Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:11]=1.I[CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]([CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:17]([OH:19])=[O:18])=[CH:14][CH:15]=1
Reactant: ICC1CCCC1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: O=C(O)C(CC1CCCC1)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (78.0 mL of a 0.91M stock solution, 70.98 mmol) cooled to −78° C. was treated with (4-chloro-phenyl)-acetic acid (5.76 g, 33.8 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (84 mL, 3:1). The resulting solution was stirred at −78° C. for 1 h. Iodomethylcyclopentane (7.45 g, 35.49 mmol) was then added in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2 mL). This solution was stirred at −78° C. for 4 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 16 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (20 mL). The excess solvent was removed in vacuo. The residue was acidified to pH=1 with a 1N aqueous hydrochloric acid solution. The mixture was then poured into water (150 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded 2-(4-chloro-phenyl)-3-cyclopentyl-propionic acid (6.76 g, 79.1%) as a yellow solid: mp 82-84° C.: EI-HRMS m/e calcd for C14H17ClO2 (M+) 252.0917, found 252.0906.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:20]([NH:23][C:24]2[CH:28]=[CH:27][S:26][C:25]=2[C:29]([O:31]C)=[O:30])(=[O:22])=[O:21])=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>O1CCCC1.CO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:20]([NH:23][C:24]2[CH:28]=[CH:27][S:26][C:25]=2[C:29]([OH:31])=[O:30])(=[O:21])=[O:22])=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([N:17]([CH3:18])[CH3:19])=[CH:15][CH:16]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1-c1ccc(N(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)c1ccc(-c2cc(C(C)(C)C)ccc2S(=O)(=O)Nc2ccsc2C(=O)O)cc1
Temperature: 77.5 °C
Yield: 93.6 %

Procedure:
To a solution of 14 (50.0 mg; 0.11 mmol) in tetrahydrofuran (1 mL) and methanol (1 mL) was added aqueous lithium hydroxide (2 mL; 2M). The reaction mixture was heated at 75-80° C. for 6 hours, allowed to cool to room temperature and then concentrated under reduced pressure. The resulting residue was dissolved in chloroform (15 mL) and washed with aqueous hydrochloric acid (2×10 mL; 2N). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield the title compound as a brown solid (47.2 mg).
Reaction SMILES: [Si]([O:8][C@H:9]1[C@H:13]([CH3:14])[N:12]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([Cl:23])[C:16]=2[CH3:24])[C:11](=[O:25])[C:10]1([CH3:27])[CH3:26])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.O>C1COCC1>[Cl:23][C:17]1[C:16]([CH3:24])=[C:15]([N:12]2[C@@H:13]([CH3:14])[C@H:9]([OH:8])[C:10]([CH3:27])([CH3:26])[C:11]2=[O:25])[CH:22]=[CH:21][C:18]=1[C:19]#[N:20]
Reactant: Cc1c(N2C(=O)C(C)(C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]2C)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(N2C(=O)C(C)(C)[C@@H](O)[C@@H]2C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 55.9 %

Procedure:
To a solution of rac-4-[(4R,5S)-4-(tert-butyldimethylsilyloxy)-3,3,5-trimethyl-2-oxopyrrolidin-1-yl]-2-chloro-3-methylbenzonitrile (103 mg) in THF (5 mL) was added tetrabutylammonium fluoride-THF solution (1.00 mL, 1 mol/L), and the mixture was stirred at room temperature for 17 hr. The reaction mixture was added to water, 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 (eluent: hexane/ethyl acetate=50/1→1/3), and recrystallized from hexane-ethyl acetate to give the title compound as a colorless solid (yield: 41.4 mg, 28.4%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:13]=[O:14]>>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH2:13][OH:14])=[N:11][CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(-n2cncn2)c1
Reactant: C=O
Product: OCc1ncnn1-c1cccc(F)c1
Temperature: 150 °C

Procedure:
A mixture of the crude 1-(3-Fluorophenyl)-1,2,4-triazole and formaldehyde (10 mL of 37 wt % in water) is heated at 150° C. in a sealed tube for 48 h. After cooling the reaction vessel, the reaction mixture is extracted with dichloromethane, dried (MgSO4), concentrated, and the residue purified using silica gel chromatography to afford 1-(3-Fluorophenyl)-5-hydroxymethyl-1,2,4-triazole. 1H NMR (CDCl3): δ 8.02 (s, 1H), 7.42-7.53 (m, 3H), 7.22-7.29 (m, 1H), 4.81 (s, 2H). LCMS 194.2 (MH−).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:6]([C:8](=[CH2:20])[CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH3:19])=[O:17])[CH2:12][CH2:11]1)=[O:7].S(=O)(=O)(O)O>>[CH3:25][O:24][C:23]1[CH:22]=[C:21]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[C:6](=[O:7])[CH:8]([CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH3:19])=[O:17])[CH2:12][CH2:11]1)[CH2:20]2
Reactant: C=C(CC1CCN(C(=O)OC)CC1)C(=O)c1ccc(OC)c(OC)c1
Agent: O=S(=O)(O)O
Product: COC(=O)N1CCC(CC2Cc3cc(OC)c(OC)cc3C2=O)CC1

Procedure:
According to WO 9722584, methyl 4-[2-(3,4-dimethoxybenzoyl)ally]piperidin-1-carboxylate is cyclized in the presence of sulfuric acid to give methyl 4-(5,6-dimethoxy-1-oxoindan-2-ylmethyl)piperidin-1-carboxylate, decarboxylated and then treated with benzyl bromide to give donepezil.
Reaction SMILES: O[CH:2]([CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)[CH2:3][C:4](=[O:6])[CH3:5]>C(O)(=O)C>[F:18][C:16]([F:17])([F:19])[C:13]1[CH:14]=[CH:15][C:10]([S:9][CH2:8][CH2:7][CH:2]=[CH:3][C:4](=[O:6])[CH3:5])=[CH:11][CH:12]=1
Reactant: CC(=O)CC(O)CCSc1ccc(C(F)(F)F)cc1
Solvent: CC(=O)O
Product: CC(=O)C=CCCSc1ccc(C(F)(F)F)cc1
Yield: 69.3 %

Procedure:
1.46 Grams of 4-hydroxy-6-(4-trifluoromethylphenylthio)-2-hexanone were dissolved in 12 ml of an aqueous solution of acetic acid and the mixture was refluxed for 1 hour with stirring. After having been cooled, the mixture was washed with a saturated aqueous sodium hydrogencarbonate solution and then with a saturated aqueous sodium chloride solution. Then the mixture was dried over anhydrous magnesium sulfate. Removing the solvent from the mixture under reduced pressure gave 1.27 g of 6-(4-trifluoromethylphenylthio)-3-hexen-2-one (trans : cis =6.5 : 1) (purity: 74.7%). The yield was 69.3%. Percent recovery of the starting material was 11.4%.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:17]=[CH:16][C:10]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:9]([O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[CH:8]=2)[N:6]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>>[C:27]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:17]=[CH:16][C:10]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:9]([O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[CH:8]=2)[N:6]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: CS(=O)(=O)Nc1ccc(-c2csc(N)n2)cc1Oc1ccc(F)cc1F
Product: CC(=O)Nc1nc(-c2ccc(NS(C)(=O)=O)c(Oc3ccc(F)cc3F)c2)cs1

Procedure:
A solution of 4'-(2-amino-4-thiazolyl)-2'-(2,4-difluorophenoxy)methanesulfonanilide (1.2 g) in acetic anhydride (3 ml) was stirred for 30 minutes at 80° C. The mixture was concentrated, and then evaporated with xylene and ethanol. The residue (1.4 g) was purified by column chromatography on silica gel (30 g) eluting with a mixture of toluene and ethyl acetate (1:1), and recrystallized from ethanol to afford pale brown crystals of 4'-(2-acetamido-4-thiazolyl)-2'-(2,4-difluorophenoxy)methanesulfonanilide (0.82 g).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:9]([N:22]1[CH2:25][CH:24]([OH:26])[CH2:23]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CN=C1>C(Cl)Cl>[CH:9]([N:22]1[CH2:25][CH:24]([O:26][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:23]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 113 %

Procedure:
tert-Butyldimethylsilyl chloride (1.524 g, 10.11 mmol) was added to 1-benzhydrylazetidin-3-ol (CAS no. 18621-17-5) (2.2 g, 9.19 mmol) and imidazole (1.565 g, 22.98 mmol) in DCM (46.0 mL) at r.t. under nitrogen. The resulting solution was stirred at r.t. for 3 hours. The reaction mixture was quenched with water, poured onto a phase separator and evaporated to afford the product (3.66 g, 113%). 1H NMR (400 MHz, CDCl3) δ 0.00 (6H, s), 0.85 (9H, s), 2.81 (2H, s), 3.52 (2H, s), 4.35 (1H, s), 4.40-4.49 (1H, m), 7.08-7.43 (10H, m); m/z (ES+) (M+H)+=354.55; HPLC tR=2.04 min.
Reaction SMILES: [CH3:1][O:2][NH2:3].C([O:12][C@@H:13]1[C@H:17]([O:18]C(=O)C2C=CC=CC=2)[C@@H:16]([CH2:27][O:28]C(=O)C2C=CC=CC=2)[O:15][C@H:14]1[N:37]1[CH:45]=[N:44][C:43]2[C:38]1=[N:39][C:40]([Cl:47])=[N:41][C:42]=2Cl)(=O)C1C=CC=CC=1.N>>[Cl:47][C:40]1[N:41]=[C:42]([NH:3][O:2][CH3:1])[C:43]2[N:44]=[CH:45][N:37]([C:38]=2[N:39]=1)[C@@H:14]1[O:15][C@H:16]([CH2:27][OH:28])[C@@H:17]([OH:18])[C@H:13]1[OH:12]
Reactant: CON
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: N
Product: CONc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 60.3 %

Procedure:
The title compound was prepared according to method A as described in example 4 by reacting O-methylhydroxylamine (0.20 g, 2.0 mmol) with 9-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.27 g, 2.0 mmol) and debenzoylating the purified product using methanolic ammonia to provide the title 2-chloro-N-methoxyadenosine (0.40 g, 45%) (after column chromatography) as a colourless foam which became crystalline on trituration with dichloromethane, providing 0.20 g of a white solid, mp 123°-125° C. 1H NMR (DMSO-d6)γ 3.52-3.59 (1H, m, H-5'a), 3.63-3.70 (1H, m, H-5'b), 3.78 (3H, s,--OCH3), 3.96 (1H, q, H-4'), 4.14 (1H, q, H-3'), 4.52 (1H, q, H-2'), 5.06 (1H, t, 5'-OH), 5.22, 5.51 (2H, 2d, 2'- and 3'-OH), 5.87 (1H, d, H-1'), 8.50 (1H, s, H-8), 11.60 (1H, s, N-H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N:11]2[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[CH:4]=[CH:3][CH:2]=1.[N:18]1([C:24]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:25]=2[CH:26]=[CH:27][NH:28]3)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[NH:28]1[C:29]2[C:25](=[C:24]([N:18]3[CH2:23][CH2:22][N:21]([CH:14]4[CH2:15][CH2:16][N:11]([C:9]5[CH:8]=[CH:7][CH:6]=[C:5]6[C:10]=5[N:1]=[CH:2][CH:3]=[CH:4]6)[CH2:12][CH2:13]4)[CH2:20][CH2:19]3)[CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:27]1
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Reactant: O=C1CCN(c2cccc3cccnc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: c1cnc2c(N3CCC(N4CCN(c5cccc6[nH]ccc56)CC4)CC3)cccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.8 %

Procedure:
To a solution of 0.270 g of 1-quinolin-8-yl-piperidin-4-one (Example A, Step 6, above) and 0.240 g of 4-piperazino-indole (commercially available) in 15 mL CH2Cl2 was added 0.327 g of sodium triacetoxyborohydride and 0.2 mL acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2Cl2. The organic phase was washed with water, dried over magnesium sulfate and evaporated. The product crystallized to give 0.200 g of the desired product. Mp: 256° C.; MS (ES) m/z (relative intensity): 412 (M++−H, 100).
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@H:14]([OH:15])[CH2:13][N:12]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C@@H:11]1[CH2:26]O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)[F:34])CC)C.C(=O)([O-])O.[Na+]>COCCOC>[C:1]([O:9][C@H:10]1[C@H:14]([OH:15])[CH2:13][N:12]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C@H:11]1[CH2:26][F:34])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O[C@H]1[C@H](O)CN(C(=O)OCc2ccccc2)[C@@H]1CO)c1ccccc1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: O=C(O[C@H]1[C@H](O)CN(C(=O)OCc2ccccc2)[C@H]1CF)c1ccccc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 43.9 %

Procedure:
The compound (257 mg, 0.69 mmol) synthesized in Example 1 (1h) was dissolved in 1,2-dimethoxyethane (5 mL) and diethylaminosulfur trifluoride (0.11 mL, 0.83 mmol) was added thereto at −20° C. The temperature of the mixture was gradually raised and the mixture was stirred at 60° C. for 1 hour. After saturated aqueous sodium hydrogencarbonate solution was added thereto at 0° C. until foaming did not occur, the mixture was extracted with ethyl acetate (15 mL) and the organic layer was washed with saturated brine (15 mL) and dried with anhydrous sodium sulfate, followed by distilling off of the solvent under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane:ethyl acetate, 3:1, V/V) to obtain a colorless oil (113 mg, 44%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[BH3-]C#N.[Na+].O>CC(O)=O>[OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2
Reactant: Oc1cccc2[nH]ccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Oc1cccc2c1CCN2
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
A solution of 4-hydroxyindole (0.16 g; 1.2 mmol) in AcOH (6 ml) was treated with NaBH3CN (0.23 g; 3.6 mmol), at rate keeping the temperature below 15° C. The mixture was then stirred for 1 h at room temperature and H2O (0.4 ml) was added and solvents removed in vacuo. The residue was diluted to 15 ml with EtOAc, washed with 5% NaHCO3, brine, dried over anhydrous MgSO4, filtered and filtrate evaporated under reduced pressure to give the title compound (0.16 g; 99%) as creamy solid. 1H-NMR (CDCl3) 2.93 (tr, 2H, J=8.4 Hz); 3.58 (tr, 2H, J=8.4 Hz); 3.74 (broad s, 2H); 6.17 (d, 1H, J=8 Hz); 6.26 (d, 1H, J=7.72 Hz); 6.88 (tr, 1H, J=7.85 Hz).
Reaction SMILES: [CH:1]12[CH:14]=[CH:13][CH:5]([CH:6]3[C:11](=[O:12])O[C:8](=[O:9])[CH:7]31)[CH:4]1[CH:2]2[CH2:3]1.[N+:15]([C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)([O-:17])=[O:16].O>C(O)(=O)C>[N+:15]([C:18]1[CH:24]=[CH:23][C:21]([N:22]2[C:8](=[O:9])[CH:7]3[CH:6]([CH:5]4[CH:13]=[CH:14][CH:1]3[CH:2]3[CH:4]4[CH2:3]3)[C:11]2=[O:12])=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: O=C1OC(=O)C2C3C=CC(C4CC34)C12
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: CC(=O)O
Product: O=C1C2C3C=CC(C4CC34)C2C(=O)N1c1ccc([N+](=O)[O-])cc1
Temperature: 60 °C

Procedure:
250 g of tricyclo-[3.2.2.02.4 ]-non-8-ene-6,7-dicarboxylic acid anhydride (prepared from cycloheptatriene and maleic acid anhydride, K. Alder, Ber. 86, 1528-39 (1953)) and 200 g of 4-nitroaniline are refluxed in 1500 ml of glacial acetic acid for 3 hours. The reaction mixture cooled to 60° C is poured into 2000 ml of hot water, whereupon the crude product precipitates. After cooling, the crude product is filtered off, dried, and recrystallised from ethyl acetate; M.P. 210°-212° C.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10](=[O:23])[NH:11][CH2:12][CH2:13][C:14]1[CH:22]=[CH:21][C:17]2[O:18][CH2:19][O:20][C:16]=2[CH:15]=1)[CH3:9])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:7][C@@H:8]([CH3:9])[C:10]([NH:11][CH2:12][CH2:13][C:14]1[CH:22]=[CH:21][C:17]2[O:18][CH2:19][O:20][C:16]=2[CH:15]=1)=[O:23]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)NCCc1ccc2c(c1)OCO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)C(=O)NCCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
[1-(2-Benzo[1,3]dioxol-5-yl-ethylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (350 mg, 1.04 mmol) was dissolved in TFA:DCM (1:1, 4 mL) and allowed to stir at room temperature for 2 h. After this time, the solution was concentrated down under N2 gas and dissolved in DCM. The solution was washed several times with 1M NaOH (aq). The organic layer was dried with Na2SO4 and concentrated down under N2. The crude material was purified by flash chromatography (DCM to 9:1 DCM/MeOH) to afford 189 mg (77% yield) of (S)-2-amino-N-(2-benzo[1,3]dioxol-5-yl-ethyl)-propionamide. [M+H]+ 237.10.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[C:6]#[N:7].[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=1)[C:28]([O:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:29]>>[C:6]([C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:3][CH2:2][N:22]([CH3:21])[CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=1)[C:28]([O:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:29])#[N:7]
Reactant: CCCCOC(=O)c1cccc(CCNC)c1
Reactant: COc1ccc(C(C#N)(CCCBr)C(C)C)cc1OC
Product: CCCCOC(=O)c1cccc(CCN(C)CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)c1

Procedure:
Reaction of 1f with 2m produced 3ar. MS found M+H=495. The oxalate salt of 3ar was recrystallized from methanol/ether; mp 97-103° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[CH:4][N:3]=1.[Li]CCCC.CN([CH:25]=[O:26])C.[BH4-].[Na+]>CCOCC>[Si:10]([O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:25][OH:26])=[N:3][CH:4]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Br)nc1
Reactant: CN(C)C=O
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCc1ccc(CO)nc1

Procedure:
The reaction was carried out as described in Example 1, Step 3 using 2-bromo-5-(tert-butyldimethylsilyloxymethyl)pyridine (12 g, 39.7 mmol), BuLi (37 ml of a 1.6 M solution in hexanes, 59.6 mmol) DMF (9.2 ml, 0.12 mol) and NaBH4 (1.5 g, 39.7 mmol) to yield, after column chromatography on silica using Et2O as eluent, the title alcohol (6.66 g, 66%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.Cl.[CH2:18]([NH2:20])[CH3:19].C(N(CC)CC)C>C(O)(C)C>[CH2:18]([NH:20][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1)[CH3:19]
Reactant: O=[N+]([O-])c1cnc(-c2ccccc2)nc1Cl
Reactant: CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCNc1nc(-c2ccccc2)ncc1[N+](=O)[O-]
Yield: 93.3 %

Procedure:
A mixture of 4-chloro-5-nitro-2-phenylpyrimidine (3 g), ethylamine hydrochloride (1.6 g), triethylamine (3.9 g) and isopropanol (60 ml) is refluxed for three hours. The reaction mixture is concentrated under reduced pressure, and to the residue are added chloroform and water. The chloroform layer is separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform), and recrystallized from isopropanol to give the desired compound (2.9 g).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][N:19]([CH3:21])[C:18](=[O:22])[N:17]([CH3:23])[CH2:16]2)=[CH:11][C:10]=1Br.[C:25]1(B(O)O)[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=1>>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][N:19]([CH3:21])[C:18](=[O:22])[N:17]([CH3:23])[CH2:16]2)=[CH:11][C:10]=1[C:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=1
Reactant: OB(O)C1=CCCCC1
Reactant: CN1CC(c2ccc(N)c(Br)c2)CN(C)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CN1CC(c2ccc(N)c(C3=CCCCC3)c2)CN(C)C1=O
Yield: 38 %

Procedure:
5-(4-Amino-3-bromo-phenyl)-1,3-dimethyl-tetrahydro-pyrimidin-2-one trifluoroacetic acid salt (as prepared in the previous step, 92 mg, 0.30 mmol) was reacted with cyclohex-1-enyl boronic acid (48.7 mg, 0.375 mmol) according to the Suzuki coupling procedure of Example 4, step (e) and purified on silica (2% MeOH-EtOAc) to afford the title compound (35 mg, 38%): Mass spectrum (ESI, m/z): Calcd. for C18H25N3O, 300.2 (M+H). found 300.3.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:20]2=[N:21][C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([CH3:34])=[CH:31][CH:32]=4)[NH:27][N:26]=3)=[CH:23][N:24]=[C:19]2[N:18]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:17]=1)=[O:15])([CH3:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.Cl[CH2:56][CH2:57][N:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Si:1]([O:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:20]2=[N:21][C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([CH3:34])=[CH:31][CH:32]=4)[N:27]([CH2:56][CH2:57][N:58]4[CH2:63][CH2:62][O:61][CH2:60][CH2:59]4)[N:26]=3)=[CH:23][N:24]=[C:19]2[N:18]([C:35]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:17]=1)=[O:15])([CH3:11])[CH3:12])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: ClCCN1CCOCC1
Reactant: Cc1ccc2c(-c3cnc4c(n3)c(C(=O)NC(C)(C)CO[Si](C)(C)C(C)(C)C)cn4C(c3ccccc3)(c3ccccc3)c3ccccc3)n[nH]c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(-c3cnc4c(n3)c(C(=O)NC(C)(C)CO[Si](C)(C)C(C)(C)C)cn4C(c3ccccc3)(c3ccccc3)c3ccccc3)nn(CCN3CCOCC3)c2c1
Temperature: 90 °C
Yield: 72.3 %

Procedure:
A mixture of N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(6-methyl-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (200 mg, 0.277 mmol), 4-(2-chloroethyl)morpholine hydrochloride (62 mg, 0.333 mmol) and K2CO3 (191 mg, 1.385 mmol) in dry DMF (20 mL) was heated to 90° C. for 3 hours. Reaction mixture was extracted with ethyl acetate (100 mL), organic phase washed with water (3×10 mL) and brine (2×10 mL). The organic layer was dried over Na2SO4, filtered and concentrated to afford N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(6-methyl-1-(2-morpholinoethyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (167 mg, crude) as a yellow oil. LCMS: (M+H)+=834.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:23])[NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1C(O)=O.C(=O)(O)[O-].[Na+].[Br:32]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:32][C:4]1[CH:5]=[N:6][N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:23])=[CH:10][N:9]=2)[C:3]=1[O:2][CH3:1]
Reactant: COc1c(C(=O)O)cnn1-c1ccc(C(=O)NCC2CCOCC2)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(Br)cnn1-c1ccc(C(=O)NCC2CCOCC2)cn1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
Combined 5-methoxy-1-(5-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)pyridin-2-yl)-1H-pyrazole-4-carboxylic acid (329.5 mg, 0.914 mmol) and sodium bicarbonate (307 mg, 3.66 mmol) in DMF (3 mL) then added 1-bromopyrrolidine-2,5-dione (163 mg, 0.914 mmol) at 23° C. The reaction mixture was stirred at 23° C. for 30 minutes and then diluted with water (15 mL) to give a suspension. The suspension was filtered, rinsed with water (3×5 mL), and dried in vacuo to give the title compound (302 mg, 84% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.28 (m, 2H) 1.62 (dd, J=12.88, 1.77 Hz, 2H) 1.80 (dddt, J=14.78, 11.12, 7.39, 3.44, 3.44 Hz, 1H) 3.16-3.23 (m, 2H) 3.23-3.31 (m, 2H) 3.81-3.89 (m, 2H) 4.05 (s, 3H) 7.79 (dd, J=8.59, 0.76 Hz, 1H) 7.84 (s, 1H) 8.38 (dd, J=8.46, 2.40 Hz, 1H) 8.75 (t, J=5.81 Hz, 1H) 8.96 (dd, J=2.53, 0.76 Hz, 1H). MS m/z [M+H]+ 395.3, 397.3.