Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[S:15][C:16]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[C:17]([C:19]#[N:20])[N:18]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[O:29]1CCCC1.O>O>[C:1]([O:5][C:6](=[O:28])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[S:15][C:16]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[C:17]([C:19](=[O:29])[NH2:20])[N:18]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2nc(C#N)c(Nc3ccccn3)s2)C1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2nc(C(N)=O)c(Nc3ccccn3)s2)C1
Temperature: 150 °C

Procedure:
A solution of {(R)-1-[4-cyano-5-(pyridin-2-ylamino)-thiazol-2-yl]-piperidin-3-yl}-carbamic acid tert-butyl ester (455 mg, 1.14 mmol) in 10:1 v/v tetrahydrofuran/water (16.5 mL total volume) was degassed by bubbling in argon for 10 minutes with stiffing. Hydrido-(dimethylphosphinous acid-kP)[hydrogen bis(dimethylphosphnito-kP]platinum (II) (CAS number 173416-05-2) (78 mg, 183 μmol) was added and the mixture was heated to 150° C. by microwave for 45 minutes. The reaction mixture was cooled to ambient temperature, poured into water (150 mL) and extracted with 1:1 v/v tetrahydrofuran/ethyl acetate (4×50 mL), the combined organic extracts were washed with brine (2×40 mL), dried over sodium sulfate, filtered and concentrated in vacuo to a yellow solid. The crude product was purified by chromatography using silica gel gradient eluted from 30% up to 70% v/v ethyl acetate in hexanes. The product containing fractions were combined and concentrated in vacuo to obtain {(R)-1-[4-carbamoyl-5-(pyridin-2-ylamino)-thiazol-2-yl]-piperidin-3-yl}-carbamic acid tert-butyl ester as an off white solid (362 mg, 76%). LC/MS: m/z calculated for C19H26N6O3S ([M−H]−): 417.5. Found: 417.4 (negative mode electrospray ionization).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([C:20](=[O:32])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][C:29](O)=[O:30])[CH:22]=2)=[N:8][CH:7]=1)=[O:5])C.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[CH3:17][O:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[O:18][CH3:19])[C:9]([C:20](=[O:32])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][C:29]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[O:30])[CH:22]=1)=[N:8][CH:7]=[C:6]2[C:4]([OH:3])=[O:5]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1cnc(C(=O)c2cccc(OCC(=O)O)c2)c2cc(OC)c(OC)cc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(C(=O)O)cnc(C(=O)c3cccc(OCC(=O)N4CCOCC4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
To a solution of 1-(3-carboxymethoxybenzoyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid ethyl ester (93.3 mg, 0.20 mmol) in 8 ml of methylene chloride was added 10 equivalent of morpholine, 1.2 equivalent of HBTU and 4 equivalent of triethylamine. The mixture was stirred at room temperature overnight. The solvents were evaporated and the residue was extracted with ethyl acetate and water. The organic phase was dried and solvents were evaporated. The residue was dissolved in 4 ml of methanol and aqueous lithium hydroxide was added (0.5N, 1 ml). The mixture was stirred overnight until all starting material disappeared. The reaction was loaded on a preparative HPLC for purification to give 6,7-Dimethoxy-1-[3-(2-morpholin-4-yl-2-oxo-ethoxy)-benzoyl]-isoquinoline-4-carboxylic acid as a fluffy solid (20 mg, 21%). ES-MS calcd for C25H24N2O8 (m/e) 480.5, obsd 481.3 (M+H).
Reaction SMILES: [OH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[CH:3]=1.[C:9]1([CH3:18])[C:10]([N:15]=[C:16]=[O:17])=[CH:11][CH:12]=[CH:13][CH:14]=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:16]([NH:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH3:18])=[O:17]
Reactant: Cc1cc(O)n(C)n1
Reactant: Cc1ccccc1N=C=O
Solvent: Cc1ccccc1C
Product: Cc1ccccc1NC(=O)c1c(C)nn(C)c1O

Procedure:
A mixture of 22.4 g (0.2 mol) 5-hydroxy-1,3-dimethyl-1H-pyrazole [K. Auwers, J.Prakt.Chem., 110, 153 (1925)], 26.6 g (0.2 mol) o-tolylisocyanate in 150 ml xylene containing 1 ml triethylamine is heated to reflux for 1.5 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]4[CH:19]=[CH:20][C:21]([C:23](O)=[O:24])=[CH:22][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[NH2:28][CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:33][N:32]([CH3:34])[C:30]([CH2:29][NH:28][C:23]([C:21]1[CH:20]=[CH:19][C:13]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:27]=[CH:26][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:22]=1)=[O:24])=[O:31]
Reactant: COCCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CN(C)C(=O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCC(=O)N(C)C)ccc21
Yield: 24.8 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carboxylic acid dimethylcarbamoylmethyl-amide (24 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carboxylic acid (80 mg), 2-amino-N,N-dimethyl-acetamide (40 mg), HBTU (95 mg), and DIEA (70 uL) in DMF (1 mL). LC/MS: m/z 486.5. 1H NMR (DMSO-d6, 400 MHz): δ 8.57-8.56 (m, 1H), 8.11 (s, 1H), 8.01-8.00 (d, 1H), 7.84-7.82 (m, 1H), 7.63-7.61 (d, 1H), 7.57-7.54 (d, 1H), 7.46-7.44 (m, 1H), 4.43-4.40 (t, 2H), 4.14-4.13 (d, 2H), 3.75-3.72 (t, 2H), 3.24 (s, 3H), 3.04 (s, 3H), 2.87 (s, 3H), —NH proton signal was not observed.
Reaction SMILES: [S:1]1[C:5](B(O)O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.Br[C:14]1[CH:27]=[CH:26][C:17]([O:18][CH2:19][CH2:20][N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:16][CH:15]=1>>[S:1]1[C:5]([C:14]2[CH:27]=[CH:26][C:17]([O:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:16][CH:15]=2)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: OB(O)c1cc2ccccc2s1
Reactant: Brc1ccc(OCCN2CCCC2)cc1
Product: c1ccc2sc(-c3ccc(OCCN4CCCC4)cc3)cc2c1
Yield: 76 %

Procedure:
By essentially following the procedure detailed in Example 1, Part B, the title compound was prepared from benzo[b]thiophene-2-boronic acid and 1-[2-(4-bromophenoxy)ethyl]pyrrolidine in 76% yield as a white solid following flash chromatography (SiO2; 36:4:60 THF-TEA-hexanes).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]2[N:9]=[C:10]([N:15]([CH3:36])[C:16]3[CH:17]=[C:18]([NH:22][C:23](=[O:35])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([C:33]#[N:34])([CH3:32])[CH3:31])[CH:25]=4)[CH:19]=[CH:20][CH:21]=3)[N:11]=[CH:12][C:13]=2[N:14]=1)=[O:4].C(N(CC)CC)C.[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.C(=O)([O-])O.[Na+]>O1CCCC1>[C:33]([C:30]([C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[C:23]([NH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([N:15]([CH3:36])[C:10]2[N:11]=[CH:12][C:13]3[N:14]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)[S:7][C:8]=3[N:9]=2)[CH:17]=1)=[O:35])([CH3:32])[CH3:31])#[N:34]
Reactant: C1COCCN1
Reactant: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(NC(=O)CCl)sc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(NC(=O)CN3CCOCC3)sc2n1
Temperature: 60 °C
Reaction time: 4 h
Yield: 65.3 %

Procedure:
To a solution of N-{3-[{2-[(chloroacetyl)amino][1,3]thiazolo[5,4-d]pyrimidin-5-yl}(methyl)amino]phenyl}-3-(1-cyano-1-methylethyl)benzamide (141 mg, 271 μmol) produced in Example D10 in tetrahydrofuran (4 mL) were added triethylamine (113 μL, 813 μmol) and morpholine (71 μL, 813 μmol), and the mixture was stirred at 60° C. for 4 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL), and the mixture was extracted with ethyl acetate (15 mL, 10 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0=98/2), and the fractions containing the object product were concentrated under reduced pressure. To the obtained residue were added diisopropyl ether and ethyl acetate, and the precipitate was collected by filtration to give the title compound (101 mg, 50%) as a pale-red amorphous solid.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[NH2:6][C:7]1[N:8]=[C:9](O)[C:10]2[CH:15]([C:16]([O:18][CH3:19])=[O:17])[CH2:14][CH2:13][C:11]=2[N:12]=1>>[NH2:6][C:7]1[N:8]=[C:9]([Cl:3])[C:10]2[CH:15]([C:16]([O:18][CH3:19])=[O:17])[CH2:14][CH2:13][C:11]=2[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)C1CCc2nc(N)nc(O)c21
Product: COC(=O)C1CCc2nc(N)nc(Cl)c21
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
Phosphorus oxychloride (16.0 mL, 172 mmol) was added to methyl 2-amino-4-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxylate (5.84 g, 27.9 mmol). The resulting mixture was heated in a sealed tube at 100° C. in the microwave for 3 hours. The solvent was evaporated. The residue was dissolved in 6 mL acetonitrile and 6 mL ice/water was added. The resulting mixture was stirred at RT for 15 minutes and purified by reverse phase preparative HPLC on a SunFire column using a gradient from 0 to 100% acetonitrile over 10 minutes (11 injections) to afford the title compound. Additional product was obtained by re-purification of mixed fractions: LC/MS (M+H)=228, 230.
Reaction SMILES: [CH2:1]([P:8]([O:13][CH2:14][CH3:15])(=[O:12])[O:9][CH2:10][CH3:11])[CH:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH3:7].CI.[CH2:18](P(OCC)(=O)OCC)C=CC.C(Br)C1C=CC=CC=1>>[CH3:18][CH:1]([P:8]([O:9][CH2:10][CH3:11])(=[O:12])[O:13][CH2:14][CH3:15])[CH:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CC=CCP(=O)(OCC)OCC
Reactant: CCCCC=CCP(=O)(OCC)OCC
Agent: BrCc1ccccc1
Solvent: CI
Product: CCCCC=CC(C)P(=O)(OCC)OCC
Yield: 89.9 %

Procedure:
The same procedure as in Example A-1 was repeated except that 2,34 g of diethyl 2-heptenephosphonate and 1.42 g of methyl iodide were used instead of 1.92 g of the diethyl 2-butenephosphonate and 1.7 g of the benzyl bromide respectively. Vacuum distillation of the reaction mixture afforded 2.23 g of diethyl 1-methyl-2-heptene-phosphonate having a boiling point of 128° C. (3 mmHg) in a yield of 90%.
Reaction SMILES: II.Br[C:4]1[CH:9]=[CH:8][C:7](Cl)=[C:6](OCC)[CH:5]=1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[C:14]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOc1cc(Br)ccc1Cl
Reactant: O=C(Cl)c1ccccc1
Agent: II
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
8.7 g (357.06 mmol) of Mg and a small amount of iodine were dissolved in 200 ml of THF, and 84.6 g (324.6 mmol) of 1-bromo-4-chloro-3-ethoxybenzene dissolved in 500 ml of THF was added dropwise to the resulting solution. After addition, the resulting mixture was refluxed for 3 hours to prepare a Grignard reagent which was then cooled to room temperature. Thereafter, a Grignard reagent containing 50.2 g (357.06 mmol) of benzoyl chloride was added dropwise to the obtained product and stirred for 5 hours. After a reaction, the reaction solution was washed with water, the solvent was removed, and the obtained product was purified by column chromatography to obtain a benzophenone derivative represented by the following formula (42) as 29.6 g (113.6 mmol, yield of 35%) of a white solid.
Reaction SMILES: C(O[CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7])C.Cl.[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:20])=[C:16]([NH:18][NH2:19])[CH:17]=1.C(N(CC)C(C)C)(C)C>CO>[NH2:9][C:8]1[N:18]([C:16]2[CH:17]=[C:12]([F:11])[CH:13]=[CH:14][C:15]=2[CH3:20])[N:19]=[CH:4][C:5]=1[C:6]#[N:7]
Reactant: Cc1ccc(F)cc1NN
Reactant: CCOC=C(C#N)C#N
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)cc1-n1ncc(C#N)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.11 %

Procedure:
(Ethoxymethylene)malononitrile (CAS no. 123-06-8) (3.18 g, 26.04 mmol) was added portionwise to the stirred solution of (5-fluoro-2-methylphenyl)hydrazine hydrochloride (CAS no. 325-50-8) (4.6 g, 26.04 mmol) and N,N-diisopropylethylamine (5.90 mL, 33.86 mmol) in MeOH (50 mL), under nitrogen at 5° C. The resulting solution was allowed to stir for a further 30 minutes at this temperature. The reaction mixture was then heated to reflux and was stirred for 3 hours. The reaction mixture was allowed to cool to ambient temperature. The reaction mixture was evaporated to dryness, redissolved in EtOAc (200 mL), washed with water (50 mL), and saturated brine (50 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. This was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane to afford the product (1.076 g, 19.11%). 1H NMR (400 MHz, DMSO) δ 2.00 (3H, s), 6.56 (2H, s), 7.20 (1H, dd), 7.29 (1H, td), 7.43 (1H, t), 7.75 (1H, s); m/z (ES+) (M+H)+=217; HPLC tR=1.61 min.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([NH2:20])=[CH:19][C:14]=2[O:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:20][C:18]1[CH:17]=[CH:16][C:15]2[O:11][CH2:12][O:13][C:14]=2[CH:19]=1)([O-:10])=[O:9]
Reactant: Nc1ccc2c(c1)OCO2
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1Nc1ccc2c(c1)OCO2
Yield: 64.5 %

Procedure:
9.3 g (66 mmol) of 2-fluoro-nitrobenzene and 10 g (73 mmol) of benzo[d][1,3]dioxol-5-ylamine were dissolved in N,N-dimethylformamide (60 mL) and 10.9 g (79 mmol) of potassium carbonate was added thereto. Mixed solution was heated to reflux for 10 hours while stirring. The reaction mixture was poured into water, and extracted with ethyl acetate. The extracted organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (developing solvent: ethyl acetate:hexane=1:3), to obtain 11 g (yield: 65%) of N-(2-nitrophenyl)benzo[d][1,3]dioxol-5-ylamine as red-purple crystals.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]([F:23])([F:22])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=2)[N:3]=1.[NH2:24][C:25]1[CH:29]=[C:28]([CH3:30])[N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[N:26]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:22][C:14]([F:23])([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=1)[C:4]1[N:3]=[C:2]([NH:24][C:25]2[CH:29]=[C:28]([CH3:30])[N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[N:26]=2)[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1cc(N)nn1C(=O)OC(C)(C)C
Reactant: COc1ccc2c(Cl)nc(C(F)(F)c3ccc(F)cn3)nc2c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(Nc3cc(C)n(C(=O)OC(C)(C)C)n3)nc(C(F)(F)c3ccc(F)cn3)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.8 %

Procedure:
To 4-chloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)-7-methoxyquinazoline (355 mg, 0.91 mmol) in DMF (5.0 mL) at rt were added tert-butyl 3-amino-5-methyl-1H-pyrazole-1-carboxylate (0.448 g, 2.27 mmol) and DIEA (0.40 mL, 2.3 mmol), and the mixture was stirred at rt for 3 h. The mixture was purified by preparative reverse-phase HPLC using TFA as a modifier, and the fractions containing the desired product were neutralized with saturated aq NaHCO3 and extracted with EtOAc (100 mL). The organic layer was separated, washed with brine (2×10 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to afford tert-butyl 3-(2-(difluoro(5-fluoropyridin-2-yl)methyl)-7-methoxyquinazolin-4-ylamino)-5-methyl-1H-pyrazole-1-carboxylate as a clear oil (104 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH:10]=O)=[CH:3][CH:2]=1.[C:15]([O:19][C:20](=[O:29])[NH:21][CH:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1)([CH3:18])([CH3:17])[CH3:16].[BH4-].[Na+].C([O-])([O-])=O.[Na+].[Na+]>CO>[C:15]([O:19][C:20](=[O:29])[NH:21][CH:22]1[CH2:23][CH2:24][CH:25]([NH:28][CH2:10][C:9]2[CH:12]=[CH:13][CH:14]=[C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH:8]=2)[CH2:26][CH2:27]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Reactant: O=Cc1cccc(-c2ccncc2)c1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCC(NCc2cccc(-c3ccncc3)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
To a solution of 3-pyridinyl benzaldehyde (10) (205 mg, 1.1 mmol) in methanol (20 ml) was added NT-Boc-1,4-diaminocyclohexane (6) (300 mg, 1.4 mmol), and the mixture was stirred at room temperature for 30 min. To this solution was added NaBH4 (0.5 g, 13.2 mmol) in portions at 0° C., and the reaction mixture was stirred at room temperature overnight. The reaction was worked up by addition of saturated aqueous Na2CO3 (2 ml), and the mixture was then extracted with chloroform (3×6 ml). The combined organic layers were dried over anhydrous MgSO4. The solvent was removed under vacuum and the residue was purified by a flash chromatography on silica gel (CH2Cl2/MeOH=10/1) to give 18 (398 mg) in 95% yield; 1H NMR (300 MHz, CDCl3): 8.66 (d, J=8.1 Hz, 2H), 7.39-7.61 (m, 6H), 4.30-4.50 (br, 1H), 3.88 (s, 2H), 3.30-3.50 (br, 1H), 2.40-2.60 (m, 1H), 1.90-2.10 (m, 4H), 1.70-1.90 (br, 1H), 1.44 (s, 9H), 1.06-1.40 (m, 4H) 13C NMR (75 MHz, CDCl3): 155.2, 150.0, 148.3, 141.5, 138.1, 129.1, 128.7, 126.6, 125.5, 121.6, 79.0, 55.6, 51.0, 49.4, 31.9, 28.3; HRMS (ESI) calcd for C23H31N3O2 (M+H+) 382.24890; found 382.24896.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[S:9][C:8]=1[C:16]([O:18][CH3:19])=[O:17])[CH3:2].OO.NC(N)=[O:25].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>CC#N>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[C:15]2[C:10](=[N+:11]([O-:25])[CH:12]=[CH:13][CH:14]=2)[S:9][C:8]=1[C:16]([O:18][CH3:19])=[O:17])[CH3:2]
Reactant: CCOC(=O)COc1c(C(=O)OC)sc2ncccc12
Reactant: NC(N)=O
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: CCOC(=O)COc1c(C(=O)OC)sc2c1ccc[n+]2[O-]
Temperature: 70 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
To a mixture of methyl 3-(2-ethoxy-2-oxoethoxy)thieno[2,3-b]pyridine-2-carboxylate (500 mg), urea hydrogen peroxide (239 mg) and CH3CN (8 mL) was added TFAA (0.353 mL) at room temperature. The mixture was stirred at room temperature for 4 h and at 70° C. overnight. To the mixture were added urea hydrogen peroxide (80 mg) and TFAA (0.118 mL). The mixture was stirred at 70° C. for 2 h. After cooling, to the mixture was added saturated aqueous NaHCO3. The resulting precipitate was collected by filtration to give the title compound (246 mg). The filtrate was concentrated. The residue was extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo to give the title compound (85.1 mg). Total yield: 331 mg.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[CH:2].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)#[CH:2]
Reactant: C1COCCN1
Reactant: C#Cc1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: C#Cc1cccc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
To a mixture of 3-ethynylbenzaldehyde (650 mg, 5 mmol) and morpholine (0.87 mL, 10 mmol) in DCE (15 mL) was added NaBH(OAc)3 (1.325 g, 6.25 mmol), followed by AcOH (0.2 mL). The resulting mixture was stirred for 2 h at rt. Aqueous workup followed by extraction with EtOAc gave crude 4-(3-ethynylbenzyl)morpholine (0.98 g) as a light brown oil. The title compound (1.75 g, quantitative yield over 2 steps) was obtained as a light brown oil using the method (PhCH3=12 mL, 1 mol % HRuCl(CO)(PPh3)3, 50° C., 2 h) for the preparation of Example A42A. 1H NMR (400 MHz, CDCl3) δ7.47 (s, 1H), 7.46-7.37 (m, 2H), 7.35-7.27 (m, 2H), 6.19 (d, J=18.4 Hz, 1H), 3.78-3.68 (m, 4H), 3.52 (s, 2H), 2.52-2.42 (m, 4H), 1.32 (s, 12H); MS ESI 330.1 [M+H]+, calcd for [C19H28BNO3+H]+ 330.2.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][OH:41])=[CH:33][C:32]=2[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:53][S:54](Cl)(=[O:56])=[O:55].Cl>ClCCl>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][O:41][S:54]([CH3:53])(=[O:56])=[O:55])=[CH:33][C:32]=2[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCO)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCOS(C)(=O)=O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazole (0.1 g) and triethylamine (0.026 mL) in dichloromethane (3 mL) was added methanesulfonyl chloride (0.013 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with ethylacetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-5-isopropyl-4-({4-[3-(methanesulfonyloxy)propoxy]-2-methylphenyl}methyl)-1H-pyrazole (0.11 g). This material was dissolved in a solution of acetonitrile (2 mL) and methanol (2 mL). To the solution were added 3-benzylaminopropionamide (46 mg) and sodium iodide (24 mg), and the mixture was stirred at 60° C. for 3 days. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1-10/1) to give the title compound (78 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:13][N:14]1[CH:18]=[C:17]([S:19](Cl)(=[O:21])=[O:20])[N:16]=[CH:15]1>>[CH3:13][N:14]1[CH:18]=[C:17]([S:19]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:21])=[O:20])[N:16]=[CH:15]1
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2cn(C)cn2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 1-methylimidazole-4-sulfonyl chloride as described in the synthetic METHOD B to give a white solid (3.2 mg) with purity >90%. LCMS (pos) m/z 331.0.