Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[C:6]2[CH3:18].Br[CH2:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25]>>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25])[C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[C:6]2[CH3:18]
Reactant: N#Cc1cccc(CBr)c1
Reactant: Cc1c(-c2cccnc2)[nH]c2ccc(Cl)cc12
Agent: Cl
Product: Cc1c(-c2cccnc2)n(Cc2cccc(C#N)c2)c2ccc(Cl)cc12

Procedure:
5-Chloro-3-methyl-2-pyridin-3-yl-1H-indole hydrochloride (Example 2) and 3-bromomethyl-benzonitrile are processed according to the method described in Example 11 to give 3-(5-chloro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrile. 1H NMR (400 MHz, MeOD) δ ppm 2.25 (s, 3H), 5.36 (s, 2H), 7.03 (d, J=7.8 Hz, 1H), 7.14 (s, 1H), 7.18 (dd, J=8.6, 2.0 Hz, 1H), 7.33 (d, J=8.6 Hz, 1H), 7.36 (t, J=7.7 Hz, 1H), 7.49-7.56 (m, 2H), 7.62 (d, J=2.0 Hz, 1H), 7.81 (dt, J=7.8, 1.9 Hz, 1H), 8.47 (d, J=2.3 Hz, 1H), 8.58 (dd, J=5.1, 1.8 Hz, 1H). HRMS (ESI) m/z 358.1102 [(M+H)+ Calcd for C22H17ClN3, 358.1111].
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[O:14])=[CH:10][CH:11]=2)[NH:6][CH:5]=1)[CH3:2].[Br:21][C:22]1[CH:23]=[N:24][C:25](Cl)=[N:26][CH:27]=1>>[Br:21][C:22]1[CH:23]=[N:24][C:25]([N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[C:9]([C:13]([N:15]4[CH2:16][CH2:17][O:18][CH2:19][CH2:20]4)=[O:14])[CH:8]=3)[C:4]([S:3][CH2:1][CH3:2])=[CH:5]2)=[N:26][CH:27]=1
Reactant: CCSc1c[nH]c2cc(C(=O)N3CCOCC3)ccc12
Reactant: Clc1ncc(Br)cn1
Product: CCSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)N3CCOCC3)ccc12

Procedure:
The product 29a) (1.5 g, 5.17 mmol, 1.0 eq) and 5-bromo-2-chloropyrimidine (1.0 g, 5.17 mmol, 1.0 eq) were reacted as described in procedure 1c). Yield: 700 mg. Mass spectroscopy: m/z: [M+H]+=446.6/448.7
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:14])[CH2:12][OH:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>CN(C=O)C>[Si:20]([O:13][CH2:12][CH:11]([OH:14])[C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)c1ccc(C(O)CO)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(C(O)CO[Si](C)(C)C(C)(C)C)cc1
Reaction time: 6 h

Procedure:
(4-tert-butylphenyl)ethane 1,2 diol (0.5 g, 2.57 mmol) is dissolved in DMF in a 25 ml round bottom flask and to this were added imidazole (0.210 g, 3.09 mmol) and tert-butyldimethylsilyl chloride (0.46 g, 3.09 mmol). The mixture is stirred for 6 hours after which it is extracted in dichloromethane and the organic layer washed with water and dried. Purification by flash chromatography (silica gel; ethyl acetate/hexanes) affords the above mentioned product.
Reaction SMILES: [H-].[Na+].[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].Br[CH2:19][CH2:20][CH2:21][N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32]>C1COCC1>[C:26]1(=[O:27])[N:22]([CH2:21][CH2:20][CH2:19][C:4]([CH2:19][CH2:20][CH2:21][N:22]2[C:26](=[O:27])[C:25]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]3[C:23]2=[O:32])([C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:23](=[O:32])[C:24]2=[CH:31][CH:30]=[CH:29][CH:28]=[C:25]12
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(CCCN1C(=O)c2ccccc2C1=O)(CCCN1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
Sodium hydride (4.08 g, 102 mmol, 60% by weight) is washed with hexanes and mixed with 30 mL of THF. The mixture is cooled to 0° C. and treated with a solution of di-tert-butyl malonate (10.0 g, 46.23 mmol) and N-(3-bromopropyl)phthalimide (24.7 g, 92.46 mmol) in 80 mL of THF. After the addition the reaction is allowed to stir at room temperature for 2 hours and then is heated to reflux overnight. The reaction is cooled and the volatiles are removed under reduced pressure. The residue is partitioned between water and chloroform. The organic layer is dried with Na2SO4 and the solvents are removed under reduced pressure. The resulting product is recrystallized from hexane-ethyl acetate to give 19.66 g of di-tert-butyl bis(3-phthalimidopropyl)malonate as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([OH:10])=[C:4]([O:11][CH3:12])[C:3]=1[O:13][CH3:14].[C:15]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:14][O:13][C:3]1[C:4]([O:11][CH3:12])=[C:5]([O:10][CH3:15])[C:6]([O:8][CH3:9])=[CH:7][C:2]=1[CH3:1]
Reactant: COc1cc(C)c(OC)c(OC)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(C)c(OC)c(OC)c1OC
Yield: 97.6 %

Procedure:
According to a modification of the procedure by Brimble et al.,36 11 (0.660 g, 3.33 mmol) and K2CO3 (4.08 g, 29.5 mmol) were added to a flame-dried 250 mL round bottom flask followed by dry acetone (120.0 mL) and MeI (2.0 mL, 32 mmol) at room temperature. A water-jacketed reflux condenser was attached and the reaction was heated under reflux for 12 hours. The reaction was then cooled, filtered, and the solvent was removed under reduced pressure. The brown residue was then resuspended in CH2Cl2, dried over MgSO4, filtered, and condensed. The resulting colorless oil was then purified by flash chromatography (1:9 EtOAc:hexanes) to provide 6 (0.690 g, 3.25 mmol, 99%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[OH:9][C:10]([CH3:14])([CH3:13])[C:11]#[CH:12].P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(N(CC)CC)C.[Pd].[Cu]I>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]#[C:11][C:10]([OH:9])([CH3:14])[CH3:13])=[CH:3][CH:4]=1
Reactant: C#CC(C)(C)O
Reactant: Fc1ccc(Br)cc1
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC(C)(O)C#Cc1ccc(F)cc1
Temperature: 70 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
To a solution of 35.2 g (0.19 mole) of 4-bromofluorobenzene and 25.2 g (0.3 mole) of 3-hydroxy-3-methyl-1-butine in 250 ml of triethylamine are added, under nitrogen, 1 g of the palladium complex PdCl2 [P(C6H5)3 ]2 and 0.2 g of copper(I) iodide. The reaction mixture is subsequently stirred for 24 hours at 70° C. After filtering off triethylammonium bromide and removing excess triethylamine by evaporation, the residue is taken up in 200 ml of ether and the solution is washed twice with 100 ml of 5% aqueous HCl solution and 100 ml of water, dried, treated with activated charcoal, and evaporated to dryness. The residue is chromatographed on silica gel with a 1:1 mixture of ether/hexane, affording 26.4 g (78%) of 1-fluoro-4-(3-hydroxy-3-methyl-1-butyn-1-yl)-benzene with a melting point of 124° C.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[N:5]([CH2:8][C@H:9]1[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21](OC3C(F)=C(F)C(F)=C(F)C=3F)=[O:22])=[C:17]([F:35])[CH:16]=2)[CH2:10]1)=[N+:6]=[N-:7].C(N(C(C)C)CC)(C)C>C1COCC1>[N:5]([CH2:8][C@H:9]1[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:4][O:3][CH3:2])=[O:22])=[C:17]([F:35])[CH:16]=2)[CH2:10]1)=[N+:6]=[N-:7]
Reactant: CON
Reactant: [N-]=[N+]=NC[C@@H]1CN(c2ccc(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)c(F)c2)C(=O)O1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CONC(=O)c1ccc(N2C[C@@H](CN=[N+]=[N-])OC2=O)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
N-Methoxyamine hydrochloride (123 mg, 1.5 mmol) was added to a solution of 5-(S)-azidomethyl-3-[4′-(pentafluorophenoxy)carbonyl-3′-fluorophenyl]-oxazolidine-2-one (600 mg, 1.3 mmol) and diisopropylethylamine (0.26 ml, 1.5 mmol) in THF (8 ml), and the mixture stirred overnight at r.t. Solvent was removed under vacuum, and ethyl acetate with 3% aq. citric acid added. Organic layer was washed twice with 3% citric acid, brine, and dried (Na2SO4). Solvent was removed under vacuum, and the crude material crystallized from ethanol-ether to give a white crystalline product (335 mg, 83%). HPLC Rt=4.8. MS (m/z): [M+H]+=310.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7]([C:10]2[C:18]([Cl:19])=[C:13]3[CH2:14][CH2:15][CH2:16][CH2:17][N:12]3[N:11]=2)[C:8]=1[NH2:9])(=O)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1.O>C(COC)OC>[NH2:9][C:8]1[N:7]([C:10]2[C:18]([Cl:19])=[C:13]3[CH2:14][CH2:15][CH2:16][CH2:17][N:12]3[N:11]=2)[N:6]=[CH:5][C:4]=1[C:1](=[S:29])[CH3:2]
Reactant: CC(=O)c1cnn(-c2nn3c(c2Cl)CCCC3)c1N
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: O
Solvent: COCCOC
Product: CC(=S)c1cnn(-c2nn3c(c2Cl)CCCC3)c1N

Procedure:
0.28 g (1 mmol) 4-Acetyl-5-amino-1-(3-chloro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)pyrazole was dissolved in 5 ml dimethoxyethane and treated with 0.28 (0.6 mmol) Lawesson's reagent. After heating under reflux for 2 hours with stirring, the reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography. (Hexane/ethyl acetate 1:1).
Reaction SMILES: [H-].[Na+].[N+:3]([CH2:6][CH3:7])([O-:5])=[O:4].[O:8]=[C:9]1[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]1>O1CCCC1>[OH:8][C:9]1([CH:6]([N+:3]([O-:5])=[O:4])[CH3:7])[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CC[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC([N+](=O)[O-])C1(O)CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 58.3 %

Procedure:
To a suspension of sodium hydride (72 mg, 1.75 mmol, 60% wt) in tetrahydrofuran (1 mL) cooled to 0° C. was added nitroethane (125 μL, 1.75 mmol). The suspension was allowed to warm to room temperature and was stirred for 15 minutes, then cooled back to 0° C. To the suspension was added dropwise a solution of 1,1-dimethylethyl 3-oxoazetidine-1-carboxylate (300 mg, 1.75 mmol, in 2 mL of tetrahydrofuran), prepared using procedures similar to those described in Reference 3. The suspension was stirred at room temperature for 1 hour. The reaction mixture was quenched by adding 20% aqueous citric acid, and then was partitioned with ethyl acetate. The aqueous portion was extracted twice using ethyl acetate and the combined organic portion was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a colorless oil that was purified by column chromatography. Eluting with 30% ethyl acetate in hexanes, the isolated product was concentrated in vacuo to afford 250 mg, 1.02 mmol (58%) of 1,1-dimethylethyl 3-hydroxy-3-(1-nitroethyl)azetidine-1-carboxylate as a colorless oil. 1H NMR (400 MHz, DMSO): 6.46 (s, 1H), 5.01 (q, 1H), 4.24-3.97 (m, 2H), 3.77-3.60 (m, 2H), 1.41 (d, 3H), 1.39 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CCOCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:16][C:15]([F:18])([F:17])[O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:4]=[N:3][C:2]([C:23]3[CH:24]=[CH:25][C:20]([NH2:19])=[CH:21][CH:22]=3)=[CH:7][CH:6]=2)=[CH:9][CH:10]=1
Reactant: Nc1ccc(B(O)O)cc1
Reactant: FC(F)(F)Oc1ccc(-c2ccc(Cl)nn2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: Nc1ccc(-c2ccc(-c3ccc(OC(F)(F)F)cc3)nn2)cc1
Yield: 55.6 %

Procedure:
To a solution containing 3-chloro-6-(4-trifluoromethoxyphenyl)-pyridazine (157 mg, 0.57 mmol), 4-aminophenylboronic acid (118 mg, 0.86 mmol) and 2 M K2CO3 (0.57 mL, 1.14 mmol) dissolved in 3.5 mL of dry 1,4-dioxane was added dichlorobis(triphenylphosphine)palladium(II) (4 mg, 0.006 mmol). The mixture was irradiated using a CEM Discover microwave at 190° C. for 30 min. The mixture was diluted with 100 mL of ether and washed with brine (30 mL). The organic phase was then dried over MgSO4, filtered and concentrated. The residue was purified via radial chromatography using a 97:3 CHCl3/CH3OH solution as the eluent (Rf=0.26) to afford the title compound (105 mg, 56%). 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J=8.6 Hz, 2H), 8.01 (d, J=8.6 Hz, 2H), 7.30-7.45 (m, 4H), 6.82 (d, J=8.6 Hz, 2H), 3.96 (bs, 2H); EIMS 331 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH2:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][NH:15]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:15]3[CH2:16][CH2:17][C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:14]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: O=C(c1cc2ncc(Cl)cn2n1)N1CCc2ccccc2C1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1,2,3,4-Tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]4[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[C:17]([CH3:23])[N:16]=4)[N:14]=[C:7]3[C:6]=2[CH:24]=1.[CH3:25][N:26](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N>[CH:20]([N:19]1[C:15]([C:13]2[N:14]=[C:7]3[C:6]4[CH:24]=[C:2]([C:25]#[N:26])[CH:3]=[CH:4][C:5]=4[O:11][CH2:10][CH2:9][N:8]3[CH:12]=2)=[N:16][C:17]([CH3:23])=[N:18]1)([CH3:22])[CH3:21]
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(Br)ccc2OCC3)n(C(C)C)n1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cn3c(n2)-c2cc(C#N)ccc2OCC3)n(C(C)C)n1
Temperature: 150 °C

Procedure:
A microwave vial was charged with a solution of 10-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (0.200 mg, 0.466 mmol) in 1.4 ml DMF. To this solution was added zinc cyanide (160 mg, 1.4 mmol). The reaction mixture was degassed by bubbling nitrogen through the stirred mixture via a syringe. After several minutes the syringe was removed and Bis(ditertbutyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (66 mg, 0.093 mmol) was added and the reaction vial was quickly sealed. The sealed vial was flash heated in a microwave at 150° C. for 30 minutes. The cooled reaction was diluted with EtOAc and the organic solution was washed with water×1, saline×1 and dried (Na2SO4) before concentration in vacuo. The crude residue was purified by preparative RP-HPLC to give 455. MS: (ESI+)=335.1
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[N:18]=[CH:17][N:16]=[C:15]2[NH:24][C:25]1[S:26][C:27]2[CH:33]=[C:32]([NH2:34])[CH:31]=[CH:30][C:28]=2[N:29]=1>>[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[N:18]=[CH:17][N:16]=[C:15]2[NH:24][C:25]1[S:26][C:27]2[CH:33]=[C:32]([NH:34][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:31]=[CH:30][C:28]=2[N:29]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cc2ncnc(Nc3nc4ccc(N)cc4s3)c2cc1OC
Product: COc1cc2ncnc(Nc3nc4ccc(NC(=O)c5ccccc5)cc4s3)c2cc1OC

Procedure:
N-[2-(6,7-Dimethoxyquinazolin-4-ylamino)benzothiazol-6-yl ]benzamide was prepared from benzoyl chloride (14 μL, 0.113 mmol) and N2-(6,7-dimethoxyquinazolin-4-yl)benzothiazole-2,6-diamine (40 mg, 0.113 mmol) according to GP 2 (yellowish solid, 40 mg, 87 mmol, 77%). LC/ESI-MS: m/z=458 [M+H]+; m/z=456 [M−H]−; Rt=3.13 min.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[O:12])[CH:9]=2)[CH2:4][CH2:3]1>C1(C)C=CC=CC=1.C1COCC1>[OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[O:12])[CH:9]=2)[CH2:4][CH2:3]1
Reactant: C[Si](C)(C)CCOC(=O)c1ccc2c(c1)C(=O)CC2
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOC(=O)c1ccc2c(c1)[C@@H](O)CC2

Procedure:
To a solution of R-CBS reagent (90 μL, 1M sol.) and BH3DMS (220 μL, 2.34 mmol) in 3.6 ml of toluene at −10° C. was dropwise added over about 2 h, a solution of the product from Step 1 (500 mg, 1.8 mmol) in 1.8 mL of THF. After addition was complete, the reaction mixture was quenched with 0.5 N HCl. The resulting mixture was transferred to a seperatory funnel and the aqueous layer was washed 3× with EtOAc. The organic layers were combined, dried over MgSO4, filtered and concentrated to yield an oil, which was was purified by chiral HPLC (77% ee prior to chiral separation) to afford the title compound.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:9][C@@H:8]([C:10]([O:12][CH3:13])=[O:11])[C@H:7]([CH2:14][N:15]=[N+]=[N-])[C@@H:6]1[NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:4].S1C=CC=C1[CH2:31][C:32](O)=[O:33]>>[C:22]([O:21][C:19]([NH:18][C@H:6]1[C@@H:7]([CH2:14][NH:15][C:32](=[O:33])[CH3:31])[C@H:8]([C:10]([O:12][CH3:13])=[O:11])[CH2:9][C@@H:5]1[C:3]([OH:2])=[O:4])=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: O=C(O)Cc1cccs1
Reactant: COC(=O)[C@H]1C[C@@H](C(=O)OC)[C@H](CN=[N+]=[N-])[C@@H]1NC(=O)OC(C)(C)C
Product: COC(=O)[C@@H]1C[C@H](C(=O)O)[C@@H](NC(=O)OC(C)(C)C)[C@H]1CNC(C)=O
Yield: 48 %

Procedure:
(±)-(1S,2S,3R,4R)-2-(t-Butyloxycarbonylamino)-3-(azidomethyl)-cyclopentane-1,4-dicarboxylic acid dimethyl ester (506 mg, 1.42 mmole) and thiolacetic acid (0.4 mL) were reacted at room temperature for 6 hours. The reaction mixture was concentrated in vacuo and the crude product was purified by silica gel chromatography using 3% methanol in chloroform to provide the title compound (yield: 255 mg, 48%). MS: (M+H)+=373.
Reaction SMILES: [O:1]=[C:2]([CH2:8][C:9](=[O:11])[CH3:10])[C:3]([O:5]CC)=O.[Cl-].C[C:14](=[NH2+:16])C>C(#N)C>[C:9]([C:8]1[CH2:14][NH:16][C:3](=[O:5])[C:2]=1[OH:1])(=[O:11])[CH3:10]
Reactant: CCOC(=O)C(=O)CC(C)=O
Reactant: CC(C)=[NH2+]
Agent: [Cl-]
Solvent: CC#N
Product: CC(=O)C1=C(O)C(=O)NC1
Temperature: -40 °C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
A solution of ethyl 2,4-dioxovalerate (1.13 g, 7.11 mmole), dimethylmethylene ammonium chloride (0.67 g, 7.11 mmole) and acetonitrile (3 ml) was stirred at 25° C. over 45 minutes. The resulting yellow homogeneous solution was then cooled to -40° C. and ammonia gas was bubbled through the mixture over 5 minutes, during which time a yellow solid precipitated out of solution. The stirred mixture was allowed to slowly warm to 5° C. over a period of 1 hour before addition of concentrated ammonium hydroxide (4 ml). After stirring for 1 hour, the mixture was concentrated under reduced pressure, diluted with 3N HCl (6 ml) and extracted with ethyl acetate (50 ml×10). The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to give 0.34 g of the title compound as a yellow amorphous solid. M.P. 178°-180° C. (dec); 1H nmr (250 MHz, DMSO-d6 ) δ 2.42 (s, 3H), 3.78 (s, 2H), 8.87 (s, 1H); Anal. calcd. for C5H7NO3 : C, 51.07; H, 5.00; N, 9.92. Found: C, 51.18; H, 5.23; N, 9.73.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])=[N:5][N:4]=1.C(N(CC)CC)C.[Cl:26][CH2:27][C:28](Cl)=[O:29]>C1C=CC=CC=1>[F:18][C:2]([F:1])([F:17])[C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][C:28](=[O:29])[CH2:27][Cl:26])[CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])=[N:5][N:4]=1
Reactant: CN1CCC(O)N(c2nnc(C(F)(F)F)s2)C1=O
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CN1CCC(OC(=O)CCl)N(c2nnc(C(F)(F)F)s2)C1=O

Procedure:
Tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol- 2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Chloroacetyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield the desired product tetrahydro-1-(5-trifluoromethyl- 1,3,4-thiadiazol-2-yl)-3-methyl-6-chloroacetyloxy- 2(1H)-pyrimidinone as the residue.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.OS(O)(=O)=O.[CH3:20]O>>[NH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]([CH3:14])([CH3:13])[C:10]([O:12][CH3:20])=[O:11])=[CH:5][CH:4]=1
Reactant: CC(C)(C(=O)O)c1ccc(N)nc1
Reactant: CO
Agent: Cl
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)(C)c1ccc(N)nc1
Temperature: 25 °C

Procedure:
A solution of 2-(6-aminopyridin-3-yl)-2-methylpropanoic acid hydrochloride (35.0 g, 0.162 mmol) and concentrated H2SO4 (5 mL) in MeOH (250 mL) was heated at reflux overnight. After cooling to ambient temperature, the reaction was quenched cautiously with saturated aqueous NaHCO3 and concentrated in vacuo. The residue was partitioned between ethyl acetate and water, the organic phase separated and the aqueous phase re-extracted with ethyl acetate (×3). The combined organic extract was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue (31.6 g, 100%) was judged pure by a combination of TLC and 1H nmr analysis and was used without further purification in the subsequent reaction.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH2:59])=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1>C1COCC1>[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH:59][C:6](=[O:8])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: O=C(O)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccc(F)cc3)nc12

Procedure:
From 4-fluoro-benzoic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (±)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. ES-MS m/e (%): 389 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:8]C1C=CC=CC=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].II.C([C:23]1[CH:30]=[CH:29][C:26](C=O)=[CH:25][CH:24]=1)C(C)C>O1CCCC1>[C:23]1([CH:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[OH:8])[CH:30]=[CH:29][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)Cc1ccc(C=O)cc1
Reactant: Brc1ccccc1OCc1ccccc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 164.2 %

Procedure:
A Grignard reagent was prepared from 2-benzyloxy-bromobenzene (0.20 g), magnesium (0.026 g), a catalytic amount of iodine and tetrahydrofuran (1 mL). The obtained Grignard reagent was added to a solution of 4-isobutylbenzaldehyde (0.16 g) in tetrahydrofuran (2 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was purified by column chromatography on aminopropyl silica gel (eluent: tetrahydrofuran) to give a diphenylmethanol compound (0.23 g). The obtained diphenylmethanol compound was dissolved in ethanol (3 mL) and concentrated hydrochloric acid (0.1 mL). To the solution was added a catalytic amount of 10% palladium-carbon powder, and the mixture was stirred under a hydrogen atmosphere at room temperature overnight. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/hexane=1/1) to give 2-(4-isobutylbenzyl)phenol (0.10 g).