Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].CC(=CC)C.[C:16]([O:20][C:21](=[O:35])[N:22]([CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH:33]=[O:34])[CH3:23])([CH3:19])([CH3:18])[CH3:17]>O.O1CCOCC1>[C:16]([O:20][C:21]([N:22]([CH3:23])[CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([OH:6])=[O:34])=[O:35])([CH3:19])([CH3:17])[CH3:18]
Reactant: CN(CCOc1ccccc1C=O)C(=O)OC(C)(C)C
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1COCCO1
Solvent: O
Product: CN(CCOc1ccccc1C(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 124.1 %

Procedure:
A solution of sodium chlorite (2.85 g; 31.5 mmol; 5.5 eq.) and sodium dihydrogenphosphate (2.47 g; 20.6 mmol; 3.6 eq.) in water (25 mL) was added dropwise to a mixture of 2-methyl-2-butene (5.7 mL) and [2-(2-formyl-phenoxy)-ethyl]-methyl-carbamic acid tert-butyl ester (1.6 g; 5.73 mmol; 1 eq.) in 1,4-dioxane (25 mL). The reaction mixture was stirred at room temperature for 1.5 hour. After dilution with EA, the solution was washed with 1M HCl, dried over magnesium sulfate and concentrated in vacuo to afford the title compound (2.1 g, 93%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 7.66-7.59 (dd, J=7.7, 1.8 Hz, 1H), 7.52-7.42 (m, OH), 7.16-7.10 (d, J=8.4 Hz, 1H), 7.03-6.94 (td, J=7.5, 1.0 Hz, 1H), 4.18-4.07 (m, 1H), 3.54-3.48 (t, J=5.4 Hz, 2H), 2.96-2.86 (d, J=11.7 Hz, 3H), 1.42-1.31 (m, 9H).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Cl.O[CH2:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.O1CCOCC1>[NH:17]1[CH:18]=[C:14]([CH2:13][N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)[N:15]=[CH:16]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: OCc1c[nH]cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: c1ccc2c(c1)CCCN2Cc1c[nH]cn1
Temperature: 25 °C

Procedure:
A mixture of 1,2,3,4-tetrahydro-quinoline (Intermediate F1) (Commercially available from Aldrich) (1.62 mL, 12.6 mmol) and 4-hydroxymethyl-imidazole hydrochloride salt (commercially available from Aldrich) (Intermediate F2) (0.70 g, 5.1 mmol) and sodium carbonate (1.6 g, 15.1 mmol) in water (20 mL) and dioxane (10 mL) were heated at reflux for 24 h. The mixture was cooled to rt and extracted with ethyl acetate. The organic solution was dried over MgSO4, filtered and freed of solvent. The resultant oil was purified by chromatography on silica gel with 5% NH3-MeOH: dichloromethane to give 1-(1H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinoline (Intermediate F3) as a solid, 0.54 g (50%).
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:17])([F:16])[F:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:18](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:15])([F:16])[F:17])=[CH:7][C:3]=1[C:4]([O:6][CH3:18])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(C(=O)O)cc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1C
Temperature: 60 °C
Yield: 90.2 %

Procedure:
To a solution of 2-methyl-3-nitro-5-(trifluoromethyl)benzoic acid (21.0 g, 84.3 mmol) in DMF (200 mL) was added potassium carbonate (35.0 g, 253 mmol) and methyl iodide (24.0 g, 169 mmol). The mixture was stirred at 60° C. and after stirring for 6 h the reaction mixture was cooled to 23° C. and was filtered. The filtrate was concentrated in vacuo and the residue was dissolved in EtOAc and water. The aqueous phase was extracted with EtOAc (2×250 mL and the combined organic layers were concentrated in vacuo. The residue was purified by column chromatography (SiO2 heptane-EtOac=4/1) to give the titled compound (20.0 g, 90% yield). 1H-NMR (400 MHz, CDCl3) δ (ppm); 8.27 (s, 1H), 8.11 (s, 1H), 3.99 (s, 3H), 2.71 (s, 3H); MS (ES) [M−H] 261.9.
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].C([Li])CCC.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2([C:22]#[N:23])[CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1.O>O1CCCC1>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2([C:22]([NH2:23])=[CH:1][S:2]([CH3:5])(=[O:4])=[O:3])[CH2:21][CH2:20][CH2:19]2)=[CH:16][CH:17]=1
Reactant: N#CC1(c2ccc(Cl)cc2)CCC1
Reactant: CS(C)(=O)=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)C=C(N)C1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of dimethylsulphone (8.3 g), in dry tetrahydrofuran (150 ml) was added dropwise to a stirred ice-cold solution of butyllithium (30 ml of 2.6M solution in hexane). The mixture was stirred at room temperature for 15 minutes and then a solution of 1-(4-chlorophenyl)cyclobutanecarbonitrile (15 g) in tetrahydrofuran (25 ml) was added over 15 minutes and the resulting solution was heated under reflux for 16 hours. The solution was cooled and treated with water and the organic layer separated. The aqueous layer was extracted with ether and the ether extracts combined with the previously separated organic layer, dried and the solvents were removed by evaporation. The resulting oil crystallised, and the solid was washed with petroleum ether (b.p. 40°-60° C.) to give 1-[1-(4-chlorophenyl)cyclobutyl]-2-methylsulphonylvinylamine (m.p. 125°-126°).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH:17]=[CH:16][C:15]=1[S:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:39])[CH3:38])=[CH:32][CH:31]=1>C(O)C>[CH3:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH2:21][O:20][C:18]1[CH:17]=[CH:16][C:15]([S:29][C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:39])[CH3:38])=[CH:32][CH:31]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: CC(=O)Nc1ccc(Sc2ccc(OCc3ccccc3C)cc2N)cc1
Solvent: CCO
Product: CC(=O)Nc1ccc(Sc2ccc(OCc3ccccc3C)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (18 mg, 0.085 mmol) was reacted in ethanol (1 mL) with the product from Example 119a (32 mg, 0.085 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (23 mg, 42%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J=7.35 Hz, 3H) 1.69-1.94 (m, 2H) 2.02 (s, 3H) 2.32 (s, 3H) 2.99 (t, J=7.35 Hz, 2H) 5.14 (s, 2H) 6.32 (d, J=6.99 Hz, 1H) 6.98-7.30 (m, 7H) 7.41 (dd, J=11.40, 8.82 Hz, 4H) 7.80 (d, J=8.82 Hz, 1H) 8.38 (d, J=6.99 Hz, 1H) 8.97 (d, J=8.46 Hz, 1H) 9.98 (s, 1H) 11.02 (s, 1H) 14.37 (s, 1H); MS (ESI+) m/z 549 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH:10]1[NH:14]C(=O)N[C:11]1=[O:16].[OH-:17].[Na+].Cl>>[NH2:14][CH:10]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[C:7]([OH:8])[C:2]=1[CH3:1])[C:11]([OH:16])=[O:17]
Reactant: Cc1c(O)cc(O)cc1C1NC(=O)NC1=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: Cc1c(O)cc(O)cc1C(N)C(=O)O

Procedure:
A solution of 5-(2-methyl-3,5-dihydroxyphenyl)-hydantoin (400 mg, 1.8 mmol) in 2M sodium hydroxide (4.5 ml, 9 mmol) was heated in a sealed vessel at 110° C. for 48 hours. The reaction mixture was allowed to cool, neutralised with 2M hydrochloric acid and purified by cation-exchange chromatography (Dowex 50×8-100; column eluted sequentially with water,water:THF 1:1 and water again. The amino acid was finally eluted with water:pyridine 9:1). The pyridine was removed in vacuo and the residual solid redissolved in water and freeze-dried to give the title compound as a light brown solid, m.p. 215° C. (dec).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26](S(C)=O)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:40][CH2:39][C:38]5[CH:41]=[CH:42][C:35]([Cl:34])=[CH:36][CH:37]=5)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)c1nccc(-c2n[nH]c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1
Reactant: NCc1ccc(Cl)cc1
Product: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4ccnc(NCc5ccc(Cl)cc5)n4)n[nH]c3n2)CC1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
The mixture of {4-[3-(2-methanesulfinyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 9 supra) (150 mg, 0.32 mmol) and 4-chlorobenzylamine (179 mg, 1.3 mmol) was heated at 130° C. with stirring for 2 hours. The resulting oil was purified by chromatography (silica gel, 6 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to 30:1) and then further purified by prep-HPLC to afford (4-{3-[2-(4-chloro-benzylamino)-pyrimidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester. (Yield 35 mg, 20.1%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Ca+2].[C:14](Cl)(Cl)=[S:15].[CH3:18][C:19]1[C:20]([N:25]=[C:26]=[S:27])=[N:21][CH:22]=[CH:23][CH:24]=1.[N-]=C=S>C(#N)C>[CH3:8][C:7]1[C:2]2=[N:1][C:14](=[S:15])[N:25]([C:20]3[C:19]([CH3:18])=[CH:24][CH:23]=[CH:22][N:21]=3)[C:26](=[S:27])[N:3]2[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccnc1N
Reactant: S=C(Cl)Cl
Reactant: Cc1cccnc1N=C=S
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Agent: [N-]=C=S
Solvent: CC#N
Product: Cc1cccnc1-n1c(=S)nc2c(C)cccn2c1=S

Procedure:
Following the procedure of Examples 1A and 2A, 21.6 g. of 2-amino-3-methylpyridine, 42 g. of calcium carbonate and 24.5 g. of thiophosgene are converted into 3-methyl-2-pyridylisothiocyanate with a b.p. of 84° C. at 0.5 mm. of Hg. 10 G. of the freshly distilled isothiocyanate is dissolved in 100 ml. of acetonitrile and the reaction mixture carried out as in Examples 1B and 2B affording 9-methyl-3-(3-methyl-2-pyridyl) pyrido (1,2-a) 1,3,5-triazine-2,4-dithione m.p. 131°-132° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH2:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)#[N:16].[C:25](#[N:29])[CH2:26][C:27]#[N:28].Cl>>[NH2:29][C:25]1[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:4]=2)[C:10](=[O:11])[NH:12][CH:21]([C:20]2[CH:23]=[CH:24][C:17]([C:15]#[N:16])=[CH:18][CH:19]=2)[C:26]=1[C:27]#[N:28]
Reactant: NC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: N#CCC#N
Reactant: N#Cc1ccc(C=O)cc1
Agent: Cl
Product: N#CC1=C(N)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
400 mg (1.97 mmol) N-[3-(trifluoromethyl)phenyl]urea, 199 mg (1.51 mmol) 4-cyanobenzaldehyde and 100 mg (1.51 mmol) malononitrile are suspended in 2 ml of THE, and catalytic amounts of concentrated hydrochloric acid are added. The mixture is stirred at reflux for 18 hours. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with dichloromethane/methanol as eluent.
Reaction SMILES: [Br:1][CH:2]1[CH2:23][CH2:22][C:5]2=[CH:6][C:7]3[C:8]4[CH:17]=[CH:16][C:15]([C:18](=[O:21])[CH2:19]Br)=[CH:14][C:9]=4[CH2:10][O:11][C:12]=3[CH:13]=[C:4]2[C:3]1=[O:24].[CH3:25][O:26][C:27]([NH:29][C@@H:30]([C@@H:42]([CH3:45])[CH2:43][CH3:44])[C:31]([N:33]1[C@@H:37]([CH3:38])[CH2:36][CH2:35][C@H:34]1[C:39]([OH:41])=[O:40])=[O:32])=[O:28].C([O-])([O-])=O.[K+].[K+]>ClCCl>[CH3:25][O:26][C:27]([NH:29][C@@H:30]([C@@H:42]([CH3:45])[CH2:43][CH3:44])[C:31]([N:33]1[C@@H:37]([CH3:38])[CH2:36][CH2:35][C@H:34]1[C:39]([O:41][CH2:19][C:18]([C:15]1[CH:16]=[CH:17][C:8]2[C:7]3[CH:6]=[C:5]4[CH2:22][CH2:23][CH:2]([Br:1])[C:3](=[O:24])[C:4]4=[CH:13][C:12]=3[O:11][CH2:10][C:9]=2[CH:14]=1)=[O:21])=[O:40])=[O:32])=[O:28]
Reactant: O=C(CBr)c1ccc2c(c1)COc1cc3c(cc1-2)CCC(Br)C3=O
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N1[C@@H](C)CC[C@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N1[C@@H](C)CC[C@H]1C(=O)OCC(=O)c1ccc2c(c1)COc1cc3c(cc1-2)CCC(Br)C3=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a slurry of 9-bromo-3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (4.00 g, 8.88 mmol) in dichloromethane (50 mL) was added (2S,5S)-1-((2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoyl)-5-methylpyrrolidine-2-carboxylic acid (2.80 g, 9.32 mmol) and K2CO3 (1.84 g, 13.31 mmol). The resulting slurry was stirred at room temperature for 18 h. The reaction was diluted with dichloromethane and washed with aqueous HCl (0.5 M) and Brine. The aqueous layers were back extracted with dichloromethane (2×), and the combined organic layers were dried over Na2SO4 and concentrated. The crude product was taken directly into the next reaction.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH:9]([NH:11][CH2:12][C:13]#[CH:14])=[O:10]>C(NC(C)C)(C)C.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.[Cu]I>[CH:9]([NH:11][CH2:12][C:13]#[C:14][C:5]1[CH:6]=[CH:7][C:2]([C:14]#[C:13][CH2:12][NH:11][CH:9]=[O:10])=[N:3][CH:4]=1)=[O:10]
Reactant: C#CCNC=O
Reactant: Brc1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Product: O=CNCC#Cc1ccc(C#CCNC=O)nc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
A mixture of 2,5-dibromopyridine (100 g), N-formylpropargylamine (87.7 g), PdCl2(PPh3)2 (2.96 g), and CuI (0.2 g) in diisopropylamine (3 L) was heated at 70° C. for 6 h under a nitrogen atmosphere. The mixture was cooled to 20-22° C. and filtered. The cake was dried and then slurried in water (3 L) at 0-5° C. for 3 h. The slurry was filtered, and the cake was dried to afford 95.4 g of the title compound 9-1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:15]2[CH:20]=[C:19]([CH:21]=[CH2:22])[CH:18]=[C:17]([CH:23]=O)[CH:16]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[N:2].[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.[Na].Cl>CO.C(O)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:15]2[CH:20]=[C:19]([CH:21]=[CH2:22])[CH:18]=[C:17]([CH2:23][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:16]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: C1CCNC1
Reactant: C=Cc1cc(C=O)cc(C(Nc2ccc(C#N)cc2)C(=O)OC)c1
Agent: Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: CO
Product: C=Cc1cc(CN2CCCC2)cc(C(Nc2ccc(C#N)cc2)C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Eine suspension von 200 mg of the aldehyde described in Example 80.1 and 0.062 ml of pyrrolidine in 2 ml of MeOH was adjusted to pH 6 by the dropwise addition of acetic acid. Then, 46 mg of sodium cyanoborhydride were added and the mixture was stirred overnight at room temperature. It was acidified to pH 3 with 1N HCl and subsequently evaporated. The crude product was isolated by extraction and purified by chromatography on silica gel gereinigt. There were obtained 200 mg of methyl (RS)-(4-cyano-phenylamino)-(3-pyrrolidin-1-ylmethyl-5-vinyl-phenyl)-acetate as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:7][CH2:6]1.[CH:15]1([CH:18]=O)[CH2:17][CH2:16]1.[BH4-].[Na+].O>C(O)C>[CH:15]1([CH2:18][NH:14][CH2:13][CH2:12][CH2:11][N:8]2[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:18][CH:15]3[CH2:17][CH2:16]3)[CH2:10][CH2:9]2)[CH2:17][CH2:16]1
Reactant: O=CC1CC1
Reactant: NCCCN1CCN(CCCN)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C(CNCC1CC1)CN1CCN(CCCNCC2CC2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1,4-bis(3-aminopropyl)piperazine (0.51 mL, 2.5 mmol) and cyclopropanecarboxaldehyde (6392 μL, 5.24 mmol) in absolute ethanol (20 mL), 3 Å molecular sieves are added. After stirring the mixture at room temperature for 12 h, NaBH4 (1.9 g, 49.92 mmol) was added portionwise and the mixture was stirred for 12 h at room temperature. The reaction was quentched by dropwise addition of water (20 mL) and ethanol was removed under reduced pressure. The aqueous residue was extracted with CH2Cl2 (3×30 mL). Combined organic layers were extracted with HCl 1M. The combined aqueous layers were neutralized with NaOH 1M and extracted with CH2Cl2. Combined organic layers were dried over MgSO4. Crude compound is purified by flash chromatography on neutral aluminium oxide (CH2Cl2/MeOH).
Reaction SMILES: [CH3:1][N:2]1[CH2:7]N(C)CN(C)C1.[ClH:10].[C:11]([SH:15])([CH3:14])([CH3:13])[CH3:12]>C(#N)C>[ClH:10].[C:11]([S:15][CH2:7][NH:2][CH3:1])([CH3:14])([CH3:13])[CH3:12]
Reactant: CN1CN(C)CN(C)C1
Reactant: CC(C)(C)S
Agent: Cl
Solvent: CC#N
Product: CNCSC(C)(C)C
Temperature: -30 °C
Reaction time: 8 h

Procedure:
Two hundred ml. of acetonitrile and 6.45 g. (0.05 mole) of 1,3,5-trimethylhexahydro-s-triazine are charged to a 500 ml. 3-neck round bottom flask equipped with a stirrer, thermometer and dropping funnel. The mixture is stirred and cooled to -30° C. with a dry ice/acetone bath. Six grams of hydrogen chloride gas are added, followed by slow addition of 13.5 g. (0.15 mole) of tert.-butyl mercaptan dissolved in 50 ml. of acetonitrile. The mixture is then allowed to warm to room temperature and stand overnight.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.CC(=O)OCC>>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][N:23]([CH2:2][C:3]2[S:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:22][CH2:21]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: ClCc1nc2cccnc2s1
Solvent: CCOC(C)=O
Product: COc1ccccc1N1CCN(Cc2nc3cccnc3s2)CC1

Procedure:
The product from Example 38A (200 mg, 1.1 mmol), 1-(2-methoxyphenyl)piperazine (229 mg, 1.2 mmol), and D1 EA (380 μL, 2.2 mmol) were processed as described in Example 38B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.74 (m, 4H) 3.02 (m, 4H) 3.78 (s, 3H) 4.04 (s, 2H) 6.91 (m, 3H) 7.56 (dd, J=8.31, 4.75 Hz, 2H) 8.33 (dd, J=8.14, 1.70 Hz, 1H) 8.59 (dd, J=4.75, 1.70 Hz, 1H); (ESI) m/z 341 (M+H)+.
Reaction SMILES: [Cl:1][CH:2]([Cl:31])[C:3]([NH:5][C@H:6]([CH2:29][F:30])[C@@H:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:19][C:18]([CH2:20][NH:21]C(=O)OC(C)(C)C)=[N:17][N:16]=2)=[CH:11][CH:10]=1)[OH:8])=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:21][CH2:20][C:18]1[S:19][C:15]([C:12]2[CH:13]=[CH:14][C:9]([C@@H:7]([OH:8])[C@H:6]([NH:5][C:3](=[O:4])[CH:2]([Cl:1])[Cl:31])[CH2:29][F:30])=[CH:10][CH:11]=2)=[N:16][N:17]=1
Reactant: CC(C)(C)OC(=O)NCc1nnc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1nnc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)s1
Yield: 135.3 %

Procedure:
To a stirred solution of tert-butyl ((5-(4-((1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-hydroxypropyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)carbamate (100 mg, 0.203 mmol) in CH2Cl2 (10 mL) is added trifluoroacetic acid (1.0 mL). After 2 hours the reaction mixture is concentrated in vacuo and the residue washed with diethyl ether. The residue is dissolved in 10% methanol in CH2Cl2 and evaporated to dryness, washed with n-pentane, dried under vacuum to give the title compound (108 mg): 1H-NMR (400 MHz, DMSO-d6) δ 4.27-4.28 (m, 1H), 4.31-4.35 (m, 0.5H), 4.43-4.47 (m, 0.5H), 4.59-4.61 (m, 0.5H), 4.64 (s, 2H), 4.70-4.74 (m, 0.5H), 4.96 (t, J=2.76 Hz, 1H), 6.10 (d, J=4.28 Hz, 1H), 6.48 (s, 1H), 7.54 (d, J=8.32 Hz, 2H), 7.94 (d, J=8.32 Hz, 2H), 8.60 (bs, 2H), 8.64 (d, J=9.12 Hz, 1H). LC-Ms (m/z): [M+H]=393.10.
Reaction SMILES: [C:1]([O:4][CH2:5][C@@:6]([NH:27]C(=O)C)([CH2:25][CH3:26])[CH2:7][CH2:8][C:9]1[O:10][C:11]([C:14]#[C:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:12][CH:13]=1)(=[O:3])[CH3:2].O1CCCC1.CO.[OH2:38].[OH-:39].[Li+]>O>[C:2]([OH:39])(=[O:38])[C:1]([OH:4])=[O:3].[NH2:27][C@:6]([CH2:25][CH3:26])([CH2:7][CH2:8][C:9]1[O:10][C:11]([C:14]#[C:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)=[CH:12][CH:13]=1)[CH2:5][OH:4]
Reactant: CC[C@@](CCc1ccc(C#CCCOC2CCCCC2)o1)(COC(C)=O)NC(C)=O
Reactant: O
Reactant: [OH-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CC[C@](N)(CO)CCc1ccc(C#CCCOC2CCCCC2)o1
Product: O=C(O)C(=O)O
Yield: 99 %

Procedure:
To a solution of (2R)-1-acetoxy-2-acetylamino-2-ethyl-4-[5-(4-cyclohexyloxybut-1-ynyl)furan-2-yl]butane obtained in Example (25a) in a mixed solvent of tetrahydrofuran (0.5 ml), methanol (0.5 ml) and water (0.5 ml) was added lithium hydroxide monohydrate (44.7 mg, 1.07 mmol) with stirring, and the resulting mixture was stirred at 50° C. for 4 hours. After cooling, water was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane. The extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by chromatography on a basic silica gel column (NH type) using a mixed solvent of dichloromethane and methanol (1:0-50:1) as the eluent to afford the crude (2R)-2-amino-2-ethyl-4-[5-(4-cyclohexyloxybut-1-ynyl)furan-2-yl]butan-1-ol (35.3 mg, yield: 99%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]1COC[CH2:12]1.[CH2:16]([C@H:18]1[O:23][CH2:22][C@@H:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:20]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:19]1=[O:37])[CH3:17].ICC>COCCOC>[CH2:16]([C:18]1([CH2:11][CH3:12])[O:23][CH2:22][C@@H:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:20]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:19]1=[O:37])[CH3:17]
Reactant: C1CCOC1
Reactant: CC[C@H]1OC[C@@H](c2ccccc2)N(C(=O)OC(C)(C)C)C1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCI
Solvent: COCCOC
Product: CCC1(CC)OC[C@@H](c2ccccc2)N(C(=O)OC(C)(C)C)C1=O
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a 1 M solution of sodium bis(trimethylsilyl)amide in THF (1.64 mL, 1.64 mmol) at −78° C. was added dropwise a solution of tert-butyl (2R,5R)-2-ethyl-3-oxo-5-phenylmorpholine-4-carboxylate from Step C (500 mg, 1.64 mmol) in DME (25 mL) at −78° C. The resulting mixture was stirred at −78° C. for 10 min then iodoethane (0.131 mL, 1.64 mmol) was added. After stirring at −78° C. for 30 min, then at −30° C. for 30 min, the reaction mixture was cooled to −78° C. and quenched with saturated aqueous NH4Cl (20 mL) then extracted with EtOAc (2×40 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—95:5 to 70:30, to give the title compound. MS: m/z=278 (M−C4H7).