Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[CH:10]=[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26]CC4C=CC=CC=4)[CH:21]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(#N)C.[ClH:37]>C(O)C>[N:1]1([C:7]2[N:8]=[C:9]([C:20]3[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=3)[CH:10]=[C:11]([NH:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[N:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1.[ClH:37]
Reactant: c1ccc(COc2cccc(-c3cc(Nc4cccnc4)nc(N4CCOCC4)n3)c2)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCO
Product: Oc1cccc(-c2cc(Nc3cccnc3)nc(N3CCOCC3)n2)c1
Reaction time: 20 h

Procedure:
{2-Morpholin-4-yl-6-[3-(phenylmethoxy)phenyl]pyrimidin-4-yl}-3-pyridylamine (1 eq) is suspended in ethanol in a round bottom flask, purged with N2. 10% Pd/C (20% wt) was added. The flask was evacuated and filled up with H2 (contained in a balloon) for five times, then the reaction mixture was stirred under H2 for 20 h. The catalyst was filtered off through a pad of celite washing thoroughly with EtOH, MeOH, CH2Cl2, and acetonitrile (almost one liter of the mixture of solvents was used to ensure the complete solubilization of the product). The solvent was evaporated under reduced pressure and the residue purified by reverse phase chromatography (Buffer A: 0.1% TFA in H2O, Buffer B: 0.1% TFA in CH3CN; Column: Waters, C18, 47×300 mm; gradient: 1.1%, 10%-60% B in 45 min). The free base thus obtained was lyophilized from a 1:1 mixture of acetonitrile and 1N HCl, obtaining the desired 3-[2-morpholin-4-yl-6-(3-pyridylamino)pyrimidin-4-yl]phenol as the bis HCl salt. The spectral data are the following:
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C:2]1[NH:9][C:7](=[O:8])[NH:6][C:4](=[O:5])[CH:3]=1.[OH-].[Na+:13].CCO>O>[C:1]([O-:11])(=[O:10])[C:2]1[NH:9][C:7](=[O:8])[NH:6][C:4](=[O:5])[CH:3]=1.[Na+:13]
Reactant: O=C(O)c1cc(=O)[nH]c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C([O-])c1cc(=O)[nH]c(=O)[nH]1
Reaction time: 1 h

Procedure:
FIG. 2 illustrates the synthesis of Sodium Methotrexate Orotate. Orotic acid (1.74 g) was treated with sodium hydroxide (0.45 g) in water (100 mL). The mixture was warmed, stirred for 1 h and stored in the refrigerator overnight. Etanol (30 mL) was added to the solution and the precipitate was collected by filtration to give sodium orotate as a colorless solid which was dried in vacuum over night and used for the next step (1.51 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:26]=[C:27]([NH:31][C:32](=[O:34])[CH3:33])[CH:28]=[CH:29][CH:30]=2)[CH2:21][CH2:20]1>>[C:32]([NH:31][C:27]1[CH:26]=[C:25]([CH:22]2[CH2:23][CH2:24][N:19]([CH2:18][CH2:17][CH2:16][NH:15][C:12]([C:8]3([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10][CH2:11]3)=[O:14])[CH2:20][CH2:21]2)[CH:30]=[CH:29][CH:28]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCC1
Product: CC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CCC3)CC2)c1

Procedure:
Example 74 was prepared from 1-(4-chlorophenyl)cyclo butanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.55 (s, 1H), 7.36–7.26 (m, 7H), 6.97 (d, 1H, J=7.2 Hz), 6.50 (brs, 1H), 3.30 (dd, 2H, J=6.0, 12.0 Hz), 2.98–2.95 (m, 2H), 2.87–2.80 (m, 2H), 2.53–2.42 (m, 3H), 2.34 (t, 2H, J=6.4 Hz), 2.20 (s, 3H), 2.15–1.82 (m, 6H), 1.74–0.161 (m, 4H); ESMS m/e: 468.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][Si](CC)(CC)CC)=[CH:9][C:8]=2[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:6][CH2:5]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[CH:14])=[CH:9][C:8]=2[C:22]([CH3:23])([CH3:25])[CH3:24])[CH2:6][CH2:5]1)[CH3:2]
Reactant: CCOC1(c2ccc(C#C[Si](CC)(CC)CC)cc2C(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(C2(OCC)CC2)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure E; [4-(1-ethoxycyclopropyl)-3-tert-butyl-phenylethynyl]-triethylsilane (Intermediate 111, 215.0 mg, 0.69 mmol) in methanol (10 mL) was treated with potassium carbonate (80.0 mg, 0.58 mmol) and stirred overnight at ambient temperature. The crude alkyne, 169 mg, was used directly in the next reaction.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:11]=1[C:19]([F:22])([F:21])[F:20]>OS(O)(=O)=O>[I:1][C:13]1[CH:14]=[C:15]([N+:16]([O-:18])=[O:17])[C:10]([CH3:9])=[C:11]([C:19]([F:20])([F:21])[F:22])[CH:12]=1
Reactant: Cc1c([N+](=O)[O-])cccc1C(F)(F)F
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Product: Cc1c([N+](=O)[O-])cc(I)cc1C(F)(F)F
Temperature: 2.5 °C
Reaction time: 0.67 h

Procedure:
To H2SO4 (110 mL, 96%) stirring under a nitrogen atmosphere at 0-5° C. was added N-iodosuccinimide (41.13 g, 1.5 eq). The resulting black/dark red mixture was stirred at 0-5° C. for 40 minutes. To this was added dropwise commercially available 2-methyl-3-nitrobenzotrifluoride (25.0 g, 121.9 mmol) in H2SO4 (75 mL). Once the addition was completed, ca. 1 hour, the mixture was stirred at 5-10° C. for 5 hours. The resulting mixture was poured into ice (600 mL) and extracted with EtOAc (400 mL, 3×200 mL). The extracts were combined, washed with saturated aqueous Na2SO3 (500 mL) and H2O (400 mL). The organic phase was then dried (anhydrous MgSO4). After filtration the solvent was removed in vacuo to give a dark oil. Purification was carried out by column chromatography (silica gel, eluting hexane) to give the title compound as a light yellow/green oil which solidified on standing (34.81 g, 86%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:11])[C:7]=1[C:8]([OH:10])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[Cl:45][C:46]1[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:47]=1[CH2:53][N:54]1[CH:58]=[CH:57][C:56]([NH2:59])=[N:55]1>CN(C)C=O>[Cl:45][C:46]1[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:47]=1[CH2:53][N:54]1[CH:58]=[CH:57][C:56]([NH:59][C:8]([C:7]2[C:6]([F:11])=[CH:5][N:4]=[CH:3][C:2]=2[F:1])=[O:10])=[N:55]1
Reactant: Nc1ccn(Cc2ccc(Cl)cc2Cl)n1
Reactant: O=C(O)c1c(F)cncc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccn(Cc2ccc(Cl)cc2Cl)n1)c1c(F)cncc1F
Reaction time: 0.08 h
Yield: 114.8 %

Procedure:
To a solution of 3,5-difluoro-4-pyridinecarboxylic acid (15.9 mg, 0.1 mmol, Frontier Scientific) in dimethylformamide (0.1 ml) was added HATU (38 mg, 0.1 mmol) in dimethylformamide (0.2 mL), followed by N,N-diisopropylethylamine (0.050 ml, 0.286 mmol) and the resulting solution left for 5 min. Finally, a solution of 1-[(2,4-dichlorophenyl)methyl]-1H-pyrazol-3-amine (24.2 mg, 0.01 mmol, ChemCollect GmbH) in N,N-dimethylformamide (0.1 ml) was added and the resulting solution shaken for 10 min. The solution was then left to stand for 16 h at ambient temperature after which the solvent was removed. A 1:1 mixture of dimethylsulphoxide:methanol (0.6 ml) was added and the solution purified by MDAP on SUNFIRE C18 column (Method D). The appropriate fraction was concentrated in vacuo then under nitrogen flow to give the title compound (4.4 mg);
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([CH:10](C(OCC)=O)[C:11]([O:13][CH2:14][C:15]2C=CC=CC=2)=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]>C(O)C.[Pd]>[N+:1]([C:4]1[N:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C(C(=O)OCc1ccccc1)c1ccc([N+](=O)[O-])nc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Cc1ccc([N+](=O)[O-])nc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of benzyl ethyl 2-(6-nitro-3-pyridinyl)malonate (5.26 g, 15.3 mmol,) in ethanol was added palladium on carbon (530 mg) and stirred for 6 h under hydrogen atmosphere at room temperature. The catalyst was filtered off through a pad of celite and the filtrate was concentrated to give a title compound as yellow brown oil.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:44]=[CH:43][C:16]([CH2:17][N:18]([C:30]3[CH:42]=[CH:41][C:33]4[O:34]C(C)(C)[O:36][C:37](=[O:38])[C:32]=4[CH:31]=3)[C:19]([C:21]3[S:22][C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[CH:25]=3)=[O:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CCO>[S:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[CH:25]=[C:21]1[C:19]([N:18]([CH2:17][C:16]1[CH:43]=[CH:44][C:13]([C:12]#[C:11][C:8]2[CH:7]=[CH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:10][CH:9]=2)=[CH:14][CH:15]=1)[C:30]1[CH:42]=[CH:41][C:33]([OH:34])=[C:32]([CH:31]=1)[C:37]([OH:38])=[O:36])=[O:20]
Reactant: CCCCc1ccc(C#Cc2ccc(CN(C(=O)c3cc4ccccc4s3)c3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)c3cc4ccccc4s3)c3ccc(O)c(C(=O)O)c3)cc2)cc1

Procedure:
The titled compound was prepared following the procedure C using N-{4-[(4-butylphenyl)ethynyl]benzyl}-N-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-6-yl)-1-benzothiophene-2-carboxamide and NaOH 5M aq. in the presence of EtOH as a beige powder (37%). 1H NMR (CDCl3/MeOD 35:1, 300 MHz) δ 7.67 (m, 3H), 7.45-7.24 (m, 9H) 7.11 (m, 3H), 6.91 (d, J=9 Hz, 1H) 5.05 (s, 2H), 2.61 (t, J=7.5 Hz, 2H), 1.58 (m, 2H), 1.34 (m, 2H), 0.91 (t, J=7.2 Hz, 3H). M− (ESI): 558.3; M+ (ESI): 560.1 HPLC, Rt: 5.62 min (Purity: 99.2%).
Reaction SMILES: Cl.CN.[CH2:4]([N:6](CC)CC)C.[F:11][C:12]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:13]=1[C:14](Cl)=[O:15]>ClCCl>[F:11][C:12]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:13]=1[C:14]([NH:6][CH3:4])=[O:15]
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1cc(I)ccc1F
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)c1cc(I)ccc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 87 %

Procedure:
Add methylamine hydrochloride (0.57 g, 8.4 mmol) and triethylamine (2.17 mL, 15.5 mmol) to a solution of 2-fluoro-5-iodobenzoyl chloride (2.0 g, 7.0 mmol) in dichloromethane (100 mL) at 0° C. Warm to room temperature and stir 20 h. Concentrate and purify by silica gel chromatography, eluting with a gradient of 75:25 to 60:40 hexanes:ethyl acetate, to give the title compound as a white solid (1.7 g, 87%).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[O:19])[CH2:7][CH2:8][CH3:9])C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]1[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:30]=1[CH3:36]>CN(C=O)C>[CH3:36][C:30]1[CH:31]=[CH:32][C:33]([CH3:35])=[CH:34][C:29]=1[CH2:28][N:12]1[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:10]([CH:6]([CH2:7][CH2:8][CH3:9])[CH2:5][C:4]([OH:3])=[O:20])[C:11]1=[O:19]
Reactant: Cc1ccc(C)c(CBr)c1
Reactant: CCCC(CC(=O)OCC)n1c(=O)[nH]c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCC(CC(=O)O)n1c(=O)n(Cc2cc(C)ccc2C)c2ccccc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
3-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-hexanoic acid ethyl ester (40 mg, 0.145 mmol), prepared as described above, was dissolved in DMF (1 mL), and potassium carbonate (69 mg, 0.50 mmol) was added followed by 2-bromomethyl-1,4-dimethyl-benzene (56.3 mg, 0.28 mmol). The resulting mixture was heated at 80° C. for 4 h, cooled, filtered, and the solution was treated directly with the Amberlyst® resin (524 mg, 0.7 mmol). This reaction mixture was agitated overnight and the resin was then filtered and washed with several portions of methanol. The product was eluted by treating the resin with a 20% solution of formic acid in methanol (2×3 mL) and washing with methanol (2×3 mL). The combined eluant and final wash was evaporated to provide the title compound (25 mg, 47%). LCMS (ESMS): m/z 367 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([N:12]2[CH2:16][CH:15]([C:17]([F:20])([F:19])[F:18])[CH:14]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[CH2:13]2)=[O:11])[CH:3]=[CH:2]1.[CH2:35]1OCCOCCOCCOCCOCCOC1.CC([O-])(C)C.[K+].CI>CCOCC>[CH3:35][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([N:12]2[CH2:16][CH:15]([C:17]([F:19])([F:20])[F:18])[CH:14]([CH2:21][N:22]3[CH2:23][CH2:24][CH:25]([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)[CH2:26][CH2:27]3)[CH2:13]2)=[O:11])[CH:3]=[CH:2]1
Reactant: O=C(c1cccc2cc[nH]c12)N1CC(CN2CCC(c3ccc(F)cc3)CC2)C(C(F)(F)F)C1
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOCC
Product: Cn1ccc2cccc(C(=O)N3CC(CN4CCC(c5ccc(F)cc5)CC4)C(C(F)(F)F)C3)c21
Reaction time: 0.08 h

Procedure:
To a solution of 0.033 g (0.07 mmol) of 1-(7-indolecarbonyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(trifluoromethyl)pyrrolidine and 0.022 g (0.084 mmol) of 18-Crown-6 ether in 2 mL of ether at rt was added 0.084 mL of KOt-Bu (1M in t-BuOH). After stirring for 5 min, 0.006 mL (0.098 mmol) of MeI was added and the reaction was stirred for 1 h. The reaction mixture was concentrated and the residue was purified by chromatography (silica, acetone:hexanes, 1:3) to give the title compound.
Reaction SMILES: [NH2:1][C:2]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH3:27])[C:22](=[O:28])[CH:21]=[C:20]2[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=1)([C:11]1[N:15]([CH3:16])[CH:14]=[N:13][CH:12]=1)[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1>[Ni].CO.N>[NH2:1][C:2]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH2:8])=[CH:9][CH:10]=1)([C:11]1[N:15]([CH3:16])[CH:14]=[N:13][CH:12]=1)[C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH3:27])[C:22](=[O:28])[CH:21]=[C:20]2[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=1
Reactant: Cn1cncc1C(N)(c1ccc(C#N)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Agent: [Ni]
Agent: N
Solvent: CO
Product: Cn1cncc1C(N)(c1ccc(CN)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Reaction time: 8 h

Procedure:
Raney nickel (0.55 g) was added to a mixture of 4-[amino[4-(3-chlorophenyl)-1,2-dihydro-1-methyl-2-oxo-6-quinolinyl](1-methyl-1H-imidazol-5-yl)methyl]-benzonitrile, (0.0011 mol) in CH3OH/NH3 7N (12 ml) under N2 flow. The mixture was hydrogenated overnight under a 5 bar pressure, then filtered over celite. The filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 92/8/0.5; 15–40 μm). The pure fractions were collected and the solvent was evaporated, yielding 0.36 g (65%)g of 6-[amino[4-(aminomethyl)phenyl](1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone, mp. 150° C.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[CH2:6][N:5]([C@H:15]([CH2:26][CH:27]2[CH2:30][CH2:29][CH2:28]2)[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:4]1)=O.[NH:31]1[CH2:36][CH2:35][CH:34]([N:37]2[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=3[N:39]=[CH:38]2)[CH2:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.CN(C=O)C>[N:37]1([CH:34]2[CH2:33][CH2:32][N:31]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=4)[CH2:6][N:5]([C@H:15]([CH2:26][CH:27]4[CH2:28][CH2:29][CH2:30]4)[C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[CH2:4]3)[CH2:36][CH2:35]2)[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[N:39]=[CH:38]1
Reactant: O=C[C@H]1CN([C@H](CC2CCC2)C(=O)OCc2ccccc2)C[C@@H]1c1cccc(F)c1
Reactant: c1ccc2c(c1)ncn2C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)[C@@H](CC1CCC1)N1C[C@H](CN2CCC(n3cnc4ccccc43)CC2)[C@@H](c2cccc(F)c2)C1
Yield: 72 %

Procedure:
The title compound was prepared from 22 mg of α-(R)-(3-(R)-formyl-4-(S)-(3-fluorophenyl)pyrrolidin-1-yl)-3-cyclobutylpropionic acid, benzyl ester (prepared above as Aldehyde 2), 27 mg of 1-piperidin-4-yl-1-H-benzoimidazole (from Example 95, Step C) and 40 mg of sodium triacetoxyborohydride in 4 mL of THF and 1 mL of DMF, using a procedure analogous to that described in Example 95, Step D to provide 23 mg of the title compound.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]2[N:13]=[C:14]([N:17]=[C:18]([NH2:20])[NH2:19])[S:15][CH:16]=2)[CH:9]=[C:8](Cl)[CH:7]=1)(=[O:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([NH:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]2[N:13]=[C:14]([N:17]=[C:18]([NH2:19])[NH2:20])[S:15][CH:16]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)NCc1cc(Cl)cc(-c2csc(N=C(N)N)n2)n1
Agent: [Pd]
Solvent: CO
Product: CC(=O)NCc1cccc(-c2csc(N=C(N)N)n2)n1
Yield: 90.9 %

Procedure:
4-(6-Acetylaminomethyl-4-chloropyridin-2-yl)-2-(diaminomethyleneamino)thiazole (160 mg) was hydrogenated over 10% palladium on carbon (50% wt) (50 mg) in methanol (5 ml) at atmospheric pressure of hydrogen for 8 hours at ambient temperature. After the catalyst was removed by filtration, the solvent was evaporated in vacuo and the residue was mixed with water. The solution was adjusted to pH 10 with aqueous potassium carbonate and the free base was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo to give 4-(6-acetylaminomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole (0.13 g). IR (Nujol): 1655, 1590, 1545 cm-1
Reaction SMILES: [N-:1]=[C:2]=[S:3].[C:4]([O:8][CH2:9][CH3:10])(=[O:7])[NH:5][NH2:6]>>[C:4]([NH:5][NH:6][C:2]([NH2:1])=[S:3])([O:8][CH2:9][CH3:10])=[O:7]
Reactant: [N-]=C=S
Reactant: CCOC(=O)NN
Product: CCOC(=O)NNC(N)=S

Procedure:
For the synthesis of compounds of formula (I) wherein E=--S--, Reaction Schemes 13 and 14 may be utilized. In Reaction Scheme 13, the isothiocyanate 22 is reacted with ethyl carbazate (8) to give the 1-(carbethoxy)thiosemicarbazide 48. By standard conditions, 48 is S-alkylated to yield 49, which can be cyclized to the triazolinone 50 by heating, optionally in the presence of base or acid [F. Kurzer and D. R. Hanks, Chem. Ind. (London), 1143 (1966)]. Finally, alkylation of the triazolinone as in Reaction Scheme 1 provides the fully substituted product 51. ##STR58##
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH2:13][CH:14]2[CH2:16][CH2:15]2)(=[O:12])=[O:11])[CH2:7][N:6]1[C:17]1[N:18]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([Cl:29])[CH:24]=2)[N:19]=[C:20]([CH3:22])[CH:21]=1)=[O:4].[OH-].[Li+]>>[Cl:29][C:25]1[CH:24]=[C:23]([N:18]2[C:17]([N:6]3[CH2:7][C@H:8]([S:10]([CH2:13][CH:14]4[CH2:15][CH2:16]4)(=[O:12])=[O:11])[CH2:9][C@H:5]3[C:3]([OH:4])=[O:2])=[CH:21][C:20]([CH3:22])=[N:19]2)[CH:28]=[CH:27][N:26]=1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)CC2CC2)CN1c1cc(C)nn1-c1ccnc(Cl)c1
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(N2C[C@H](S(=O)(=O)CC3CC3)C[C@H]2C(=O)O)n(-c2ccnc(Cl)c2)n1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-1-[2-(2-chloro-pyridin-4-yl)-5-methyl-2H-pyrazol-3-yl]-4-cyclopropylmethanesulfonyl-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as off-white solid which was used in the next step without further purification. MS (ESI): m/z=425.0 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:35])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[Cl:34])[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C1(C)C=CC=CC=1>Cl.C(O)C>[Cl:34][C:28]1[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:27]=1[CH2:26][CH2:25][O:24][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[O:22][CH3:23])[C:15]([NH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:35]
Reactant: COc1ccc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)cc1OCCc1ccc(Cl)cc1Cl
Agent: Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)NC2CCNCC2)cc1OCCc1ccc(Cl)cc1Cl

Procedure:
1.4 g 4-{3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-piperidine-1-carboxylic acid tert-butyl ester was suspended in 20 ml HCl in ethanol at RT. After 2 h a clear solution was obtained. Addition of 50 ml toluene followed by evaporation of the solvent and repeatedly coevaporation of the residue with toluene yielded the product as a white foam.
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]([F:16])([F:15])[F:14])=[N:11][NH:10][C:9](=O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:20])=O.C(=O)([O-])O.[Na+].ClCCl>C(#N)C>[Cl:20][C:9]1[N:10]=[N:11][C:12]([C:13]([F:16])([F:15])[F:14])=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(-c2ccccc2)c(C(F)(F)F)n[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: FC(F)(F)c1nnc(Cl)cc1-c1ccccc1
Yield: 12768.7 %

Procedure:
To a stirred solution of 5-phenyl-6-trifluoromethyl-2H-pyridazine-3-one (D2) (20.66 g, 0.086 mol) in acetonitrile (150 ml) was added phosphorous oxychloride (20 ml, 0.215 mmol) and the reaction heated at reflux for 1 h. After this period, the reaction mixture was poured into a saturated solution of sodium hydrogen carbonate, ice and dichloromethane. Further solid sodium hydrogen carbonate was then added until gas evolution had ceased. The organic layer was then separated, dried (Na2SO4) and the solvents evaporated in vacuo. The crude residue was then filtered through silica gel, eluting with dichloromethane, in order to remove the minor isomer. After evaporation of the solvent, the crude product was then re-purified by column chromatography (silica; 0-25% ethyl acetate/heptane) to yield D3 (7.1 g, 32%). C11H6ClF3N2 requires 258; Found 259 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].[N:13]1[CH:18]=[CH:17][N:16]=[C:15]([N:19]2[CH2:23][CH2:22][CH:21](O)[CH2:20]2)[N:14]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:11])[F:9])=[CH:4][C:3]=1[O:12][CH:21]1[CH2:22][CH2:23][N:19]([C:15]2[N:14]=[N:13][CH:18]=[CH:17][N:16]=2)[CH2:20]1
Reactant: OC1CCN(c2nccnn2)C1
Reactant: Oc1cc(C(F)(F)F)ccc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(Cl)c(OC2CCN(c3nccnn3)C2)c1

Procedure:
Compound 42 is prepared from 2-chloro-5-trifluoromethylphenol and intermediate 5d according to synthesis method 3 in toluene in the presence of DIAD, under the operating conditions described for example 8 (86% yield).
Reaction SMILES: [N:1]([C@@H:4]([C@@H:8]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[C:5]([OH:7])=O)=[N+]=[N-].[NH2:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([F:54])[C:28]=1[CH2:29][CH2:30][C@H:31]1[O:36][CH2:35][C@H:34]([CH2:37][O:38][C:39]([NH:41][CH2:42][C:43]([F:46])([F:45])[F:44])=[O:40])[N:33](C(OC(C)(C)C)=O)[CH2:32]1>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C@@H:8]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C@@H:4]([C:5]([NH:22][C:23]2[CH:24]=[N:25][CH:26]=[C:27]([F:54])[C:28]=2[CH2:29][CH2:30][C@H:31]2[O:36][CH2:35][C@@H:34]([CH2:37][O:38][C:39](=[O:40])[NH:41][CH2:42][C:43]([F:45])([F:46])[F:44])[NH:33][CH2:32]2)=[O:7])[NH2:1])=[CH:16][CH:17]=1
Reactant: [N-]=[N+]=N[C@H](C(=O)O)[C@@H](c1ccc(F)cc1)C1CCOCC1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cncc2F)OC[C@@H]1COC(=O)NCC(F)(F)F
Product: N[C@H](C(=O)Nc1cncc(F)c1CC[C@@H]1CN[C@H](COC(=O)NCC(F)(F)F)CO1)[C@@H](c1ccc(F)cc1)C1CCOCC1

Procedure:
The title compound was prepared from the product of step 1 and the product of step 4 of Example 89 using the procedures given in steps 2-4 of Example 93. MS (ES) m/z=630 (M+H)+.