Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]1([NH:10][C:11]2[C:12]3[CH:19]=[CH:18][N:17]([C@@H:20]4[CH2:24][C@@H:23]([CH2:25][OH:26])[C@@H:22]([OH:27])[C@H:21]4[OH:28])[C:13]=3[N:14]=[CH:15][N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Si:29](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].N1C=CN=C1>CN(C=O)C>[Si:29]([O:26][CH2:25][C@@H:23]1[CH2:24][C@@H:20]([N:17]2[C:13]3[N:14]=[CH:15][N:16]=[C:11]([NH:10][C@@H:1]4[C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[CH2:3][CH2:2]4)[C:12]=3[CH:19]=[CH:18]2)[C@H:21]([OH:28])[C@@H:22]1[OH:27])([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC[C@@H]1C[C@@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)[C@H](O)[C@@H]1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)[C@H](O)[C@@H]1O
Reaction time: 1 h

Procedure:
A solution of (1R,2S,3R,5S)-3-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-5-(hydroxymethyl)cyclopentane-1,2-diol (166 mg, 0.436 mmol, as prepared in Example 15a), tert-butyldimethylsilyl chloride (69.0 mg, 0.458 mmol), 1H-imidazole (44.6 mg, 0.654 mmol) in DMF (2.00 mL) was stirred under an atmosphere of nitrogen. After 2 h additional tert-butyldimethylsilyl chloride (6.00 mg, 0.0365 mmol) was added and the solution was stirred for 1 hour. The reaction was quenched with water and extracted with EtOAc. The combined organics were washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue filtered through a plug of silica gel eluting with 60% EtOAc in hexanes to afford the title compound as an off white solid (179 mg, 83%). LC/MS: Rt=1.51 min, ES+ 495 (FA standard).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:6][C:7]1[CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=[CH:11][C:12]=1[O:13]C)[CH:4]=[CH2:5]>CS(C)=O>[CH2:3]([O:6][C:7]1[CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=[CH:11][C:12]=1[OH:13])[CH:4]=[CH2:5]
Reactant: C=CCOc1cc([N+](=O)[O-])ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: C=CCOc1cc([N+](=O)[O-])ccc1O
Temperature: 65 °C

Procedure:
To one liter of dimethyl sulfoxide was added 750 mL of 2 N aqueous sodium hydroxide and the mixture was heated to 65° C. The pale yellow solid 3-allyloxy-4-methoxynitrobenzene prepared above was added in portions over a 30 minute period and then the temperature was raised to 95° C. and maintained for 3 hours, after which time the starting material had been consumed. The mixture was allowed to cool and poured into a mixture of 1 L ice and 1 L 2 N HCl. 73 Grams of crude but homogeneous (by tlc 1:1 CH2Cl2/hexane) desired product was isolated as a light brown solid by filtration. This material was subsequently dissolved in 1:1 hexane/methylene chloride and filtered through silica gel to give 68 g of pale yellow solid, which, when recrystallized from ethyl/acetate/hexane, gave m.p. 61-62° C. The aqueous mother liquors from the initial crystallization above were extracted with 2 L of ethyl acetate. This was dried over sodium sulfate, filtered and evaporated to a dark oil. Column chromatography on silica with 1:1 CH2Cl2/hexane gave an additional 12 g of the title compound as a yellow solid. Elution with 2% MeOH in CHCl3 gave 12 g of a dark oil which slowly crystallized in vacuum. This proved to be the Claisen product, 3-allyl-4-nitrocatechol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37][NH2:38]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:29])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:38][CH2:37][C:36]4[CH:39]=[CH:40][CH:41]=[C:34]([O:33][CH3:32])[CH:35]=4)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: COc1cccc(CN)c1
Product: COc1cccc(CNC(=O)c2ccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3C(F)(F)F)CCN4)cc2)c1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 3-methoxybenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z=566.97 (M+H+); retention time=0.91 minutes.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:17][CH2:16][CH2:15]2)[C:11]([C:18]([F:21])([F:20])[F:19])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].C([O:28][C:29](=O)[CH2:30][C:31](=[O:51])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[C:42]([CH2:43][O:44][CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][O:46]3)=[CH:41][N:40]=[N:39]2)[CH:33]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:17][CH2:16][CH2:15]2)[C:11]([C:18]([F:20])([F:21])[F:19])=[CH:10][C:9]=1[NH:22][C:29](=[O:28])[CH2:30][C:31](=[O:51])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[C:42]([CH2:43][O:44][CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][O:46]3)=[CH:41][N:40]=[N:39]2)[CH:33]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCC2)c(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(N2CCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1

Procedure:
The title compound was prepared from (2-amino-5-azetidin-1-yl-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J17) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert.-butyl ester (Example K5) according to the general procedure M. Obtained as a yellow foam (450 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4]2[CH2:5][C:6]3[C:10]([C@H:3]12)=[C:9]([CH3:11])[S:8][C:7]=3[C:12]([OH:14])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH2:47][CH2:48][C:49]1[CH:59]=[CH:58][C:52]([O:53][CH2:54][CH:55]([OH:57])[CH3:56])=[CH:51][C:50]=1[O:60][CH3:61]>CN(C=O)C>[OH:57][CH:55]([CH3:56])[CH2:54][O:53][C:52]1[CH:58]=[CH:59][C:49]([CH2:48][NH:47][C:12]([C:7]2[S:8][C:9]([CH3:11])=[C:10]3[C:6]=2[CH2:5][C@H:4]2[C:2]([CH3:1])([CH3:15])[C@H:3]23)=[O:14])=[C:50]([O:60][CH3:61])[CH:51]=1
Reactant: COc1cc(OCC(C)O)ccc1CN
Reactant: Cc1sc(C(=O)O)c2c1[C@H]1[C@@H](C2)C1(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OCC(C)O)ccc1CNC(=O)c1sc(C)c2c1C[C@@H]1[C@H]2C1(C)C
Reaction time: 0.5 h
Yield: 42.5 %

Procedure:
A solution of (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid (9.6 mg, 0.043 mmol), TBTU (13.8 mg, 0.043 mmol) and ethyl-diisopropylamine (22 μL, 0.129 mmol) in DMF (1 mL) is allowed to stand at rt for 30 min. The solution is added to (rac)-1-(4-aminomethyl-3-methoxy-phenoxy)-propan-2-ol (9.1 mg, 0.043 mmol) and the mixture is allowed to stand at rt for 1 h. The mixture is separated by prep. HPLC to afford (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-((R/S)-2-hydroxy-propoxy)-2-methoxy-benzylamide (7.6 mg) as a colourless oil. LC-MS: tR=0.98 min, [M+1]+=402.16; 1H NMR (CDCl3): δ 7.20 (d, J=8.2 Hz, 1H), 6.50 (d, J=2.3 Hz, 1H), 6.44 (d, J=8.2 Hz, 1H), 6.16 (t br, J=5.3 Hz, 1H), 4.47 (d, J=5.9 Hz, 2H), 3.93 (dd, J=2.9, 11.1 Hz, 1H), 3.87 (s, 3H), 3.82-3.72 (m, 1H), 2.90 (dd, J=5.3, 17.6 Hz, 1H), 2.69 (d, J=18.1 Hz, 1H), 2.35 (s, 3H), 1.92-1.85 (m, 2H), 1.30 (d, J=6.4 Hz, 3H), 1.11 (s, 3H), 0.72 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH:16]=O)=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:18].[NH2:19][OH:20]>C(O)C>[ClH:18].[C:1]1([C:7]2[C:15]([CH:16]=[N:19][OH:20])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=Cc1c(-c2ccccc2)nn2ccccc12
Agent: Cl
Solvent: CCO
Product: ON=Cc1c(-c2ccccc2)nn2ccccc12
Yield: 45.5 %

Procedure:
A mixture of 2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde (0.5 g) and hydroxylamine hydrochloride (0.17 g) in ethanol (5 ml) was refluxed for 1.5 hours and evaporated in vacuo. The residue was triturated with ethyl acetate and recrystallized from a mixture of ethanol and ethyl acetate to give 2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde oxime hydrochloride (0.28 g).
Reaction SMILES: [CH:1]1([C:4]([NH2:6])=[O:5])[CH2:3][CH2:2]1.[H-].[Na+].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[C:17]1[S:18][C:19]2[C:24](S(C)(=O)=O)=[N:23][CH:22]=[N:21][C:20]=2[N:29]=1>CN(C=O)C>[Cl:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([Cl:9])[C:11]=1[C:17]1[S:18][C:19]2[C:24]([NH:6][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])=[N:23][CH:22]=[N:21][C:20]=2[N:29]=1
Reactant: NC(=O)C1CC1
Reactant: CS(=O)(=O)c1ncnc2nc(-c3c(Cl)cccc3Cl)sc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ncnc2nc(-c3c(Cl)cccc3Cl)sc12)C1CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 29.9 %

Procedure:
To a solution of cyclopropylcarboxamide (19 mg, 0.22 mmol) in DMF (1.5 mL) at 0° C. was added NaH (9.8 mg, 0.24 mmol). The reaction mixture was stirred at 0° C. for 10 minutes. A solution of 2-(2,6-dichlorophenyl)-7-(methylsulfonyl)thiazolo[4,5-d]pyrimidine (940 mg, 0.11 mmol) in DMF (0.5 mL) was then added at 0° C. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction was quenched with ice-water and extracted with EtOAc (3×25 mL). The combined organic extract was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC (Gemini-NX, 3×10 cm, gradient: 30-70% CH3CN/H2O, 0.1% NH4OH/H2O, flow rate 60 mL/min, 10 min) to give the desired compound as a yellow solid (12 mg, 31%). 1H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 8.98 (s, 1H), 7.75-7.70 (m, 2H), 7.66 (dd, J=9.4, 6.6 Hz, 1H), 2.19-2.10 (m, 1H), 0.95 (tt, J=7.6, 4.2 Hz, 4H). LCMS (Method B): RT=4.69 min, m/z: 365.0 [M+H+].
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:12]=[C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:10]=[C:9]([CH3:19])[C:5]=1[C:6]([NH2:8])=[O:7])[CH3:2].[OH-].[Na+].[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1>C1C=CC=CC=1.O1CCCC1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:8][C:6](=[O:7])[C:5]2[C:9]([CH3:19])=[CH:10][C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[CH:12][C:4]=2[S:3][CH2:1][CH3:2])=[CH:25][CH:24]=1
Reactant: CCSc1cc(N2CCOCC2)cc(C)c1C(N)=O
Reactant: Clc1ccc(CBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CCSc1cc(N2CCOCC2)cc(C)c1C(=O)NCc1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 50 %

Procedure:
To a solution of 2-ethylsulfanyl-6-methyl-4-morpholin-4-yl-benzamide (synthesized according to the methods described in sections b) and c) of example 1) (0.20 g, 0.71 mmol) in benzene-tetrahydrofuran (1:1) (16 ml) are added tetrabutylammonium hydrogensulfate (0.024 g, 0.071 mmol) and 50% sodium hydroxide solution (6 ml) at RT. The reaction mixture is heated to 70° C. and 4-chlorobenzyl bromide (0.15 g, 0.71 mmol) is added. The reaction mixture is stirred at 70° C. for 20 min. After completion of the reaction (monitored by TLC), the organic layer is separated and the aqueous layer is extracted with ethyl acetate (2×20 ml). The organic layer is washed with water (20 ml), brine (20 ml), dried over anhydrous sodium sulfate and evaporated to get the crude product, which is purified by column chromatography (silica gel, 28% ethyl acetate/hexane) to yield N-[(4-chlorophenyl)-methyl]-2-ethylsulfanyl-6-methyl-4-morpholin-4-yl-benzamide (example 2) (0.095 g, 0.24 mmol, 50%). [M+H]+ 405.1.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][O:12][C:13]([C:15]1([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][CH:16]1[CH2:18][CH:19]=O)=[O:14]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:11][O:12][C:13]([C:15]1([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][CH:16]1[CH2:18][CH:19]=[CH2:1])=[O:14]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CC1CC=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC1CC1(NC(=O)OC(C)(C)C)C(=O)OC
Reaction time: 0.5 h

Procedure:
Methyltriphenylphosphonium bromide (4.6 mmol) was suspended in THF (10 mL) at room temperature. NaHMDS (1.0 M in THF, 4.1 mmol) was added dropwise at room temperature to produce a dark yellow turbid solution which was allowed to stir for 30 min. A THF (6 mL) solution of 1-tert-butoxycarbonylamino-2-(2-oxo-ethyl)-cyclopropanecarboxylic acid methyl ester was added dropwise to the ylide solution and allowed to age at room temperature for 30 min. The reaction was partitioned between EtOAc and saturated NH4Cl. The aqueous layer was extracted with EtOAc (3×10 mL) and the combined organics washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. Purification by column chromatography on SiO2 (0→10% EtOAc/hex) afforded 2-allyl-1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid methyl ester as a colorless film (0.070 g, 15%). (1H-NMR (300 MHz, CDCl3): δ 5.90-5.72 (m, 1H); 5.14 (br s, 1H); 5.08-4.94 (m, 2H); 3.71 (s, 3H); 2.34 (m, 2H); 1.55 (m, 2H); 1.45 (s, 9H), 1.37 (m, 1H)).
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[N+:10]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1)([O-:12])=[O:11].S([O-])(O)(=O)=O.[Na+]>O1CCCC1.[Zn]>[F:8][C:2]([F:9])([CH:17]([OH:18])[C:16]1[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:20][CH:19]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)C(F)(F)Br
Agent: O=S(=O)([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)C(O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 31.3 %

Procedure:
A suspension of ethyl bromodifluoroacetate (20.3 g, 100 mmol) and zinc powder (6.5 g, 100 mmol) in tetrahydrofuran (100 mL) was heated under reflux for 10 min, and 4-nitrobenzaldehyde (8.4 g, 55.8 mmol) was added dropwise. The reaction mixture was refluxed for 4 hr and allowed to cool to room temperature. Aqueous sodium hydrogensulfate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5%-40% ethyl acetate/hexane) to give the title compound (4.80 g, yield 20%) as a yellow oil.
Reaction SMILES: C[N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]([O:28][C:29]1[C:34]([NH:35][C:36]2[C:37]3[C:44]([CH3:45])=[C:43]([C:46]([OH:48])=O)[S:42][C:38]=3[N:39]=[CH:40][N:41]=2)=[CH:33][CH:32]=[CH:31][N:30]=1)([CH3:27])[CH3:26].CCN(C(C)C)C(C)C.N.CO>CN(C=O)C.CCOC(C)=O>[CH:25]([O:28][C:29]1[C:34]([NH:35][C:36]2[C:37]3[C:44]([CH3:45])=[C:43]([C:46]([NH2:2])=[O:48])[S:42][C:38]=3[N:39]=[CH:40][N:41]=2)=[CH:33][CH:32]=[CH:31][N:30]=1)([CH3:26])[CH3:27]
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3OC(C)C)c12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1c(C(N)=O)sc2ncnc(Nc3cccnc3OC(C)C)c12
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
HATU (182.0 mg) was added to an ice cooled solution of 150 mg 4-(2-Isopropoxypyridin-3-ylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and DIPEA (83.0 μl) in DMF (3.0 ml). The mixture was stirred at 0° C. for 20 min then ammonia/MeOH (7M; 1.5 ml) was added and it was allowed to warm to room temperature overnight. The mixture was diluted with EtOAc and washed with water, 2M NaOH and concentrated in vacuo. The residue was triturated with Et2O and filtered to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:25][C@@:23]3([CH3:24])[C@@H:19]([CH2:20][C@@H:21]([CH3:31])[C@@H:22]3[C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[C@H:18]3[C:9]2=[C:10]2[C:15]([CH2:16][CH2:17]3)=[CH:14][C:13](=[O:32])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[CH3:33][O:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[N:39][CH:40]=1>>[CH:28]1([C:26]([C@H:22]2[C@H:21]([CH3:31])[CH2:20][C@H:19]3[C@H:18]4[C:9]([C@@H:8]([C:5]5[CH:6]=[CH:7][C:2]([C:37]6[CH:38]=[N:39][CH:40]=[C:35]([O:34][CH3:33])[CH:36]=6)=[CH:3][CH:4]=5)[CH2:25][C@:23]23[CH3:24])=[C:10]2[C:15](=[CH:14][C:13](=[O:32])[CH2:12][CH2:11]2)[CH2:16][CH2:17]4)=[O:27])[CH2:30][CH2:29]1
Reactant: COc1cncc(B(O)O)c1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(Br)cc3)C[C@]2(C)[C@H]1C(=O)C1CC1
Product: COc1cncc(-c2ccc([C@H]3C[C@@]4(C)[C@@H](C[C@@H](C)[C@@H]4C(=O)C4CC4)[C@@H]4CCC5=CC(=O)CCC5=C43)cc2)c1
Yield: 41 %

Procedure:
(11β,16α,17β)-11-(4-Bromophenyl)-17-cyclopropylcarbonyl-16-methylestra-4,9-dien-3-one and 5-methoxy-3-pyridinylboronic acid were used as described in example 1 step h. Purification by LCMS followed by lyophilisation gave the product (41% yield). 1H NMR (400 MHz, CDCl3): δ 0.35 (s, 3H), 0.80-2.86 (m, 24H), 3.92 (s, 3H), 4.46 (d, J=7 Hz, 1H), 5.80 (s, 1H), 7.24-7.29 (m, 2H), 7.35 (dd, J=3 and 1 Hz, 1H), 7.48-7.53 (m, 2H), 8.28 (d, J=3 Hz, 1H), 8.45 (d, J=1 Hz, 1H).
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@H:9]2[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@H:12]([OH:17])[O:11][C@@H:10]2[CH2:18][OH:19])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].[O:24]=[CH:25][C@@H:26]([C@H:28]([C@@H:30]([C@@H:32]([CH2:34][OH:35])[OH:33])O)[OH:29])[OH:27]>NCC(O)=O>[CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@H:9]2[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@@H:12]([O:17][C@H:30]3[C@H:28]([OH:29])[C@@H:26]([OH:27])[C@@H:25]([OH:24])[O:33][C@@H:32]3[CH2:34][OH:35])[O:11][C@@H:10]2[CH2:18][OH:19])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22]
Reactant: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: NCC(=O)O
Product: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O[C@H]3[C@H](O)[C@@H](O)[C@@H](O)O[C@@H]3CO)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 100 h

Procedure:
A portion of the amylase produced in Example I containing 90,000 amylase units/ml. was diluted 1/500 with 0.05 molar glycine buffer solution, and 80 ml. of the resulting solution were added to 250 ml. of an aqueous solution containing 0.0909 percent (weight/volume basis) amylose in 0.05 molar glycine buffer adjusted to pH 9.2 at 50° C. After 100 hours at 50° C. there was an apparent conversion of 75.5 percent of the amylose to maltose and a conversion of 4.6 percent of the amylose to glucose. A small quantity of maltotriose was also produced. Such analyses were carried out by well known procedures.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]2[C@H:12]([CH2:13][C@@H:14]([CH:19]([CH3:21])[CH3:20])[CH:15]([OH:18])CO)[O:11][C:10]([CH3:23])([CH3:22])[N:9]2[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].CCOCC>C1C=CC=CC=1>[CH:1]1([CH2:7][C@H:8]2[C@H:12]([CH2:13][C@H:14]([CH:15]=[O:18])[CH:19]([CH3:21])[CH3:20])[O:11][C:10]([CH3:22])([CH3:23])[N:9]2[C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)[C@H](C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC1CCCCC1)C(O)CO
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CC(C)[C@@H](C=O)C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC1CCCCC1
Reaction time: 0.25 h
Yield: 85.9 %

Procedure:
20.0 g (46.8 mmol) of t-butyl (4S,5S)-4-(cyclohexylmethyl)-5-[(2S,3RS)-3,4-dihydroxy-2-isopropylbutyl]-2,2-dimethyl-3-oxazolidinecarboxylate are dissolved in 250 ml of benzene, cooled to 5° and treated portionwise within 10 minutes with 20.8 g (47 mmol) of lead tetraacetate. After stirring at 5° for 4 hours 500 ml of ether are added and the reaction mixture is stirred for a further 15 minutes. Thereafter, the reaction mixture is filtered and the filtrate is evaporated under reduced pressure. Chromatography of the residue on 300 g of silica gel with methylene chloride as the eluting agent yields 15.9 g of t-butyl (4S,5S)-4-(cyclohexylmethyl)-5-[(S)-2-formyl-3-methylbutyl]-2,2-dimethyl-3-oxazolidinecarboxylate as an oil, MS: 380 (M-CH3)+.
Reaction SMILES: [CH:1]1[CH:6]=[N:5][CH:4]=[C:3]([C:7]([OH:9])=[O:8])[CH:2]=1.[O:10]=[CH:11][C:12]1[CH:20]=[CH:19][C:17](O)=[C:14]([O:15][CH3:16])[CH:13]=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl.O>[CH:11]([C:12]1[CH:20]=[CH:19][C:17]([O:8][C:7](=[O:9])[C:3]2[CH:2]=[CH:1][CH:6]=[N:5][CH:4]=2)=[C:14]([O:15][CH3:16])[CH:13]=1)=[O:10]
Reactant: O=C(O)c1cccnc1
Reactant: COc1cc(C=O)ccc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O
Product: COc1cc(C=O)ccc1OC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Niacin 1 (1.6 g, 13.1 mmol) in dichloromethane (10 mL) was added Vanillin 8 (2 g, 13.1 mmol), N-methyl morpholine (4.3 mL, 39 mmol) and EDCI.HCl (5 g, 26.2 mmol). The resulting mixture was stirred at ambient temp for 3 h. It was then diluted with water, extracted with dichloromethane, and the organic layer dried over anhydrous sodium sulfate and concentrated. The crude product thus obtained was then chromatographed using over a column of silica gel using petroleum ether:ethyl acetate (1:1) to afford the title compound as a off white solid (300 mg, 9%, mp (° C.): 92-94) 1H NMR (300 MHz, DMSO-D6): 10.02 (s, 1H), 9.25 (d, J=2 Hz, 1H), 8.93 (dd, J=5 & 1.5 Hz, 1H), 8.48 (dt, J=1.8 Hz & 8 Hz, 1H), 7.67 (m, 3H), 7.57 (d, J=8 Hz, 1H), 3.87 (s, 3H)); LCMS (m/z): 257.7 (M+1); HPLC: tRet: 6.486 (98.9%).
Reaction SMILES: FC(F)(F)C([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=O.[CH:24]([C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:35])[CH3:34])=[CH:28][CH:27]=1)=O.[B-]C#N.[Na+].C(C#N)(C)=O.Cl.O1CCOCC1>CO.C(#N)C.C(O)=O.O>[C:16]1([C@@H:14]2[CH2:15][C@H:13]2[NH:5][CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([CH2:24][C:26]3[CH:27]=[CH:28][C:29]([NH:32][C:33](=[O:35])[CH3:34])=[CH:30][CH:31]=3)[CH2:11][CH2:12]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Reactant: CC(=O)Nc1ccc(C=O)cc1
Agent: CC(=O)C#N
Agent: Cl
Agent: [B-]C#N
Solvent: C1COCCO1
Solvent: CC#N
Solvent: O
Product: CC(=O)Nc1ccc(CN2CCC(CN[C@@H]3C[C@H]3c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.3 %

Procedure:
To a solution of 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (100 mg, 0.306 mmol) in methanol (2 mL) was added N-(4-formylphenyl)acetamide (50.0 mg, 0.306 mmol). The reaction mixture was refluxed for 2 minutes, then cooled down to room temperature. Sodium cyanotrihydroborate (38.5 mg, 0.613 mmol) was added. The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was injected on preparatory HPLC (5 to 40% AcCN: H2O with 0.1% formic acid modifier). The fractions were collected and evaporated. The resulting oil was dissolved in 6 ml of EtOH and 3 ml of 1 M NaOH. The reaction mixture was stirred for 20 min, and then it was concentrated. The solution was then partitioned between 2 ml of water and 5 mL of EtOAc. Organic layer was separated and evaporated. Resulting oil was dissolved in 3 mL of acetonitrile. 0.5 mL of 4 M HCl/dioxane was added. The reaction mixture was evaporated until dryness. N-(4-((4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)phenyl)acetamide (28 mg, 0.059 mmol, 19.27% yield) was isolated as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.61 (br. s., 1H), 10.20 (s, 1H), 9.60 (br. s., 2H), 7.66 (d, J=8.59 Hz, 2H), 7.48-7.56 (m, 2H), 7.27-7.34 (m, 2H), 7.14-7.26 (m, 3H), 4.10-4.33 (m, 2H), 3.15-3.37 (m, 2H), 2.76-3.14 (m, 5H), 2.59 (ddd, J=3.54, 6.38, 10.04 Hz, 1H), 1.84-2.12 (m, 6H), 1.48-1.68 (m, 3H), 1.17-1.32 (m, 1H); LC-MS Rt=0.53 min; MS (ESI): 378.4 [M+H]+.