]1([C:9]2[N:10]=[C:5]([NH2:17])[N:6]=[N:7][CH:8]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)c1nncc(-c2ccccc2)n1
Reactant: N
Solvent: C1CCOC1
Product: Nc1nncc(-c2ccccc2)n1
Yield: 73 %

Procedure:
5-Phenyl-1,2,4-triazin-3-amine (1.70 g, 73%) was prepared from 3-(methylsulfonyl)-5-phenyl-1,2,4-triazine (3.20 g, 13.6 mmol) and 0.5 M ammonia in THF (100 mL, 500 mmol) according to the general procedure of Preparation 2.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.Br[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].O>CN(C=O)C>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][CH2:14][NH:1][C:2]1[C:11]([NH2:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1)[CH3:20]
Reactant: CCOC(=O)CCBr
Reactant: Nc1cc2ccccc2cc1N
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCNc1cc2ccccc2cc1N

Procedure:
A solution of 2,3-diaminonaphthalene (14.3 g, 90.4 mmol) and ethyl 3-bromopropionate (14 mL, 0.108 mol) in DMF (150 mL) was heated to 50° C. for 24 h. The reaction mixture was poured into water (600 mL) and the product was extracted into CH2Cl2 (2×200 mL). The combined organics were washed three times with water and dried over Na2SO4. The solvent was evaporated in vacuo and the resultant residue was purified by flash chromatography using 27% to 40% EtOAc in hexane as the eluant to give the product as a brown solid, 7.6 g (33%): MS m/z 259 (MH+); 1H NMR (DMSO-d6) δ 1.22 (t, 3H), 2.73 (t, 2H), 3.37-3.45 (m, 2H), 4.12 (q, 2H), 5.03 (br s, 2H), 5.09 (br t, 1H), 6.71 (s, 1H), 6.85 (s, 1H), 6.98-7.05 (m, 2H), 7.36-7.43 (m, 1H) and 7.47-7.53 (m, 1H).
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:5]=1[CH2:6][N:7]1[C:12]([CH3:13])=[CH:11][C:10](=[O:14])[NH:9][C:8]1=[O:15]>C(O)(=O)C>[Br:1][C:11]1[C:10](=[O:14])[NH:9][C:8](=[O:15])[N:7]([CH2:6][C:5]2[C:16]([C:20]([F:23])([F:21])[F:22])=[CH:17][CH:18]=[CH:19][C:4]=2[F:3])[C:12]=1[CH3:13]
Reactant: BrBr
Reactant: Cc1cc(=O)[nH]c(=O)n1Cc1c(F)cccc1C(F)(F)F
Solvent: CC(=O)O
Product: Cc1c(Br)c(=O)[nH]c(=O)n1Cc1c(F)cccc1C(F)(F)F
Reaction time: 2 h
Yield: 48750 %

Procedure:
Bromine (16.5 mL, 0.32 mmol) was added to 1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2-4(1H-3H)-dione 1c (48.5 g, 0.16 mol) in 145 mL of acetic acid. The resulting mixture became clear then formed precipitate within an hour. After 2 hours stirring, the yellow solid was filtered and washed with cold EtOAc to an almost white solid. The filtrate was washed with sat. NaHCO3 and dried over Na2SO4. Evaporation gave a yellow solid which was washed with EtOAC to give a light yellow solid. The two solids were combined to give 59.4 g of 1d (0.156 mol) total. 1H NMR (CDCl3) δ 2.4 (s, 3H), 5.48 (s, 2H), 7.25-7.58 (m, 3H), 8.61 (s, 1H); MS (CI) m/z 380.9 (MH+)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[F:21].[CH2:22]1[CH2:27][O:26][CH:25]=[CH:24][CH2:23]1.CS(O)(=O)=O.C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH:25]2[CH2:24][CH2:23][CH2:22][CH2:27][O:26]2)=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[F:21]
Reactant: O=[N+]([O-])c1ccc(Oc2cc3cn[nH]c3cc2Br)c(F)c1
Reactant: C1=COCCC1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Oc2cc3cnn(C4CCCCO4)c3cc2Br)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
To a solution of 6-bromo-5-(2-fluoro-4-nitrophenoxy)-1H-indazole (5.0 g, 14.2 mmol) in THF (50 mL) is added DHP (2.4 g, 28.5 mmol) and CH3SO3H (1.0 g, 10.4 mmol). The resulting mixture is stirred at RT for 1 hour. Then EtOAc and aqueous NaHCO3 solutions are added. The organic phase is separated, dried over anhydrous MgSO4, filtered and concentrated. The residue is purified by silica gel column chromatography eluting with PE:EtOAc (5:1) to give the desired product (5.5 g, 89.0% yield). MS (m/z): 436.0 (M+H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:26][CH2:27][Cl:28])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:25])[NH:13][C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:24])[CH2:22]Cl)[CH:17]=[CH:18][CH:19]=2)=[CH:7][CH:6]=1.[CH3:29][NH:30][CH3:31]>C1COCC1>[Cl:28][CH2:27][CH2:26][N:4]([CH2:3][CH2:2][Cl:1])[C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:25])[NH:13][C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:24])[CH2:22][N:30]([CH3:31])[CH3:29])[CH:17]=[CH:18][CH:19]=2)=[CH:9][CH:10]=1
Reactant: O=C(CCl)Nc1cccc(NC(=O)Nc2ccc(N(CCCl)CCCl)cc2)c1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)CC(=O)Nc1cccc(NC(=O)Nc2ccc(N(CCCl)CCCl)cc2)c1
Temperature: 55 °C

Procedure:
To a solution of N-(3-(3-(4-(bis(2-chloroethyl)amino)phenyl)ureido)phenyl)-2-chloroacetamide (0.88 g, 2 mmol) in THF (50 mL) was added dropwise dimethylamine (2M solution in THF) (2 mL, 4.0 mmol). The reaction mixture was heated at 50-60° C. for overnight. After cooling the mixture, the solvent was removed by evaporation under reduced pressure. The residue obtained was triturated with saturated aqueous solution of NaHCO3. The solid product was collected by filtration, washed successively with water and hexane, and dried to yield N-(3-(3-(4-(bis(2-chloroethyl)amino)phenyl)ureido)phenyl)-2-(dimethyl-amino)acetamide (BO-2189), 0.56 g (62%), mp 62-64° C. The product was dissolved in ethanol and excess of HCl in ethylacetate was added. The solution was evaporated in vacuo to dryness and the residue was co-evaporated several times with EtOH to dryness to form BO-2189 hydrochloride. 1H NMR (DMSO-d6) δ: 2.88 (6H, s, CH3), 3.68-3.71 (8H, m, CH2), 4.13 (2H, s, CH2), 6.71-6.73 (2H, d, J=8.8 Hz, Ar—H), 7.16-7.30 (5H, m, Ar—H), 7.78 (1H, s, Ar—H), 8.95 (1H, brs, NH), 9.24 (1H, brs, NH), 9.99 (1H, brs, NH). 13C NMR (CDCl3, 125 MHz) δ: 41.09, 43.25, 52.73, 57.88, 108.84, 112.56, 113.17, 113.55, 120.03, 129.04, 138.31, 140.73, 152.86, 162.91. HRMS [ES+]: calcd for C21H27Cl2N5O2, 452.3774 [M+H]+. found 452.1620. HPLC 97.3%.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([Cl:29])[CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([Cl:29])[CH:22]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc([N+](=O)[O-])cc23)cc1Cl
Product: COc1ccc(CNc2nc(-n3cncn3)nc3sc([N+](=O)[O-])cc23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-nitro-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-nitro-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:12]=[CH:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[CH3:22][C:23](O)=[O:24]>CCO.[Pt]>[C:23]([NH:1][C:4]1[CH:5]=[C:6]([CH:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:7]=[CH:8][CH:9]=1)(=[O:24])[CH3:22]
Reactant: CC(C)(C)OC(=O)n1cccc1-c1cccc([N+](=O)[O-])c1
Reactant: CC(=O)O
Agent: [Pt]
Solvent: CCO
Product: CC(=O)Nc1cccc(C2CCCN2C(=O)OC(C)(C)C)c1
Reaction time: 0.33 h
Yield: 35 %

Procedure:
4A (870 mg, 3.0 mmol) was hydrogenated in EtOH (12 mL) and HOAc (0.7 mL) with Pt/C (5% wt, 250 mg) using a H2 balloon for 2 days. After filtration and evaporation of solvent, the crude product was stirred in acetic anhydride (8.0 mL) for 20 min. After removal of acetic anhydride under high vacuum, the intermediate tert-butyl 2-(3-acetamidophenyl)pyrrolidine-1-carboxylate (316 mg, 35% yield for 2 steps) was obtained by chromatography (EtOAc/hexanes=1/1). This intermediate (310 mg, 1.0 mmol) was stirred in EtOAc (1.0 mL) and 4.0 N HCl/dioxane (4.4 mL, 18 eq) at rt for 1.0 h. After removal of solvent, 4B was obtained as HCl salt. 1H NMR (400 MHz, Methanol-d4) δ ppm 2.14 (s, 3H) 2.24 (m, 3H) 2.48 (m, 1H) 3.45 (m, 2H) 4.61 (m, 1H) 7.22 (d, J=7.47 Hz, 1H) 7.40 (t, J=7.69 Hz, 1H) 7.49 (m, 1H) 7.84 (s, 1H).
Reaction SMILES: [CH:1]([C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)=O.[N+](=[C:18](P(=O)(OC)OC)C(=O)C)=[N-].C([O-])([O-])=O.[K+].[K+]>CO>[C:1]([C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)#[CH:18]
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#C[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C

Procedure:
To crude (R)-tert-butyl 3-formylpiperidine-1-carboxylate in MeOH (20 mL) was added dimethyl 1-diazo-2-oxopropylphosphonate (1.28 g, 5.6 mmol), cooled to 0° C. and then added K2CO3 (2.56 g, 18.6 mmol), followed by MS, TLC. Added water (60 mL), extracted with EtOAc (3×50 mL), organic layer were evaporated and dried to give the desired product (S)-tert-butyl 3-ethynylpiperidine-1-carboxylate (0.86 g).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][NH:9][C:10](=[O:25])[C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18](=[O:20])[CH3:19])=[C:13]([O:21][C:22](=[O:24])[CH3:23])[CH:12]=1.C[Si](Cl)(C)C.[C:31]([Cl:34])(Cl)=[O:32]>ClCCl>[C:22]([O:21][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[O:17][C:18](=[O:20])[CH3:19])[C:10]([N:9]([CH3:8])[C:31]([Cl:34])=[O:32])=[O:25])(=[O:24])[CH3:23]
Reactant: O=C(Cl)Cl
Reactant: CNC(=O)c1ccc(OC(C)=O)c(OC(C)=O)c1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C(=O)N(C)C(=O)Cl)cc1OC(C)=O

Procedure:
A solution of triethylamine (6.04 g) in dried dichloromethane (20 ml) was added dropwise at room temperature to a solution of N-methyl-3,4-diacetoxybenzamide (15.0 g) and trimethylsilyl chloride (6.49 g) in dried dichloromethane (70 ml). After the mixture was refluxed for 30 minutes a solution (82 ml) of phosgene (42 ml) in dried dichloromethane was added to the mixture at a temperature of from -5° to 5° C. followed by allowing its temperature to gradually rise to room temperature. Excess phsogene and the solvent used were removed by evaporation under reduced pressure to give crude N-(3,4-diacetoxybenzoyl)-N-methylcarbamoyl chloride. The product was dissolved in cold dried dichloromethane (50 ml) and, after removing insoluble substances by filtration, made available for the subsequent reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[CH2:6][CH:7]1[CH2:12][NH:11][CH2:10][CH2:9][NH:8]1.C(Cl)Cl.C(N(CC)CC)C.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[S:31](Cl)(=[O:33])=[O:32]>C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[CH2:6][CH:7]1[NH:8][CH2:9][CH2:10][N:11]([S:31]([C:27]2[S:26][CH:30]=[CH:29][CH:28]=2)(=[O:33])=[O:32])[CH2:12]1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: COc1cccc(CC2CNCCN2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(CC2CN(S(=O)(=O)c3cccs3)CCN2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
To a 100-mL round-bottomed flask was added 2-(3-methoxybenzyl)piperazine (128 mg, 0.62 mmol), 5 mL of CH2Cl2, triethylamine (0.129 mL, 0.93 mmol) and 2-thiophenesulfonyl chloride (0.113 mL, 0.62 mmol, Aldrich, St. Louis, Mo.). The reaction mixture was stirred at 0° C. for 1 h and then diluted with aqueous saturated NaHCO3 (5 mL) and extracted with EtOAc (2×30 mL). The organic extracts were washed with saturated NaCl (10 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a light-yellow oil. The crude product was purified by silica gel chromatography, eluting with 5% MeOH in EtOAc to give 3-(3-methoxybenzyl)-1-(thiophen-2-ylsulfonyl)piperazine as a colorless oil (162 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][CH:6]=O)[CH3:2].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][N:11]=1.C(#N)C.C(O)C>C(=O)(O)[O-].[Na+]>[CH2:1]([O:3][C:4]([C:5]1[N:11]2[CH:12]=[C:13]([I:16])[CH:14]=[CH:15][C:10]2=[N:9][CH:6]=1)=[O:8])[CH3:2]
Reactant: CCOC(=O)CC=O
Reactant: Nc1ccc(I)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CC#N
Product: CCOC(=O)c1cnc2ccc(I)cn12
Yield: 78 %

Procedure:
Reflux a solution of 3-oxo-propionic acid ethyl ester (J. Med. Chem. 2001, 44(12), 1193-2003; 3.4 g, 23.7 mmol) and 2-amino-5-iodopyridine in 1:1 acetonitrile/ethanol (100 mL) overnight. Dilute with saturated aqueous sodium bicarbonate, extract into dichloromethane (4×100 mL), combine organics, and concentrate. Flash chromatography using appropriate ethyl acetate/hexane mixtures gives 3.7 g (78%) of the subtitled compound as an off-white solid. ES+ m/e 316.7 (M+1).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]2[N:18]=[C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH:20]3[C:24]3[O:28][N:27]=[C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH:25]=3)[N:16]=[C:15]([NH:35][CH:36]3[CH:40]=[C:39]([CH3:41])[NH:38][N:37]3S(C3C=CC(C)=CC=3)(=O)=O)[CH:14]=2)(=O)=O)=CC=1.[CH3:52][NH2:53].C1COCC1>>[CH3:52][NH:53][CH2:12][C:13]1[N:18]=[C:17]([N:19]2[CH2:23][CH2:22][CH2:21][CH:20]2[C:24]2[O:28][N:27]=[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[CH:25]=2)[N:16]=[C:15]([NH:35][C:36]2[CH:40]=[C:39]([CH3:41])[NH:38][N:37]=2)[CH:14]=1
Reactant: CC1=CC(Nc2cc(COS(=O)(=O)c3ccc(C)cc3)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)N(S(=O)(=O)c2ccc(C)cc2)N1
Reactant: CN
Solvent: C1CCOC1
Product: CNCc1cc(Nc2cc(C)[nH]n2)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Yield: 77 %

Procedure:
A mixture of 6-[(4-methylphenylsulphonyloxy)methyl]-2-{2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidin-1-yl}-4-(5-methyl-2-N-[4-methylphenylsulphonyl]-1H-pyrazol-3-ylamino)pyrimidine (Method 52) (190 mg, 0.26 mmol) and a solution of 2N methylamine in THF (5 ml, 10 mmol) were heated at 90° C. in a sealed vessel under microwave irradiation for 1 hour. The volatiles were removed by evaporation and the residue purified by reverse phase HPLC using a C18 column eluting with water/acetonitrile/TFA (95:5:0.2 decreasing in polarity to 0:100:0.2). Product containing fractions were combined and passed through a 50 g isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutrals, followed by 7M methanolic ammonia to elute the product. The solvent was removed by evaporation of give the title compound (87.1 mg, 77%).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH:7]1[C:11]([CH3:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:10][C:9](=[O:19])[NH:8]1>N1C=CC=CC=1>[Cl:3][CH2:6][CH:7]1[C:11]([CH3:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:10][C:9](=[O:19])[NH:8]1
Reactant: CC1(c2ccccc2)OC(=O)NC1CO
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CC1(c2ccccc2)OC(=O)NC1CCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.5 ml (10 mMole) of thionyl chloride are slowly added dropwise at 0° to +5° C to 1.04 g (5 mMole) of 4-hydroxymethyl-5-methyl-5-phenyl oxazolidin-2-one dissolved in 15 ml of pyridine. After 1 hour at 50° C, the reaction solution is stirred overnight at room temperature, poured onto ice and repeatedly extracted with chloroform. The combined chloroform phases dried over Na2SO4 are concentrated. The crystals formed are recrystallised from methanol.
Reaction SMILES: [OH:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]=1[C:11]([O:13]C)=O.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>CCOCC>[OH:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]=1[C:11]([NH:20][C:19]1[CH:21]=[CH:22][CH:23]=[C:17]([C:16]([F:15])([F:24])[F:25])[CH:18]=1)=[O:13]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1sc2ccccc2c1O
Solvent: CCOCC
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1sc2ccccc2c1O
Temperature: 170 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
A mixture of methyl 3-hydroxy-benzothiophene2-carboxylate (1.04 g; 0.005M) and 3-trifluoromethylaniline (1.61 g; 0.010M) is heated under a nitrogen atmosphere at 170° C. for 90 minutes. and then at 200° C. for 30 minutes. The reaction was cooled at room temperature, taken up in ether and the solid was collected, washed with ether and air dried. The solid was recrystallized from ethyl acetate to give 0.96 g (57% yield) of the title compound; m.p. 205°-208° C. (dec).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10]2>ClCCl>[OH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10]2
Reactant: CCOC(=O)c1cc2cc(OC)ccc2[nH]1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.2 %

Procedure:
Boron tribromide (64.58 g) was added dropwise to a stirred solution of ethyl 5-methoxyindole-2-carboxylate (20 g) in dry dichloromethane (1000 ml) at −78° C. under an atmosphere of argon. The reaction was allowed to warm to room temperature and stirred for a further 2 hours. The reaction was poured into ice/saturated aqueous sodium hydrogen carbonate solution with stirring and extracted with ethyl acetate. Combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate solution, water, aqueous saturated sodium chloride solution and dried (MgSO4). The solution was concentrated in vacuo and the residue was purified by column chromatography using 0-60% diethyl ether iso-hexane as eluent to give product as a white solid (9.02 g, 48%); NMR δ(CD3SOCD3) 1.31 (t, 3H), 4.29 (q, 2H), 6.79 (dd, 1H), 6.90 (dd, 1H), 7.22 (d, 1H), 8.84 (s, 1H), 11.52 (brs, 1H), M/z (+) 206 (MH+).
Reaction SMILES: CC([Si](C1C=CC=CC=1)(C1C=CC=CC=1)O[C:7]1([N:30]=[N+]=[N-])[CH2:10][CH:9]([CH2:11][O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)C1)(C)C.[CH:45]([O-:47])=O.[NH4+]>CO.[Pd]>[CH3:27][C:26]([Si:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[O:12][CH:11]1[CH:9]([CH2:45][O:47][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH:7]1[NH2:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)[Si](OCC1CC(N=[N+]=[N-])(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1)(c1ccccc1)c1ccccc1
Reactant: O=C[O-]
Agent: [Pd]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)[Si](OCC1CC(N)C1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 184.5 %

Procedure:
2-(((1,1-dimethylethyl)diphenylsilyloxy)-3-(((1,1-dimethylethyl)diphenyl-silyl)oxymethyl)-1-azidocyclobutane (800 mg, 1.29 mmol), the product of Step M, was dissolved in 20 mL of methanol. To this solution was added 200 mg of 5% palladium on carbon, followed by 420 mg of ammonium formate. The flask was stoppered and the reaction mixture was stirred at ambient temperature for 23 h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was dissolved in 200 mL of diethyl ether and the ether solution was washed with 100 mL of 5% aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 707 mg (92% yield) of the title compound; MS DCI-NH3M/Z: 594 (M+H)+ ; 1H NMR (CDCl3) δ 0.88-1.08 (m, 18H), 1.95-2.15 (m, 3H), 3.01 (q, 1H), 3.5 (m, 2H), 3.68 (t, 1H).