Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1.O>CN(C=O)C>[N:16]1[CH:17]=[CH:18][CH:19]=[N:20][C:15]=1[CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Brc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)c1ncccn1
Temperature: 100 °C
Yield: 49.5 %

Procedure:
To a solution of sodium hydride (4.4 g of a 60% dispersion in oil, 0.11 mol) in DMF (200 ml) was added diethyl malonate (16 ml, 0.11 mol) in DMF (50 ml) dropwise at room temperature. After 30 min 2-bromopyrimidine (8.0 g, 0.05 mol) was added portionwise and the solution heated at 100° C. for 3 h. The solution was cooled to room temperature, water (100 ml) was added and the mixture extracted with EtOAc (3×60 ml). The combined organic layers were dried (MgSO4) and evaporated. The residue was chromatographed on silica, using hexane:EtOAc (3:1) as the eluant, to afford the ester (5.9 g, 49%) as a pale yellow oil which solidified on standing at 0° C. 1H NMR (360 MHz, CDCl3) δ 1.29 (6H, t, J=7.1 Hz), 4.29 (4H, q, J=7.1 Hz), 5.10 (1H, s), 7.26 (1H, t, J=4.9 Hz), 8.74 (2H, d, J=4.9 Hz).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][NH:5][CH2:4][C@@H:3]1[CH2:7][NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[F:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][C:26](=[O:33])[N:27]2[CH2:30][CH:31]=O)=[N:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[F:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][C:26](=[O:33])[N:27]2[CH2:30][CH2:31][N:5]2[CH2:6][C@@H:2]([OH:1])[C@@H:3]([CH2:7][NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:4]2)=[N:22][CH:21]=1
Reactant: O=C(NC[C@H]1CNC[C@H]1O)OCc1ccccc1
Reactant: O=CCn1c(=O)ccc2ncc(F)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C(NC[C@H]1CN(CCn2c(=O)ccc3ncc(F)cc32)C[C@H]1O)OCc1ccccc1
Reaction time: 1 h

Procedure:
Phenylmethyl {[(3R,4S)-4-hydroxy-3-pyrrolidinyl]methyl}carbamate (1.17 g; 4.560 mmol) and (7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde (as the methyl hemiacetal)) (855 mg, 4.17 mmol) were combined in anhydrous DCM (5 ml) and anhydrous MeOH (1 ml) with a spatula of solid sodium carbonate. The reaction mixture was stirred under nitrogen for 1 h then sodium triacetoxyborohydride (2.76 g; 12.44 mmol) was added and stirred overnight. The reaction mixture was concentrated and the title compound was obtained as a pale yellow oil (1.69 mg, 87%) after column:chromatography (90:10: DCM:MeOH).
Reaction SMILES: [C-:1]#[N:2].[K+].[Cl:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9].C(O)(=O)C>CO>[Cl:4][C:5]1[CH:6]=[C:7]([CH:8]([OH:9])[C:1]#[N:2])[CH:10]=[CH:11][CH:12]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: N#CC(O)c1cccc(Cl)c1
Temperature: 15 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of potassium cyanide (5.04 g, 78 mmol) in methanol (20 mL) was added 3-chlorobenzaldehyde (7.0 g, 50 mmol) at 0° C. under nitrogen atmosphere. Then acetic acid (4.4 mL) was added dropwise at 0° C. After 30 minutes, the mixture was warmed to 15° C. and stirred for 5 hours. Then the reaction mixture was concentrated to dryness and extracted with ethyl acetate (200 mL). The organic solution was washed with water (3×25 mL), brine (25 mL), dried over anhydrous sodium sulfate and concentrated to dryness. The resulting residue was purified by column chromatography (ethyl acetate:petroleum ether, 1:15) to afford (3-chloro-phenyl)-hydroxy-acetonitrile. (Yield 8.2 g, 97%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH3:17]O>>[C:1]1([CH2:7][CH2:8][C:9]([O:11][CH3:17])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CO
Reactant: O=C(O)CCc1ccccc1
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1ccccc1

Procedure:
A solution of 3-phenylpropionic acid (50 g, 0.33 mole) and conc. sulfuric acid (5 g) in methanol (220 ml) was refluxed for 1 hour with stirring, concentrated and poured into cold H2O. The mixture was extracted thrice with methylene chloride (75 ml), the organic layer was washed thrice with H2O (125 ml), dried over anhydrous MgSO4 and evaporated. The residual crude oil (54 g) was distilled under reduced pressure to give 51.5 g of methyl 3-phenylpropionate as a colorless oil having a boiling point of 94°-95° C./5 mmHg.
Reaction SMILES: Br[CH:2]([C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)[C:3](=O)[CH3:4].[C:14]([NH2:17])(=[S:16])[CH3:15].N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([C:2]2[S:16][C:14]([CH3:15])=[N:17][C:3]=2[CH3:4])=[CH:7][CH:8]=1)#[N:11]
Reactant: CC(N)=S
Reactant: CC(=O)C(Br)c1ccc(C#N)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1nc(C)c(-c2ccc(C#N)cc2)s1
Temperature: 100 °C

Procedure:
A solution of 4-(1-bromo-2-oxopropyl)benzonitrile (0.9 g, 3.83 mmol) in toluene (2 ml) was treated with thioacetamide (0.6 g, 8 mmol) followed by pyridine (0.45 ml). The mixture was warmed to 100° C. for 1 hour, then partitioned between ethyl acetate and brine. The organic layer was dried (MgSO4) and evaporated to a yellow oil. Chromatography on silica gel, eluting with 5% ether in dichloromethane, afforded a pale yellow oil which crystallised (0.52 g, 64%), m.p. 108°-110° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C@H:14](O)[C:15](F)(F)F)[C:11](=[O:20])[N:10]([CH2:21][C:22]([NH:24][CH:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3C)[CH2:26][CH2:27][OH:28])=[O:23])[N:9]=2)=[CH:4][CH:3]=1.ClC1C=CC(C2N(C3CC3)[C:46](=[O:51])N(CC(O)=O)N=2)=CC=1.NC(C1C=CC=C(OC)C=1)CCO>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:14][CH2:15]3)[C:11](=[O:20])[N:10]([CH2:21][C:22]([NH:24][CH:25]([C:29]3[CH:30]=[CH:31][CH:32]=[C:33]([O:51][CH3:46])[CH:34]=3)[CH2:26][CH2:27][OH:28])=[O:23])[N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C(CCO)NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Agent: COc1cccc(C(N)CCO)c1
Product: COc1cccc(C(CCO)NC(=O)Cn2nc(-c3ccc(Cl)cc3)n(C3CC3)c2=O)c1

Procedure:
In the same way as for the compound from Example 86, 30 mg (0.10 mmol) of [3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetic acid (for preparation see WO 2007/134862, Example 88A) and 20 mg (0.11 mmol) of 3-amino-3-(3-methoxyphenyl)propan-1-ol were reacted. This gave 30 mg (63% of theory) of the target compound.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)([CH3:5])[C:3]#[N:4].[H][H]>[Pd].C(OCC)(=O)C>[NH2:12][C:9]1[CH:8]=[CH:7][C:6]([C:2]([CH3:5])([CH3:1])[C:3]#[N:4])=[CH:11][CH:10]=1
Reactant: CC(C)(C#N)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C#N)c1ccc(N)cc1
Yield: 92.6 %

Procedure:
2-methyl-2-(4-nitrophenyl) propanenitrile (4.5 g, 23.6 mmol) was added to a reaction vessel, to which were successively added Pd/C (450 mg) and 50 mL ethyl acetate. The system was vacuumed and hydrogen was introduced. The resulting mixture is reacted at room temperature for 15 hrs. The resulting reaction was filtered with Celite, and washed with ethyl acetate. The resulting filtrate was concentrated to obtain a colorless oil of 2-(4-aminophenyl)-2-methyl propanenitrile (3.5 g).
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([C:16]#[C:17][C:18]3[C:19]([CH3:25])=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=3)=[C:14]([CH2:26][CH3:27])[N:13]=[CH:12][N:11]=2)=[CH:6][C:5]=1[F:28].[Li+].[OH-]>O.C1COCC1>[NH2:24][C:21]1[N:20]=[C:19]([CH3:25])[C:18]([C:17]#[C:16][C:15]2[C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:29])=[O:2])=[C:5]([F:28])[CH:6]=3)=[N:11][CH:12]=[N:13][C:14]=2[CH2:26][CH3:27])=[CH:23][CH:22]=1
Reactant: CCc1ncnc(-c2ccc(C(=O)OC)c(F)c2)c1C#Cc1ccc(N)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1ncnc(-c2ccc(C(=O)O)c(F)c2)c1C#Cc1ccc(N)nc1C
Temperature: 50 °C

Procedure:
The title compound is synthesized according to general procedure GP8 starting from 4.0 g (10.2 mmol) 4-[5-(6-amino-2-methyl-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-2-fluoro-benzoic acid methyl ester using 1.29 g (30.7 mmoL) LiOH in 40 mL water and 200 mL THF. The reaction mixture is stirred over night at 50° C. The THF is removed under reduced pressure and the residue is taken up in water. Aqueous 1 M HCl is added until pH 5-6 is reached. The precipitated product is filtered off and washed with water and MeOH. After drying 1.25 g (32%) of the desired product is obtained a solid material.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[C:13]([N:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[N:12][N:11]3[C:24]=2[I:25])=[CH:4][CH:3]=1.CN(C1C=CC=CN=1)C.[C:35](=O)([O:41]C(C)(C)C)[O:36][C:37]([CH3:40])([CH3:39])[CH3:38]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[C:13]([N:18]4[CH2:23][CH2:22][N:21]([C:35]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:41])[CH2:20][CH2:19]4)=[N:12][N:11]3[C:24]=2[I:25])=[CH:6][CH:7]=1
Reactant: Cc1c(N2CCNCC2)nn2c(I)c(-c3ccc(F)cc3)nc2c1C
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Product: Cc1c(N2CCN(C(=O)OC(C)(C)C)CC2)nn2c(I)c(-c3ccc(F)cc3)nc2c1C
Yield: 78.4 %

Procedure:
A solution of 0.70 g (1.55 mmol) of 2-(4-fluorophenyl)-3-iodo-7,8-dimethyl-6-piperazin-1-ylimidazo[1,2-b]pyridazine and 19 mg (0.16 mmol) of dimethylaminopyridine in 10 mL of tetrahydrofuran is treated with 0.41 g (1.9 mmol) of di-tert-butyl carbonate for 1 hour. The solvent is then evaporated off and the solid obtained is recrystallized from acetonitrile. 0.67 g of product is thus isolated after drying.
Reaction SMILES: Cl[C:2]1[C:7](Cl)=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[C:14]([CH3:16])[CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.O.C(#N)C>[CH3:9][C:10]1[CH:11]=[C:12]([C:2]2[C:7]([C:12]3[CH:13]=[C:14]([CH3:16])[CH:15]=[C:10]([CH3:9])[CH:11]=3)=[N:6][CH:5]=[CH:4][N:3]=2)[CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: Cc1cc(C)cc(B(O)O)c1
Reactant: Clc1nccnc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(C)cc(-c2nccnc2-c2cc(C)cc(C)c2)c1
Reaction time: 1 h
Yield: 44 %

Procedure:
First, 5.00 g of 2,3-dichloropyrazine, 10.23 g of 3,5-dimethylphenylboronic acid, 7.19 g of sodium carbonate, 0.29 g of bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2), 20 mL of water, and 20 mL of acetonitrile were put into a recovery flask equipped with a reflux pipe, and the air in the flask was replaced with argon. This reaction container was subjected to irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes to be heated. Here, into the flask were further put 2.55 g of 3,5-dimethylphenylboronic acid, 1.80 g of sodium carbonate, 0.070 g of Pd(PPh3)2Cl2, 5 mL of water, and 5 mL of acetonitrile, and irradiation with microwaves (2.45 GHz, 100 W) was performed again for 60 minutes so that heating was performed. Then, water was added to this solution and the organic layer was extracted with dichloromethane. The obtained organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, water, and saturated brine, and was dried with magnesium sulfate. After the drying, the solution was filtered. The solvent of this solution was distilled off, and the obtained residue was purified by flash column chromatography using hexane and ethyl acetate as a developing solvent in a ratio of 5:1. The solvent was distilled off, and the obtained solid was purified by flash column chromatography using dichloromethane and ethyl acetate as a developing solvent in a ratio of 10:1, so that Hdmdppr (abbreviation), which was the pyrazine derivative to be produced, was obtained as a white powder in a yield of 44%. Note that the irradiation with microwaves was performed using a microwave synthesis system (Discover, manufactured by CEM Corporation). A synthesis scheme of Step 1 is shown in (h-1).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[N:10]=[CH:11][N:12]([CH3:14])[CH:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1C=C(S(Cl)(=O)=O)N=C1.C(N)(C)(C)C.C1C[O:33][CH2:32]C1>>[C:1]([NH:5][S:6]([C:9]1[N:10]=[C:11]([CH:32]=[O:33])[N:12]([CH3:14])[CH:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1cnc(S(=O)(=O)NC(C)(C)C)c1
Reactant: C1CCOC1
Agent: Cn1cnc(S(=O)(=O)Cl)c1
Solvent: CC(C)(C)N
Product: Cn1cc(S(=O)(=O)NC(C)(C)C)nc1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Step A) Preparation of N-(tert-butyl)-1-methyl-1H-imidazole-4-sulfonamide: A solution of 5.2 gm (29 mmol) 1-methyl-1H-imidazole-4-sulfonyl chloride in 30 mL THF was cooled in ice water while 7 mL tert-butylamine was added dropwise. The solution was warmed to room temperature and stirred overnight. Solids were filtered and rinsed with additional THF. The filtrate was concentrated to give a white solid that was recrystallized from water and dried in vacuo to give 4.8 gm of the subtitle compound, 1H NMR (d6-DMSO) δ 7.75 (s, 1H), 7.65 (s, 1H), 7.2 (s, 1H), 3.7 (s, 3H), 1.1 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH2:6]2.O.OC1C2N=NNC=2C=CC=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:29][CH2:30][C:31](O)=[O:32].C1CCC(N=C=NC2CCCCC2)CC1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([C:31](=[O:32])[CH2:30][CH2:29][C:25]1[S:24][CH:28]=[CH:27][CH:26]=1)[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCNC2
Reactant: O=C(O)CCc1cccs1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCN(C(=O)CCc1cccs1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-6-methoxyisoquinoline (3.29 g), hydroxybenzotriazole monohydrate (5.72 g) and 3-(2-thienyl)propanoic acid (3.31 g) in 280 ml of dry tetrahydrofuran (THF) at 0° C. was added DCC (4.37 g) in one portion. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was filtered and concentrated. The residue was taken up into 200 ml of ethyl acetate (EtOAc) refiltered, washed with 5% aq. HCl (50 ml), 5% aq. NaCl (50 ml), 10% aq. KOH (50 ml), dried (MgSO4), filtered, and concentrated. Chromatography on silica gel (elution with 20% EtOAc:hexanes) afforded 4.54 g of the desired product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:10][CH:9]=2)[N:5]=[C:4]([C:22]([O:24][CH3:25])=[O:23])[N:3]=1.Cl.[NH2:27][C@@H:28]([CH3:33])[C:29]([O:31][CH3:32])=[O:30].CCN(C(C)C)C(C)C>C(#N)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:11]2[CH:12]=[CH:13][C:8]([C:6]3[CH:7]=[C:2]([NH:27][C@@H:28]([CH3:33])[C:29]([O:31][CH3:32])=[O:30])[N:3]=[C:4]([C:22]([O:24][CH3:25])=[O:23])[N:5]=3)=[CH:9][CH:10]=2)=[CH:16][CH:17]=1
Reactant: COC(=O)[C@H](C)N
Reactant: COC(=O)c1nc(Cl)cc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1nc(N[C@@H](C)C(=O)OC)cc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Temperature: 80 °C
Yield: 56.5 %

Procedure:
To a suspension of methyl 4-chloro-6-(4-(4-fluorophenoxy)phenyl)pyrimidine-2-carboxylate (0.719 g, 2.00 mmol) in acetonitrile (10 mL) was added (S)-methyl 2-aminopropanoate hydrochloride (0.310 g, 2.22 mmol) and iPr2NEt (0.77 mL, 4.4 mmol). The mixture was heated at 50° C. for 2 h than 80° C. for 6 days. The mixture was evaporated in vacuo and the residue chromatographed over silica gel with 20-60% EtOAc/hexanes. The product fractions were evaporated in vacuo to give (S)-methyl 4-(4-(4-fluorophenoxy)phenyl)-6-((1-methoxy-1-oxopropan-2-yl)amino)pyrimidine-2-carboxylate as a pale tan oil (0.479 g, 1.13 mmol, 56% yield). LC/MS: m/z=426.2 [M+H]+.
Reaction SMILES: CO[C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[N:17][O:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]2)=[N:6][CH:5]=1.[CH:32]1([NH2:35])[CH2:34][CH2:33]1>>[CH:32]1([NH:35][C:3](=[O:31])[C:4]2[CH:9]=[CH:8][C:7]([N:10]3[CH:14]=[C:13]([C:15]4[C:16]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)=[N:17][O:18][C:19]=4[C:20]([F:21])([F:23])[F:22])[N:12]=[CH:11]3)=[N:6][CH:5]=2)[CH2:34][CH2:33]1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)nc1
Reactant: NC1CC1
Product: O=C(NC1CC1)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)nc1
Yield: 38 %

Procedure:
As described for Example 38b, 6-{4-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-yl]-imidazol-1-yl}-nicotinic acid methyl ester (100 mg, 0.23 mmol), was converted, using cyclopropylamine (66.14 μL, 0.9 mmol) instead of cyclopropanemethylamine, to the title compound (40 mg, 38%) which was obtained as a white solid. MS: m/e=458.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]1([C:21]([F:24])([F:23])[F:22])[CH2:20][O:19]1)=[O:15].Cl.[F:26][CH2:27][CH2:28][NH2:29].C(N(CC)CC)C>C(#N)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]([CH2:20][NH:29][CH2:28][CH2:27][F:26])([OH:19])[C:21]([F:23])([F:22])[F:24])=[O:15]
Reactant: NCCF
Reactant: Nc1c(C(=O)NCC2(C(F)(F)F)CO2)cnn1-c1ccc(F)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Nc1c(C(=O)NCC(O)(CNCCF)C(F)(F)F)cnn1-c1ccc(F)cc1
Reaction time: 96 h
Yield: 128.5 %

Procedure:
To a solution of 5-amino-1-(4-fluorophenyl)-N-{[2-(trifluoromethyl)-2-oxiranyl]methyl}-1H-pyrazole-4-carboxamide (1.03 g, 3 mmol) in anhydrous acetonitrile (10 ml) was added 2-fluoroethylamine hydrochloride (650 mg, 6 mmol, ca. 90% purity) and triethylamine (0.98 ml, 7 mmol) and the resulting suspension was shaken for 4 days. It was partitioned between ethyl acetate (70 ml) and water (20 ml), washed with saturated brine (20 ml), dried over sodium sulphate and evaporated to give a gum (1.57 g). This was purified on 100 g SiO2 using the Flashmaster 2 with 0-100°/0 ethyl acetate in cyclohexane 60 minute gradient as eluent. This gave the title compound (924 mg).
Reaction SMILES: [F:1][CH:2]([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][N:14]([C:16]([N:18]3[CH2:23][CH2:22][S:21](=[O:24])[CH2:20][CH2:19]3)=[O:17])[CH2:13][CH:12]([C:25](O)=[O:26])[CH2:11]2)=[CH:6][CH:5]=1.O[N:30]=[C:31]([CH:33]1[CH2:35][CH2:34]1)[NH2:32].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>CN(C=O)C>[CH:33]1([C:31]2[N:32]=[C:25]([CH:12]3[CH2:11][CH:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][CH:2]([F:1])[F:28])=[CH:5][CH:6]=4)[CH2:15][N:14]([C:16]([N:18]4[CH2:19][CH2:20][S:21](=[O:24])[CH2:22][CH2:23]4)=[O:17])[CH2:13]3)[O:26][N:30]=2)[CH2:35][CH2:34]1
Reactant: O=C(O)C1CC(c2ccc(OC(F)F)cc2)CN(C(=O)N2CCS(=O)CC2)C1
Reactant: NC(=NO)C1CC1
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: O=C(N1CCS(=O)CC1)N1CC(c2ccc(OC(F)F)cc2)CC(c2nc(C3CC3)no2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
200 mg (0.48 mmol) of the compound from Example 39A and 96 mg (0.96 mmol) of N′-hydroxycyclopropanecarboximidamide were initially charged in 1.8 ml of DMF and reacted with 274 mg (0.72 mmol) of HATU and 0.25 ml (186 mg, 1.44 mmol) of N,N-diisopropylethylamine. The reaction mixture was stirred at RT for 15 minutes and then partitioned between water and ethyl acetate. The organic phase was washed repeatedly with water, dried over sodium sulphate and concentrated under reduced pressure. The residue was dissolved in 2.0 ml of DMF and converted in a microwave at 180° C. for 2 minutes. The reaction mixture was purified by means of preparative HPLC. Yield: 25 mg (10% of theory)
Reaction SMILES: O1CCC[CH2:2]1.C[Mg]Br.[CH:9]([C:11]1[N:12]=[C:13]([CH2:58][CH2:59][CH3:60])[N:14]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[N:38]([C:39]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[N:37]=[N:36][N:35]=3)=[CH:24][CH:23]=2)[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:10].C(OCC)(=O)C.[Cl-].[NH4+]>O1CCCC1>[OH:10][CH:9]([C:11]1[N:12]=[C:13]([CH2:58][CH2:59][CH3:60])[N:14]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[N:38]([C:39]([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[N:37]=[N:36][N:35]=3)=[CH:26][CH:27]=2)[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:2]
Reactant: CCCc1nc(C=O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: C1CCOC1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CCCc1nc(C(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 3 h

Procedure:
4.0 ml of a 1M solution of methylmagnesium bromide tetrahydrofuran were added dropwise at -10° C. to a solution of 1.2 g of ethyl 4-formyl-2-propyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in step (a) above] in 5 ml of tetrahydrofuran, and the resulting mixture was stirred at a temperature between -10° C. and 0° C. for 3 hours. At the end of this time, the reaction mixture was mixed with ethyl acetate and with an aqueous solution of ammonium chloride, and the mixture was stirred at room temperature for 20 minutes. The ethyl acetate layer was then separated and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using 1:4 and 1:2 by volume mixtures of ethyl acetate and methylene chloride as the eluent, to give 1.23 g of the title compound as a viscous oil.
Reaction SMILES: C(OC([N:8]([C:24]1[CH:29]=[N:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)=[CH:26][N:25]=1)[CH:9]([C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=1)[CH2:10][CH2:11][CH3:12])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:39][C:36]([F:37])([F:38])[C:33]1[CH:34]=[CH:35][C:30]([C:27]2[N:28]=[CH:29][C:24]([NH:8][CH:9]([C:13]3[CH:14]=[CH:15][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:22][CH:23]=3)[CH2:10][CH2:11][CH3:12])=[N:25][CH:26]=2)=[CH:31][CH:32]=1
Reactant: CCCC(c1ccc(C(=O)OCC)cc1)N(C(=O)OC(C)(C)C)c1cnc(-c2ccc(C(F)(F)F)cc2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC(Nc1cnc(-c2ccc(C(F)(F)F)cc2)cn1)c1ccc(C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Part A: A round bottom flask was charged with (±)-ethyl 4-(1-((tert-butoxycarbonyl)(5-(4-(trifluoromethyl)phenyl)pyrazin-2-yl)amino)butyl)benzoate (4.85 g, 8.92 mmol), DCM (60 mL) and TFA (15 mL). Reaction mixture stirred at room temperature for 3 hours. Sodium bicarbonate (sat. aq.) used to quench the excess TFA and the aqueous layer is extracted with DCM (3×). Combined organics washed with water (1×), brine (1×), dried over sodium sulfate filtered and concentrated to provide (±)-ethyl 4-(1-((5-(4-(trifluoromethyl)phenyl)pyrazin-2-yl)amino)butyl)benzoate as a crude orange gum (4.01 g, quant.). No further purification before next step. MS (M+1): 444.3.