Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.O[CH2:18][C:19]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:20]=1[C:21]#[N:22]>>[C:21]([C:20]1[CH:23]=[C:24]([CH3:27])[CH:25]=[CH:26][C:19]=1[CH2:18][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1)#[N:22]
Reactant: Cc1ccc(CO)c(C#N)c1
Reactant: COC(=O)c1ccnc(-n2nccc2O)c1
Product: COC(=O)c1ccnc(-n2nccc2OCc2ccc(C)cc2C#N)c1

Procedure:
The title compound was prepared from methyl 2-(5-hydroxypyrazol-1-yl)pyridine-4-carboxylate (PREPARATION 6) and 2-(hydroxymethyl)-5-methylbenzonitrile according to the procedure for the preparation of Example 125, part B. 1H NMR (400 MHz, CDCl3): δ 3.40 (3H, s), 3.97 (3H, s), 5.40 (2H, s), 5.83 (1H, d, J=1.2 Hz), 7.43 (1H, d, J=8.8 Hz), 7.50 (1H, s), 7.58-7.62 (2H, m), 7.76 (1H, d, J=5.2 Hz), 8.33 (1H, s), 8.68 (1H, d, J=5.2 Hz). [M+H] Calc'd for C19H16N4O3, 349. Found, 349.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C@@H:3]([NH2:5])[CH3:4].[F:7][C:8]1[C:13]([F:14])=[C:12]([C:15](O)=[O:16])[C:11]([F:18])=[C:10]([F:19])[C:9]=1[CH3:20]>>[F:14][C:13]1[C:8]([F:7])=[C:9]([CH3:20])[C:10]([F:19])=[C:11]([F:18])[C:12]=1[C:15]([NH:5][C@H:3]([CH:2]([CH3:6])[CH3:1])[CH3:4])=[O:16]
Reactant: CC(C)[C@H](C)N
Reactant: Cc1c(F)c(F)c(C(=O)O)c(F)c1F
Product: Cc1c(F)c(F)c(C(=O)N[C@@H](C)C(C)C)c(F)c1F

Procedure:
Prepared in a similar manner to Example 162 using (S)-3-methylbutan-2-amine and 2,3,5,6-tetrafluoro-p-toluic acid acid (93%). 1H NMR (CDCl3) δ 0.98 (d, J=6.9 Hz, 6H) 1.18 (d, J=6.8 Hz, 3H), 2.29 (m, 3H), 4.09 (m, 1H), 5.72 (bs, 1H). MS (304.1, M+H) m.p. 146-147° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4](F)[CH:3]=1.Cl.Cl.[O:15]1[CH2:20][CH2:19][CH:18]([N:21]2[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]2)[CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4]([NH:27][CH:24]2[CH2:23][CH2:22][N:21]([CH:18]3[CH2:19][CH2:20][O:15][CH2:16][CH2:17]3)[CH2:26][CH2:25]2)[CH:3]=1
Reactant: O=[N+]([O-])c1cc(F)c(Br)cc1F
Reactant: NC1CCN(C2CCOCC2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)c(Br)cc1NC1CCN(C2CCOCC2)CC1
Temperature: 200 °C
Yield: 107.7 %

Procedure:
A mixture of 4-bromo-2,5-difluoro-1-nitrobenzene (1 g, 4.2 mmol), 1-(tetrahydro-2H-pyran-4yl)piperidin-4-amine dihydrochloride salt (D40, 1.08 g, 4.2 mmol), and di-iso-propylethylamine (2.2 ml, 1.26 mmol) in dimethylformamide (10 ml) was heated in microwave reactor for 5 min at 200° C. The mixture was washed with water, then extracted with dichloromethane and the extract dried over MgSO4 and concentrated under vacuum. The crude material was purified on silica column (100 g of silica, ethyl acetate/methanol: 1.0% to 0%, 3CV; 2.0% to 100% 2CV 3. 100% to 100% 5CV) to leave 1.82 g (96%) of a mixture of title compound and an unknown impurity (˜3:1 by HPLC).
Reaction SMILES: C([Li:5])CCC.[CH2:6]([C:10]1[CH2:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][CH2:8][CH3:9]>CCCCCC.C1COCC1>[CH2:6]([C:10]1([Li:5])[CH:14]=[CH:13][CH:12]=[CH:11]1)[CH2:7][CH2:8][CH3:9]
Reactant: [Li]CCCC
Reactant: CCCCC1=CC=CC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: [Li]C1(CCCC)C=CC=C1

Procedure:
Being cooled in an ice-water bath, a solution 32.9 ml of butyl lithium(0.082 mol) in 2.5M hexane was slowly dripped to a solution of 10.0 g(0.082 mol) of butyl-cyclopentadiene in 100 ml THF with stirring. After the dripping was finished, the resultant mixture was continuously stirred for 1 hour, a white muddy solution of butyl-cyclopentadienyl lithium was then obtained.
Reaction SMILES: [O:1]([CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([CH:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([CH3:19])=[O:18])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[O:1]([CH2:8][CH2:9][N:10]1[CH2:11][CH2:12][N:13]([CH:16]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:17]([OH:18])[CH3:19])[CH2:14][CH2:15]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)C(c1ccccc1)N1CCN(CCOc2ccccc2)CC1
Solvent: CO
Product: CC(O)C(c1ccccc1)N1CCN(CCOc2ccccc2)CC1
Temperature: 0 °C

Procedure:
To 1-(N-2-phenoxy-ethyl-piperazino)-1-phenylacetone (1 mole) dissolved in anhydrous methanol (1 liter) is added BH4K (1 mole) portionwise, at 0° C., with stirring. On completion of the addition (1 hour), the reaction mixture is stirred 24 hours at room temperature. The methanol is removed in vacuo over a water-bath, the resulting material is then taken up into methylene chloride which is washed with water to neutral pH. Concentration gives white crystals which melt at 100° C.
Reaction SMILES: Cl.[CH3:2][NH:3][CH:4]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([N:22]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])[CH2:23][CH2:24][CH3:25])[CH2:18][CH2:17]2)[CH2:5]1.CN1CCOCC1.[Cl:43][C:44]1[CH:52]=[CH:51][CH:50]=[CH:49][C:45]=1[C:46](Cl)=[O:47]>C(Cl)Cl>[ClH:43].[CH3:2][N:3]([CH:4]1[CH2:8][CH:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:6]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([N:22]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])[CH2:23][CH2:24][CH3:25])[CH2:18][CH2:17]2)[CH2:5]1)[C:46]([C:45]1[CH:49]=[CH:50][CH:51]=[CH:52][C:44]=1[Cl:43])=[O:47]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CCCN(C(=O)OCc1ccccc1)C1CCN(CC2CC(NC)CC2c2ccccc2)CC1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCCN(C(=O)OCc1ccccc1)C1CCN(CC2CC(N(C)C(=O)c3ccccc3Cl)CC2c2ccccc2)CC1
Reaction time: 16 h

Procedure:
To a solution of 1-(RS)-(methylamino)-3-(SR)-((4-(N-(benzyloxycarbonyl)-N-(propyl)amino)piperidin-1-yl)methyl)-4-(SR)-phenylcyclopentane hydrochloride from Step A (5.5 mg, 0.012 mmol) in methylene chloride (1 mL) was added N-methyl morpholine (0.005 mL, 0.035 mmol) and 2-chlorobenzoyl chloride (4 mg, 0.024 mmol). After 16 h, the reaction was concentrated and the residue purified on Prep TLC to afford the free amine of the title compound. This was taken up in ether and excess 1N hydrogen chloride in ether was added. The volatiles were removed under a stream of nitrogen and evaporated to dryness under vacuum.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]=[C:12]([NH:14][C:15](OC)=[O:16])[N+:11]([O-:19])=[C:10]([NH:20][C:21]([O:23][CH3:24])=[O:22])[CH:9]=2)[CH2:3]1.C(Cl)Cl.[OH-].[Na+]>O>[OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:9]=[C:10]([NH:20][C:21]([O:23][CH3:24])=[O:22])[N:11]3[O:19][C:15](=[O:16])[N:14]=[C:12]3[N:13]=2)[CH2:3]1
Reactant: COC(=O)Nc1cc(N2CCCC(O)C2)nc(NC(=O)OC)[n+]1[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)Nc1cc(N2CCCC(O)C2)nc2nc(=O)on12
Reaction time: 1 h

Procedure:
5.6 G. of dimethyl racemic-6-(3-hydroxy-1-piperidinyl)-2,4-pyrimidine-dicarbamate-3-oxide are suspended in 100 ml. of methylene chloride and 100 ml. of water. The suspension is adjusted with concentrated sodium hydroxide to pH 12.7. The mixture is stirred for 1 hour, the two phases are then separated and the aqueous phase is adjusted to pH 3 with concentrated hydrochloric acid, a white precipitate separating out. This precipitate is filtered off and recrystallized from a mixture of methylene chloride and methanol, there being obtained pure methyl racemic-5-(3-hydroxy-1-piperidinyl)-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]pyrimidine-7-carbamate, having a melting point of 244°-247° C. (decomposition).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])[CH2:2][CH3:3].[NH2:14][C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17]([NH2:19])=[O:18].C(N(CC)CC)C>C(#N)C>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH:14][C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17]([NH2:19])=[O:18])=[O:8])[CH2:2][CH3:3]
Reactant: CCCOc1ccccc1C(=O)Cl
Reactant: NC(=O)c1ccncc1N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCOc1ccccc1C(=O)Nc1cnccc1C(N)=O

Procedure:
In a similar manner to Example 68 a) reaction of 2-propoxybenzoyl chloride (0.99 g), 3-aminoisonicotinamide (0.69 g) and triethylamine (0.51 g) in acetonitrile (15 ml) afforded a crude product (1.45 g) which was recrystallized from methanol to afford 3-(2-propoxybenzamido)isonicotinamide, 0.73 g, m.p. 214-7° C.
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH:15]([NH:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])([CH3:17])[CH3:16]>ClCCl>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][N:18]([CH:15]([CH3:17])[CH3:16])[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1)[CH3:24]
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CNC(C)C
Solvent: ClCCl
Product: CCOC(=O)CN(c1ncc(C(=O)OC)cc1[N+](=O)[O-])C(C)C
Temperature: 25 °C
Yield: 79.6 %

Procedure:
Methyl 6-chloro-5-nitronicotinate (2 g, 9.23 mmol) was added to ethyl 2-(isopropylamino)acetate (5.0 g, 34.5 mmol) neat while stirring at room temperature. The viscous yellow reaction was heated to 90° C. for one h and then allowed to cool back to room temperature. The reaction was diluted with dichloromethane (20 mL) and purified via column chromatography (220 g SiO2, 20-30% gradient, ethyl acetate in hexanes) to yield the title compound (2.39 g, 83%) as a yellow oil. [M+H] calc'd for C, 14; H, 19; N, 3; O, 6, 326; found, 326.
Reaction SMILES: C(O)C.[Na].[CH2:5]([OH:17])[C@H:6]([OH:16])[C@@H:7](O)[C@H:8]([OH:14])[C:9]([C:11]([OH:13])=[O:12])=[O:10]>CC(C)=O>[O:12]=[C:11]1[O:13][C@H:7]([C@H:6]([CH2:5][OH:17])[OH:16])[C:8]([OH:14])=[C:9]1[OH:10]
Reactant: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: [Na]
Solvent: CCO
Solvent: CC(C)=O
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O

Procedure:
JP-AS 58-177986 describes a process which comprises the addition of ethanol and acetone to the sodium salt of 2-keto-L-gulonic acid, neutralization with hydrochloric acid, separation of the precipitated sodium chloride by filtration and subsequently the keeping of the reaction mixture at temperatures in the range from 25° C. to 75° C., whereby L-ascorbic acid is obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CS(O[CH:23]([CH:25]1[CH2:30][CH2:29][N:28]([C:31]2[O:35][N:34]=[C:33]([CH:36]([CH3:38])[CH3:37])[N:32]=2)[CH2:27][CH2:26]1)[CH3:24])(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:38][CH:36]([C:33]1[N:32]=[C:31]([N:28]2[CH2:27][CH2:26][CH:25]([CH:23]([O:17][C:14]3[CH:13]=[CH:12][C:11]([C:8]4[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=4)=[N:16][CH:15]=3)[CH3:24])[CH2:30][CH2:29]2)[O:35][N:34]=1)[CH3:37]
Reactant: CC(C)c1noc(N2CCC(C(C)OS(C)(=O)=O)CC2)n1
Reactant: CS(=O)(=O)c1ccc(-c2ccc(O)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1noc(N2CCC(C(C)Oc3ccc(-c4ccc(S(C)(=O)=O)cc4)nc3)CC2)n1

Procedure:
The title compound (0.295 g, 54%) was prepared as a white foam from 6-[4-(methylsulfonyl)phenyl]-3-pyridinol (0.29 g, 1.16 mmol), (±)-1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl methanesulfonate (0.53 g, crude), K2CO3 (0.32 g, 2.32 mmol) in DMF (10 mL) in a manner similar to Example 139, Step 3. The crude material was purified by chromatography on a silica gel column eluted with 1:7 acetone/CH2Cl2 to give the title compound as a white foam. 1H NMR (400 MHz, CDCl3): δ 8.38 (d, 1H, J=3.0 Hz), 8.13 (d, 2H, J=8.5 Hz), 8.00 (d, 2H, J=8.6 Hz), 7.74 (d, 1H, J=8.8 Hz), 7.35-7.25 (m, 1H), 4.35-4.25 (m, 1H), 4.25-4.15 (m, 2H), 3.10-3.00 (m, 5H), 2.87 (septet, 1H, J=7.0 Hz), 2.05-1.95 (m, 1H), 1.95-1.75 (m, 2H), 1.40-1.20 (m, 2H), 1.34 (d, 3H, J=6.3 Hz), 1.27 (d, 6H, J=6.9 Hz); LRMS (ESI), m/z 471 (M+H).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:46](=[O:47])[N:6]2[C:7]([C:33]([O:35]CC3C=CC([N+]([O-])=O)=CC=3)=[O:34])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([C:19]([C:21]5[CH:22]=[N:23][CH:24]=[C:25]([C:27]6[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=6)[CH:26]=5)=[O:20])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[CH3:48]I>>[OH:1][C@@H:2]([C@H:4]1[C:46](=[O:47])[N:6]2[C:7]([C:33]([O-:35])=[O:34])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([C:19]([C:21]5[CH:22]=[N+:23]([CH3:48])[CH:24]=[C:25]([C:27]6[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=6)[CH:26]=5)=[O:20])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5cncc(-c6ccccc6)c5)c4s3)[C@H](C)[C@H]12
Reactant: CI
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3cn4cnc(C(=O)c5cc(-c6ccccc6)c[n+](C)c5)c4s3)[C@H](C)[C@H]12

Procedure:
An N-quaternarized compound (84 mg) was prepared in substantially the same manner as in Example 24, except that 97 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(5-phenylpyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate and 0.063 ml of methyl iodide were used as the starting compounds. The title compound (20.3 mg) was prepared in substantially the same manner as in step c) of Example 1, except that this compound was used as the starting compound.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[CH2:3][CH2:4][NH:5][C:6](=[O:21])[C@H:7]([CH3:20])[CH2:8][C@H:9]([OH:19])[C@@H:10]([NH2:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C.[O:33]=[C:34]1[CH2:38][CH2:37][CH2:36][N:35]1[C:39]1[CH:40]=[C:41]([CH:45]=[C:46]([N:48]2[CH2:52][CH2:51][CH2:50][C:49]2=[O:53])[CH:47]=1)[C:42](O)=[O:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:11]([C@H:10]([NH:18][C:42](=[O:43])[C:41]1[CH:40]=[C:39]([N:35]2[CH2:36][CH2:37][CH2:38][C:34]2=[O:33])[CH:47]=[C:46]([N:48]2[CH2:52][CH2:51][CH2:50][C:49]2=[O:53])[CH:45]=1)[C@@H:9]([OH:19])[CH2:8][C@H:7]([C:6](=[O:21])[NH:5][CH2:4][CH2:3][C:2]([CH3:22])([CH3:1])[CH3:23])[CH3:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NCCC(C)(C)C
Reactant: O=C(O)c1cc(N2CCCC2=O)cc(N2CCCC2=O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(N2CCCC2=O)cc(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 64.2 %

Procedure:
To a solution of (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (3,3-dimethylbutyl)amide (D2) (46 mg, 0.145 mmol) in DMF (2 ml) was added iPr2NEt (61 μl, 0.348 mmol) followed by 3,5-bis-2-oxopyrrolidin-1-yl)benzoic acid (D8) (50 mg, 0.174 mmol) and HATU (77 mg, 0.203 mmol). The reaction mixture was stirred at room temperature for 6 hours. The solvent was evaporated to dryness and the residue was partitioned between 0.5 M HCl and DCM. The organic phase was separated and washed with NaHCO3, brine and dried over MgSO4, filtered and evaporated to afford the crude product (61 mg) as yellow oil. The product was triturated in petroleum/diethylether which yielded E5 (55 mg) as a yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:15][C:16]([F:25])([F:24])[CH2:17][CH2:18][CH:19]([C:22]#[N:23])[C:20]#[N:21]>CN(C)C=O>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][C:19]([CH2:18][CH2:17][C:16]([F:15])([F:24])[F:25])([C:20]#[N:21])[C:22]#[N:23])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CC(C#N)(C#N)CCC(F)(F)F)cc1
Yield: 44.8 %

Procedure:
Using 0.23 g of 4-t-butylbenzyl bromide, 3 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil), and 0.17 g of (3,3,3-trifluoropropyl)malononitrile, and according to the process described in the Production Example 26, there was obtained 0.14 g of 2-(4-t-butylbenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (33)).
Reaction SMILES: [F:1][C:2]1[CH:36]=[C:35]([NH:37][C:38]([NH:40][C:41](=[O:49])[CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[S:39])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[C:16]([CH:30]=[CH:31][CH:32]=3)[CH2:17][N:18]([CH2:26][CH2:27][O:28][CH3:29])C(=O)OC(C)(C)C)[S:13][C:6]=12.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:36]=[C:35]([NH:37][C:38]([NH:40][C:41](=[O:49])[CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[S:39])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:32]=[CH:31][CH:30]=[C:16]([CH2:17][NH:18][CH2:26][CH2:27][O:28][CH3:29])[CH:15]=3)[S:13][C:6]=12
Reactant: COCCN(Cc1cccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)c1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCNCc1cccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)c1
Reaction time: 12 h
Yield: 63 %

Procedure:
To a solution of 75 (440 mg, 0.6 mmol) in DCM (10 mL), TFA (145 μL, 1.9 mmol) was added and the reaction was stirred for 12 hours, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluent MeOH/EtOAc (1:10), to afford the title compound 76a (227 mg, 63% yield) as a light yellow solid. 1H NMR (DMSO) δ (ppm): 8.54 (d, J=5.5 Hz, 1H), 8.07 (s, 1H), 8.02-8.0 (m, 2H), 7.93 (d-t, J=2.0 Hz, 1H), 7.55-7.53 (m, 4H), 7.34-7.32 (m, 4H), 7.29-7.26 (m, 1H), 6.68 (d, J=5.3 Hz, 1H), 4.19 (s, 2H), 3.81 (s, 1H), 3.57 (t, J=4.9 Hz, 2H), 3.33 (s, 2H), 3.29 (s, 3H), 3.08 (t, J=4.9 Hz, 2H), 2.84 (q, J=2.2 Hz, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][O:7][C@@H:8]2[C@@H:12]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[O:11][C@@H:10]([N:18]3[CH:25]=[C:24]([F:26])[C:22](=[O:23])[NH:21][C:19]3=[O:20])[CH2:9]2)=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1.C(N(CC)CC)C>O1CCOCC1>[C:15]([O:14][CH2:13][C@H:12]1[O:11][C@@H:10]([N:18]2[CH:25]=[C:24]([F:26])[C:22](=[O:23])[N:21]([C:34](=[O:35])[C:33]3[CH:37]=[CH:38][C:30]([Cl:29])=[CH:31][CH:32]=3)[C:19]2=[O:20])[CH2:9][C@@H:8]1[O:7][CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:28][CH:27]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OCc1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)n(C(=O)c3ccc(Cl)cc3)c2=O)C[C@@H]1OCc1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 82.4 %

Procedure:
To a solution of 0.30 g of 3'-O-(4-chlorobenzyl)-5'-O-acetyl-2'-deoxy-5-fluorouridine in 30 ml of dioxane were added 0.38 g of 4-chlorobenzoyl chloride and 0.61 ml of triethylamine, and the mixture was stirred at 40° C. for 3 hours. The insolubles were removed by filtration, and the residue was dissolved in 50 ml of ethyl acetate. The solution was washed with water and dried. The ethyl acetate was distilled off, and the residue was placed on a silica gel column and eluted with chloroform-n-hexane (3:2), thereby producing 0.33 g of the title compound in a yield of 82%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[C:14]([O:18][C:19](=[O:34])[C@H:20]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[NH:21][C:22](=[O:26])[C@H:23]([CH3:25])[NH2:24])([CH3:17])([CH3:16])[CH3:15].C(N[C@H](C(O)=O)C)(OC(C)(C)C)=O.Cl.C(OC(=O)[C@H](CC1C=CC=CC=1)N)(C)(C)C>CO.C(Cl)(Cl)Cl>[C:14]([O:18][C:19](=[O:34])[C@H:20]([CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[NH:21][C:22](=[O:26])[C@H:23]([CH3:25])[NH:24][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)([CH3:15])([CH3:16])[CH3:17]
Reactant: C[C@H](N)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C

Procedure:
Following General Procedure C and using 3,5-difluorophenylacetic acid (Oakwood) and N-(L-alaninyl)-L-phenylalanine tert-butyl ester hydrochloride (prepared from N-BOC-L-alanine (Sigma) and L-phenylalanine tert-butyl ester hydrochloride (Advanced Chemtech) using General Procedure C, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a gel. The reaction was monitored by tlc (Rf=0.5 in 4% MeOH/CHCl3) and the product was purified by silica gel chromatography using 4% MeOH/CHCl3 as the eluent.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[CH2:18][OH:19]>>[NH2:1][C:2]1[CH:9]=[C:8]([O:19][CH2:18][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][N:12]2[CH3:11])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: CN1CCCCC1CO
Reactant: N#Cc1cnc(N)cc1F
Product: CN1CCCCC1COc1cc(N)ncc1C#N

Procedure:
From intermediate 21 and racemic (1-methylpiperidin-2-yl)methanol, reacted in an analogous manner to the preparation of intermediate 47. (UPLC-MS 3) tR 0.36 min; ESI-MS 247.2 [M+H]+.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7](=[O:10])[CH2:8][CH3:9])=[CH:5][N:6]=1.[CH3:11][S:12]([O-:14])=[O:13].[Na+]>CS(C)=O.C(OCC)(=O)C.[Cu](I)I>[CH3:11][S:12]([C:2]1[S:3][C:4]([C:7](=[O:10])[CH2:8][CH3:9])=[CH:5][N:6]=1)(=[O:14])=[O:13]
Reactant: CCC(=O)c1cnc(Br)s1
Reactant: CS(=O)[O-]
Agent: I[Cu]I
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCC(=O)c1cnc(S(C)(=O)=O)s1
Temperature: 120 °C
Yield: 56.3 %

Procedure:
To a solution of 1-(2-bromo-thiazol-5-yl)-propan-1-one (75 mg, 0.34 mmol) in dimethyl sulfoxide (3 mL) was added the sodium methylsulfinate (41 mg, 0.34 mmol) followed by copper iodide (65 mg, 0.34 mmol). The mixture was heated in a microwave at 120° C. for 1 h. The reaction was diluted with ethyl acetate (20 mL) and washed with sat. sodium bicarbonate solution (120 ml) and brine (10 ml). The aqueous phase was extracted with ethyl acetate (2×10 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated to give 1-(2-methanesulfonyl-thiazol-5-yl)-propan-1-one (42 mg, 56%) that was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH:15]([CH3:17])[CH3:16])[C:11]([Cl:18])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:48])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[C:39]([CH2:40][O:41][CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)=[CH:38][N:37]=[N:36]2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH:15]([CH3:16])[CH3:17])[C:11]([Cl:18])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:48])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[C:39]([CH2:40][O:41][CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)=[CH:38][N:37]=[N:36]2)[CH:30]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)Nc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Product: CC(C)Nc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1Cl

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-isopropylamino-phenyl)-carbamic acid tert-butyl ester (Example J40) (300 mg, 1.0 mmol) 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) (401 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow foam (375 mg, 60%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13](O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=[CH:6]2.P(Br)(Br)(Br)(Br)[Br:21]>>[Br:21][CH:13]([C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: BrP(Br)(Br)(Br)Br
Reactant: CCOC(=O)C(O)c1ccc2cc(OC)ccc2c1
Product: CCOC(=O)C(Br)c1ccc2cc(OC)ccc2c1

Procedure:
To 0.0476 moles of ethyl 6-methoxy- 2-naphthylglycolate there is added slowly with stirring at 40°-50°C 23 g. (0.053 moles) of phosphorus pentabromide. The mixture is stirred at room temperature for 16 hours, then diluted with 70 ml. of petroleum ether, and poured into 125 ml. of ice-cold water. The organic phase is separated, washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo to obtain ethyl α-bromo-6-methoxy-2-naphthylacetate.