Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.[OH-].[Na+].[CH3:6][CH2:7][CH2:8][C@H:9]1[CH2:13][N:12]([CH3:14])[C@H:11]([C:15]([NH:17][C@H:18]([C@@H:34]([Cl:36])[CH3:35])[C@H:19]2[O:24][C@H:23]([S:25][CH3:26])[C@H:22]([O:27]P(O)(O)=O)[C@@H:21]([OH:32])[C@H:20]2[OH:33])=[O:16])[CH2:10]1.C(O)C(O)C>O.O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[CH3:6][CH2:7][CH2:8][C@H:9]1[CH2:13][N:12]([CH3:14])[C@H:11]([C:15]([NH:17][C@H:18]([C@@H:34]([Cl:36])[CH3:35])[C@H:19]2[O:24][C@H:23]([S:25][CH3:26])[C@H:22]([OH:27])[C@@H:21]([OH:32])[C@H:20]2[OH:33])=[O:16])[CH2:10]1
Reactant: CCC[C@@H]1C[C@@H](C(=O)N[C@@H]([C@H]2O[C@H](SC)[C@H](OP(=O)(O)O)[C@@H](O)[C@H]2O)[C@H](C)Cl)N(C)C1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(O)CO
Product: CCC[C@@H]1C[C@@H](C(=O)N[C@@H]([C@H]2O[C@H](SC)[C@H](O)[C@@H](O)[C@H]2O)[C@H](C)Cl)N(C)C1

Procedure:
Manufacture Complex a) Mix ethanol and purified water using a homogeniser. b) With continuous homogenisation, add the clindamycin phosphate (weight corrected for assay and water content) to form a suspension. c) While mixing continues, slowly add sodium hydroxide 30% w/w to a pH of 7.5 (allowing clindamycin phosphate to dissolve). Record pH and calculate total amount of water added. d) Dissolve zinc acetate dihydrate in purified water and mix until a clear solution is formed. e) With continuous homogenisation add the zinc acetate solution to the pH 7.5, clindamycin phosphate solution. Continue mixing, until a homogeneous, translucent, white gel forms. This process may take place as a number of smaller sub-batches. Cellulose Gel Base f) Mix propylene glycol and ethanol 96% until homogeneous. g) While homogenising, add hydroxyethylcellulose until a clear, homogeneous, gel is formed. Final Gel Manufacture h) Add the clindamycin phosphate zinc complex to the base gel and mix until a uniform, white opaque gel is produced. i) Add water to 100% and mix to homogeneity. j) Fill into tubes.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][NH:13][C:14]2=[O:17])=[CH:9][CH:8]=1.[Na+].[I-].[Cl:20][C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[N:28]1[CH2:34][CH2:33][CH2:32][N:31](CCCCOC2C=C3C(CCC(=O)N3)=CC=2)[CH2:30][CH2:29]1.C([O-])([O-])=O.[K+].[K+]>CC#N.O>[Cl:20][C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[N:28]1[CH2:34][CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][NH:13][C:14]3=[O:17])=[CH:9][CH:8]=2)[CH2:30][CH2:29]1
Reactant: O=C1NCCc2ccc(OCCCCBr)cc21
Reactant: O=C1CCc2ccc(OCCCCN3CCCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C1NCCc2ccc(OCCCCN3CCCN(c4cccc(Cl)c4Cl)CC3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
A mixture of intermediate 21 (100 mg, 0.34 mmol) and NaI (102 mg, 0.68 mmol) in CH3CN was heated to reflux for 30 min and then cooled to rt. Intermediate 2 (144 mg, 0.51 mmol) and anhydrous K2CO3 (188 mg, 1.36 mmol) were added to the mixture. The resulting mixture was heated to reflux and stirred overnight. The reaction solution was diluted with water and extracted with EtOAc. The combined EtOAc layers were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with DCM/MeOH=30:1) to give 7-(4-(4-(2,3-dichlorophenyl)-1,4-diazepan-1-yl)butoxy)-3,4-dihydroisoquinolin-1(2H)-one (compound 6) (107 mg, 68%). 1H NMR (300 MHz, CDCl3) δ 7.58 (s, 1H), 7.20-7.09 (m, 3H), 7.02-6.98 (m, 2H), 6.04 (br., 1H), 4.05 (t, J=6.6 Hz, 2H), 3.54-3.52 (m, 2H), 3.32-3.28 (m, 4H), 2.95-2.91 (m, 6H), 2.70-2.68 (m, 2H), 2.06-2.04 (m, 2H), 1.84-1.77 (m, 4H). HPLC: 99%, RT 2.676 min. MS (ESI) m/z 462.4 [M+H]+. mp: 86-88° C.
Reaction SMILES: CC(O[CH2:5][C:6]1[C:11]2=[CH:12][CH:13]=[C:14](C=O)[C:10]2=[CH:9]OC=1)=O.C[N:18](C)CCCN>C(Cl)(Cl)Cl>[CH:9]1[NH:18][CH:5]=[CH:6][C:11]2[C:10]=1[CH:14]=[CH:13][CH:12]=2
Reactant: CN(C)CCCN
Reactant: CC(=O)OCc1cocc2c(C=O)ccc1-2
Solvent: ClC(Cl)Cl
Product: c1cc2cc[nH]cc-2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Baldrinal (2) (12.8 mg) was reacted with 3-(dimethylamino)-1-propylamine (22.5 mg) in 2 ml of chloroform. After stirring for 10 minutes at room temperature, the solution turned red and all the baldrinal was reacted. Compound (9) was separated using column chromatography with silica using 50:1 CHCl3:MeOH solvent system and 2.2 mg of product was collected.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])[N:14]([S:16]([C:19]2[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=2)[O:22][CH2:23][C:24]([O:26]CC)=[O:25])(=[O:18])=[O:17])[CH:15]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].O1CCCC1.Cl>O>[C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])[N:14]([S:16]([C:19]2[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=2)[O:22][CH2:23][C:24]([OH:26])=[O:25])(=[O:18])=[O:17])[CH:15]=1)[CH3:9])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2ccccc2F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccc(OCC(=O)O)c2)c1)C(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
Ethyl 2-(3-((4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-(2-fluorophenyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)acetate 9a (170 mg, 0.31 mmol) and lithium hydroxide (71 mg, 3.0 mmol) were added to 20 mL of a mixed solvent of tetrahydrofuran and water (V/V=1:1) and then the reaction solution was stirred for 3 h. 1M of hydrochloric acid was added dropwise until the pH of the reaction solution was 5, and then it was extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 2-(3-((4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-(2-fluorophenyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)acetic acid 9b (160 mg, a yellow oil), which was used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:19](C2C=CC(F)=CC=2)[C:20]([C:22]2([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]2)=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](I)[S:17][C:10]=12.[C:35]([CH:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]1)#[CH:36]>>[C:25]([C:22]1([C:20]([NH:19][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]3[CH:14]=[CH:13][N:12]=[C:11]4[CH:15]=[C:16]([C:36]#[C:35][CH:37]5[CH2:38][CH2:39][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:41][CH2:42]5)[S:17][C:10]=34)=[C:2]([F:1])[CH:3]=2)=[O:21])[CH2:23][CH2:24]1)(=[O:26])[NH2:27]
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: NC(=O)C1(C(=O)N(c2ccc(F)cc2)c2ccc(Oc3ccnc4cc(I)sc34)c(F)c2)CC1
Product: CC(C)(C)OC(=O)N1CCC(C#Cc2cc3nccc(Oc4ccc(NC(=O)C5(C(N)=O)CC5)cc4F)c3s2)CC1

Procedure:
Prepared from N-(3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Example 12, Step A, 350 mg, 0.592 mmol) and tert-butyl 4-ethynylpiperidine-1-carboxylate (186 mg, 0.888 mmol) using the procedure described for Example 6, Step B. The crude was purified by Biotage Flash 40M eluting with 20% EtOAc/hexanes (500 mL), 1:1 EtOAc/hexanes (1 L), followed by 2:1 EtOAc/hexanes (1.5 L). The product was isolated as a wax (293 mg, 68%). HPLC: 92% purity (254 nm); LRMS (APCI+): m/z 673, 573 (loss of BOC) (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 10.12 (s, 1H), 8.47 (d, J=6 Hz, 1H), 8.33 (s, 1H), 7.77 (m, 1H), 7.44 (m, 2H), 7.25 (m, 3H), 7.06 (t, J=9 Hz, 2H), 6.50 (d, J=6 Hz, 1H), 3.77 (m, 2H), 3.23 (m, 2H), 2.87 (m, 1H), 1.89 (m, 2H), 1.80 (m, 2H), 1.70 (m, 2H), 1.62 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: C(C1C=CC(C(NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(O)=O)C4=O)=CC=3)=NC=2)=O)=CC=1)(C)(C)C.[CH3:37][CH:38]([CH3:74])[C@H:39]([N:44]1[CH2:52][C:51]2[C:46](=[CH:47][C:48]([C:53]3[CH:58]=[N:57][C:56]([NH:59][C:60](=[O:72])[C:61]4[CH:66]=[CH:65][C:64]([O:67][C:68]([F:71])([F:70])[F:69])=[CH:63][CH:62]=4)=[CH:55][N:54]=3)=[CH:49][CH:50]=2)[C:45]1=[O:73])[C:40]([O:42]C)=[O:41]>>[CH3:37][CH:38]([CH3:74])[C@H:39]([N:44]1[CH2:52][C:51]2[C:46](=[CH:47][C:48]([C:53]3[CH:58]=[N:57][C:56]([NH:59][C:60](=[O:72])[C:61]4[CH:66]=[CH:65][C:64]([O:67][C:68]([F:69])([F:70])[F:71])=[CH:63][CH:62]=4)=[CH:55][N:54]=3)=[CH:49][CH:50]=2)[C:45]1=[O:73])[C:40]([OH:42])=[O:41]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3cnc(NC(=O)c4ccc(OC(F)(F)F)cc4)cn3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cn3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3cnc(NC(=O)c4ccc(OC(F)(F)F)cc4)cn3)cc2C1=O
Yield: 38 %

Procedure:
The compound of example 513 was prepared analogous to the compound of example 404 by hydrolysis of the compound of example 512.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]([NH:10][C@H:11]([C:15]([OH:17])=[O:16])[C@@H:12]([CH3:14])[OH:13])=[O:9])=[CH:4][CH:3]=1.[N+](=[CH2:22])=[N-]>C(OCC)C>[CH3:22][O:16][C:15](=[O:17])[C@H:11]([C@@H:12]([CH3:14])[OH:13])[NH:10][C:8](=[O:9])[CH2:7][O:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:19][CH:18]=1
Reactant: C=[N+]=[N-]
Reactant: C[C@@H](O)[C@H](NC(=O)COc1ccc(Cl)cc1)C(=O)O
Solvent: CCOCC
Product: COC(=O)[C@@H](NC(=O)COc1ccc(Cl)cc1)[C@@H](C)O
Reaction time: 0.5 h

Procedure:
After the reaction was completed, the mixture was extracted twice with ethyl ether to eliminate unreacted p-chlorophenoxychloride, and the extracted aqueous phase was acidified with hydrochloric acid to precipitate a product which was then extracted three times with ethyl acetate. The extract was evaporated to dryness, and the residue was recrystallized from ethyl acetate/benzene/hexane to obtain a color-less crystal of N-(p-chlorophenoxy)acetyl-L-threonine. To a solution of 5 m moles of N-(p-chlorophenoxy)acetyl-L-threonine in ethyl ether, a solution of an excess amount of diazomethane in ethyl ether was added, and the mixture was allowed to stand for 30 minutes at a room temperature. The mixture was evaporated to dryness under a reduced pressure to obtain N-(p-chlorophenoxyacetyl)-L-threonine methyl ester. 3.4 m moles of N-(p-chlorophenoxyacetyl)-L-threonine methyl ester was dissolved in dried pyridine, and the resulting solution was added with 3.6 m moles of p-toluenesulfonyl chloride, stirred at 0° C. for two hours and at a room temperature for two hours. The reaction mixture was then partitioned between water and ethyl acetate, and organic phase was washed with 1N hydrochloric acid and water, and dried on anhydrous sodium sulfate. The solution was evaporated to dryness, and the resulting residue was purified by a middle pressure column chromatography with silica gel to obtain N-(p-chlorophenoxyacetyl)-O-(p-toluenesulfonyl)-L-threonine methyl ester. 0.5 m moles of N-(p-chlorophenoxyacetyl)-O-(p-toluenesulfonyl)-L-threonine methyl ester was then dissolved in 10 ml of methanol, the resulting solution was added with 1.5 ml of 1N sodium hydroxide and stirred for 20 minutes at a room temperature, and methanol was distilled off. The residue was acidified with 1N hydrochloric acid, and extracted with ethyl ether, and an organic phase was dried on anhydrous magnesium sulfate. Solvent was distilled off from the mixture to obtain a residue. The residue was then chromatographically purified to obtain the title compound N-(p-chlorophenoxyacetyl)-α,β-dehydrohomoalanine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][C@@H:12]([CH3:15])[CH2:13][OH:14])[C:5]([CH3:16])=[C:4]([CH3:17])[N:3]=1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[Si:18]([O:14][CH2:13][C@@H:12]([NH:11][C:6]1[C:5]([CH3:16])=[C:4]([CH3:17])[N:3]=[C:2]([Cl:1])[C:7]=1[N+:8]([O-:10])=[O:9])[CH3:15])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(N[C@@H](C)CO)c1C
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cc1nc(Cl)c([N+](=O)[O-])c(N[C@@H](C)CO[Si](C)(C)C(C)(C)C)c1C
Temperature: 50 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
(2S)-2-[(2-Chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]propan-1-ol (3.62 g, 13.9 mmol) was dissolved in 30 mL of dry pyridine under an atmosphere of N2. tert-Butyldimethylsilyl chloride (2.52 g, 16.7 mmol) and DMAP (0.17 g, 1.39 mmol) were added sequentially, and the reaction was heated to 50° C. and stirred overnight. The reaction mixture was then concentrated under reduced pressure. The resulting residue was partitioned between 50 mL of ethyl acetate and 50 mL of H2O. The layers were separated and the organic portion was washed with H2O and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting material was passed through a plug of SiO2, eluting with a mixture of CH2Cl2, ethyl acetate and hexanes, to afford N-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)-2-chloro-5,6-dimethyl-3-nitropyridin-4-amine (4.79 g) as an orange oil.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([C:11](=[O:28])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:14][C:13]=2[O:23][CH2:24][CH:25]([CH3:27])[CH3:26])[CH:8]=[CH:7][C:6]=1[O:29][CH2:30][CH:31]([CH3:33])[CH3:32])(=O)C.[OH-].[Na+].O.Cl>C(O)C.C(Cl)(Cl)Cl>[CH2:24]([O:23][C:13]1[CH:14]=[C:15]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH:16]=[CH:17][C:12]=1[C:11]([C:9]1[CH:8]=[CH:7][C:6]([O:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[C:5]([OH:4])[CH:10]=1)=[O:28])[CH:25]([CH3:27])[CH3:26]
Reactant: CC(=O)Oc1cc(C(=O)c2ccc(OCC(C)C)cc2OCC(C)C)ccc1OCC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CC(C)COc1ccc(C(=O)c2ccc(OCC(C)C)c(O)c2)c(OCC(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
In 10 ml of ethanol is dissolved 0.48 g of 5-(2,4-diisobutoxybenzoyl)-2-isobutoxyphenyl acetate, to which is added 3.2 ml of 1 mol/L solution of sodium hydroxide. The mixture thus obtained is stirred at ambient temperature for one hour. Water and chloroform are added to the reaction mixture, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried on anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Thus, 0.40 g of (2,4-diisobutoxyphenyl)(3-hydroxy-4-isobutoxyphenyl)methanone is obtained as a light yellow solid product.
Reaction SMILES: [C:1]1(=[O:18])[N:5]([CH:6]2[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]2)[C:4](=[O:13])[C:3]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:2]12.[NH:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)N>C(O)(=O)C>[C:25]([C:24]1[CH:23]=[C:22]2[C:21](=[CH:29][CH:28]=1)[NH:19][C:9]1[CH2:10][CH2:11][CH:6]([N:5]3[C:4](=[O:13])[C:3]4=[CH:14][CH:15]=[CH:16][CH:17]=[C:2]4[C:1]3=[O:18])[CH2:7][C:8]2=1)([OH:27])=[O:26]
Reactant: O=C1CCC(N2C(=O)c3ccccc3C2=O)CC1
Reactant: NNc1ccc(C(=O)O)cc1
Solvent: CC(=O)O
Product: O=C(O)c1ccc2[nH]c3c(c2c1)CC(N1C(=O)c2ccccc2C1=O)CC3
Reaction time: 12 h
Yield: 41.7 %

Procedure:
A mixture of 4-phthalimidocyclohexanone (2.43 g) and 4-hydrazinobenzoic acid (1.52 g) were combined in acetic acid and boiled for 12 hours. The precipitate was filtered and washed with acetic acid (3×10 ml) and diethyl ether (3×10 ml) to give 6-carboxy-3-phthalimido-1,2,3,4-tetrahydrocarbazole (1.50 g) m.p. 345°-348° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C([Li])(C)(C)C.[B:18](OCCCC)([O:24]CCCC)[O:19]CCCC>CCOCC>[C:9]([CH:8]([C:4]1[CH:3]=[C:2]([B:18]([OH:24])[OH:19])[CH:7]=[CH:6][CH:5]=1)[CH3:12])([OH:11])=[O:10]
Reactant: CCCCOB(OCCCC)OCCCC
Reactant: CC(C(=O)O)c1cccc(Br)c1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CC(C(=O)O)c1cccc(B(O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(3-bromo-phenyl)-propionic acid [500 mg, 2.18 mmol, Intermediate (69)] in anhydrous ether (20 mL) is added tert-butyl lithium (1.7 M in pentane, 5.4 mL, 9.16 mmol) dropwise at −78° C. and this mixture is stirred for 30 minutes treated with tributyl borate (2.34 mL, 8.72 mmol). The reaction mixture is allowed to warm up to room temperature, stirred for 15 hours, diluted with ether, and quenched with 1 M H3PO4. After stirring for 30 minutes the ether layer is separated and extracted three times with 2 N sodium hydroxide (20 mL). The combined sodium hydroxide extracts are acidified with 6 N hydrochloric acid to pH=1 and extracted three times with ether (50 mL). The combined organic extracts are washed with brine, dried over sodium sulfate and concentrated to obtain 3-(1-carboxy-ethyl)-phenyl boronic acid [Intermediate (70)] as a solid, which is used without further purification.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)(=[O:12])=[O:11])[C:3]=1[C:4]#[N:5].[NH4+:21].[OH-]>CO.CCO>[NH2:21][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)(=[O:12])=[O:11])[C:3]=1[C:4]#[N:5]
Reactant: COc1cccc(S(=O)(=O)c2cccc(F)c2C#N)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: COc1cccc(S(=O)(=O)c2cccc(N)c2C#N)c1
Temperature: 130 °C

Procedure:
To a solution of 0.7 g (2.4 mmol) of 2-fluoro-6-[(3-methoxyphenyl)sulfonyl]benzonitrile (Example 14) in 110 ml of MeOH/EtOH (7:4) was added 20 mL of concentrated NH4OH, This mixture was sealed in a glass-lined bomb and heated at 130° C. for 3 h. After solvent removal, the resultant concentrate was purified by flash column chromatography on silica gel with 5% MeOH in methylene chloride as the eluent. This resulted in 0.16 g (23%) of 2-amino-6-[(3-methoxyphenyl)sulfonyl]benzonitrile as a solid: mp 186°-191° C.; NMR (Me2SO-d6, 200MHz) δ 3.82 (s, 3H), 6.6 (br s, 2H), 7.1 (apparent d, 1H), 7.2-7.7 (m, 6H); mass spec (CI) 289 (M+ +1, 100%). Anal. Calc. for C14H12N2 O3S: C, 58.32; H, 4.20;N, 9.72; S, 11.12. Found: C, 58.13; H, 4.17; N, 9.51; S, 10.95.
Reaction SMILES: [O:1]=[C:2]([C:5]1([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9][N:8](C(OCC)=O)[CH2:7][CH2:6]1)[CH2:3][CH3:4].[OH-].[K+]>CC(O)C>[C:17]1([NH:16][C:5]2([C:2](=[O:1])[CH2:3][CH3:4])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)N1CCC(Nc2ccccc2)(C(=O)CC)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: CCC(=O)C1(Nc2ccccc2)CCNCC1

Procedure:
A mixture of 10.2 parts of ethyl 4-(1-oxopropyl)-4-(phenylamino)-1-piperidinecarboxylate, 19.8 parts of potassium hydroxide and 90 parts of 2-propanol is stirred and refluxed for 4 hours. The reaction mixture is evaporated and 200 parts of water are added to the residue. The whole is concentrated to a volume of about 100 parts. The product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silicagel using a mixture of trichloromethane and 10% of methanol, previously saturated with ammonia, as eluent. The pure fractions are collected and the eluent is evaporated, yielding 1-[4-(phenylamino)-4-piperidinyl]-1-propanone as a residue.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[NH2:15][C:16]1[C:24]2[C:19](=[N:20][C:21]([CH3:27])=[CH:22][C:23]=2[CH2:25][OH:26])[S:18][C:17]=1[C:28]([NH2:30])=[O:29].O[C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[O:37])=[CH:34][CH:33]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[NH2:15][C:16]1[C:24]2[C:19](=[N:20][C:21]([CH3:27])=[CH:22][C:23]=2[CH2:25][O:26][C:32]2[CH:40]=[CH:39][C:35]([C:36](=[O:37])[NH2:38])=[CH:34][CH:33]=2)[S:18][C:17]=1[C:28]([NH2:30])=[O:29]
Reactant: NC(=O)c1ccc(O)cc1
Reactant: Cc1cc(CO)c2c(N)c(C(N)=O)sc2n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(COc2ccc(C(N)=O)cc2)c2c(N)c(C(N)=O)sc2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
DIAD (23 mg, 0.116 mmol) was added to a solution of 3-amino-4-hydroxymethyl-6-methyl-thieno[2,3-b]pyridine-2-carboxylic acid amide (see Example 12) (25 mg, 0.105 mmol), 4-hydroxy-benzamide (15 mg, 0.116 mmol), and Ph3P (30 mg, 0.116 mmol) in THF (2.5 mL) at 0° C. The mixture was warmed to room temperature and stirred for 24 h. The reaction mixture was concentrated and triturated with 2:1 EtOAc:MeOH giving the title compound (7 mg, 19%) as an orange solid, m.p. >250° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[C:20]([F:25])[CH:19]=1>C(O)(C)C>[ClH:2].[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[CH:5][N:4]=2)=[C:20]([F:25])[CH:19]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1ccc(Cl)cc1F
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2ncnc(Nc3ccc(Cl)cc3F)c2cc1OC
Yield: 49.2 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxyquinazoline hydrochloride (147 mg, 0.56 mmol), (prepared as described for the starting material in Example 2), and 4-chloro-2-fluoroaniline (82 mg, 0.56 mmol) in isopropanol (7 ml) was heated at reflux for 2 hours. The mixture was allowed to cool, the solid product collected by filtration, washed with isopropanol and dried to give 4-(4-chloro-2-fluoroanilino)-6,7-dimethoxyquinazoline hydrochloride (102 mg, 49%).
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@H:13]([C@@H:14]([C@@H:16]([CH2:18][OH:19])[OH:17])[OH:15])[O:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C@@H:6]1[NH2:20])(=[O:3])[CH3:2].C(N(CC)CC)C.CS[C:30](=[NH:35])[NH:31][N+:32]([O-:34])=[O:33]>CO>[C:1]([NH:4][C@H:5]1[C@H:13]([C@@H:14]([C@@H:16]([CH2:18][OH:19])[OH:17])[OH:15])[O:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C@@H:6]1[NH:20][C:30]([NH2:35])=[N:31][N+:32]([O-:34])=[O:33])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(C(=O)O)=C[C@@H]1N
Reactant: CSC(=N)N[N+](=O)[O-]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(C(=O)O)=C[C@@H]1NC(N)=N[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 2 h
Yield: 19.2 %

Procedure:
5-(Acetylamino)-4-amino-2,6-anhydro-3,4,5-trideoxy-D-glycero-D-galacto-non-2-enonic acid (200 mg, 0.689 mmol) was dissolved in absolute methanol (2.7 ml) by the addition of triethylamine (0.098 ml, 0.690 mmol). 2-Methyl-1-nitro-2-thiopseudourea (103 mg,0.757 mmol) was then added. The mixture was warmed to 40° C. with stirring under nitrogen for 2hrs, then stirred at 21° C. for 16 hr. The addition of reagent and heating and stirring was repeated twice more. The cooled mixture was then filtered and the white solid washed with methanol. Combined filtrate and washings were evaporated and the residue purified by ion exchange chromatography (Dowex 50 W×8(H+) resin, eluting with water. Appropriate fractions were combined and freeze dried. The residue was triturated with warm water (4 ml), and the off-white solid filtered and dried under high vacuum to give the title product (Yield =50 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][N:13]([CH3:28])[CH2:14][CH2:15][NH:16][C:17]([C:19]1[C:23]([CH3:24])=[C:22]([CH:25]=O)[NH:21][C:20]=1[CH3:27])=[O:18]>>[CH3:12][N:13]([CH3:28])[CH2:14][CH2:15][NH:16][C:17]([C:19]1[C:23]([CH3:24])=[C:22]([CH:25]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[NH:21][C:20]=1[CH3:27])=[O:18]
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN(C)C
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(Cl)cc32)c(C)c1C(=O)NCCN(C)C
Yield: 94.8 %

Procedure:
5-Chloro-1,3-dihydroindol-2-one (0.1 g, 0.6 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-dimethylaminoethyl)amide (0.15 g) to give 0.22 g (90%) of the title compound as a yellow solid.