Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:33])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:32])([C:24]2[CH:29]=[CH:28][C:27]([CH:30]=[CH2:31])=[CH:26][CH:25]=2)[C:8]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[O:9])[CH2:3]1>CO.[Pd].[H][H]>[F:33][C:2]1([F:1])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:32])([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH3:31])=[CH:26][CH:25]=2)[C:8]([O:10][CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH2:15][CH2:16]2)=[O:9])[CH2:3]1
Reactant: [H][H]
Reactant: C=Cc1ccc([C@@](O)(C(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)[C@@H]2CCC(F)(F)C2)cc1
Agent: [Pd]
Solvent: CO
Product: CCc1ccc([C@@](O)(C(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)[C@@H]2CCC(F)(F)C2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 50 mg of the t-butyl 4-((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-vinylphenyl)ethanoyloxy)-tetrahydropyridine-1(2H)-carboxylate as obtained in Referential Example 56 in 3 ml of methanol, 10 mg of palladium-on-carbon catalyst was added, followed by 6 hours' stirring at ambient temperature and pressure in hydrogen atmosphere. The reaction liquid was filtered with Celite, and the solvent was distilled off under reduced pressure to provide the title compound.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:17])[CH:14]([CH3:16])[CH3:15].[CH3:18][Si](Cl)(C)C.[I-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:18])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:17])[CH:14]([CH3:15])[CH3:16]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)C(=O)c1cnc2ccc(O)nc2c1O
Agent: O=S([O-])([O-])=S
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc2ncc(C(=O)C(C)C)c(O)c2n1
Temperature: 25 °C

Procedure:
To a suspension of 1-(4,6-dihydroxy-1,5-naphthyridin-3-yl)-2-methylpropan-1-one (15.5 g, 63.0 mmol) in acetonitrile (250 ml) was added trimethylsilylchloride (20.5 g, 189 mmol) and sodium iodide (28.3 g, 189 mmol) and the reaction mixture was heated at reflux for 3 h. The reaction mixture was cooled to room temperature and satd. aq. sodium thiosulfate was added. The mixture was concentrated to remove acetonitrile, diluted with brine and the solids were filtered and dried to provide the intermediate 1-(4-hydroxy-6-methoxy-1,5-naphthyridin-3-yl)-2-methylpropan-1-one. This intermediate was suspended in phosphorus oxychloride (60 mL) and catalytic N,N-dimethylformamide and the reaction mixture was stirred with heat at 70° C. for 30 min. The reaction mixture was cooled to room temperature and quenched by pouring slowly into ice-cold satd. aq. sodium bicarbonate or 3 N sodium hydroxide. The quenched reaction mixture was concentrated to remove the dichloroethane and the resulting solids were collected by filtration and purified by chromatography (silica, hexanes/ethyl acetate) to provide the desired product (12.0 g, 75% over 2 steps) as a yellow solid: ESI MS m/z 255 [M+H]+.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:9]2([CH2:13][CH2:12][CH2:11][CH2:10]2)[N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:7][C:6]2([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[NH:5]1.[CH2:27](Br)[C:28]#[CH:29]>CN(C=O)C>[O:3]=[C:4]1[C:9]2([CH2:10][CH2:11][CH2:12][CH2:13]2)[N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[CH2:7][C:6]2([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)[N:5]1[CH2:29][C:28]#[CH:27]
Reactant: CC(C)(C)OC(=O)N1CC2(CCCCCC2)NC(=O)C12CCCC2
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCN1C(=O)C2(CCCC2)N(C(=O)OC(C)(C)C)CC12CCCCCC2
Reaction time: 1 h

Procedure:
Sodium hydride (23 mg, 0.575 mmol, 60% dispersion in mineral oil) was added to a stirred solution of tert-butyl 16-oxo-6,15-diazadispiro[4.2.6.2]hexadecane-6-carboxylate from Step A (92 mg, 0.273 mmol) in DMF (1 mL). When the gas evolution had ceased, propargyl bromide (70 mg, 0.471 mmol, 80 wt % in toluene) was added to the solution at ambient temperature. After 1 h, the reaction was quenched with water (30 mL) and extracted with EtOAc (30 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to yield the title compound. MS: m/z=397 (M+Na).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[N:8]=[C:7](O)[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][N:4]=1.P(Cl)(Cl)([Cl:18])=O>>[CH3:1][N:2]([CH3:15])[C:3]1[N:8]=[C:7]([Cl:18])[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc(N(C)C)nc1O
Product: CCOC(=O)c1cnc(N(C)C)nc1Cl

Procedure:
A suspension of 16 g of 2-dimethylamino-4-hydroxy-5-carboethoxy-pyrimidine in 100 ml of phosphorus oxychloride is heated to the boil for half an hour whilst stirring and is then filtered hot, and the filtrate is evaporated under reduced pressure. 200 g of ice are added to the oily residue. 200 ml of methylene chloride are added and 30% strength sodium hydroxide solution is then added, whilst cooling with ice, until the pH reaches 8. Inorganic salts which have precipitated are then filtered off and rinsed with methylene chloride. The organic phase is washed with water, dried over sodium sulphate and evaporated. 2-Dimethylamino-4-chloro-5-carboethoxypyrimidine is obtained as a yellowish oil which can be used further without purification.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:13][C:14]1[CH:43]=[CH:42][C:17]([C:18](/[N:20]=[C:21]2\NC3C=CC(CO)=CC=3[N:25]\2[C@@H:26]2[CH2:31][CH2:30][C@H:29]([C:32](OC)=[O:33])[CH2:28][CH2:27]2)=[O:19])=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:43]=[CH:42][C:17]([C:18]([NH:20][C:21]2[N:1]([C@@H:2]3[CH2:3][CH2:4][C@H:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]3)[C:31]3[CH:30]=[C:29]([CH2:32][OH:33])[CH:28]=[CH:27][C:26]=3[N:25]=2)=[O:19])=[CH:16][CH:15]=1
Reactant: CCOC(=O)[C@H]1CC[C@@H](N)CC1
Reactant: COC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CO)cc32)CC1
Product: CCOC(=O)[C@H]1CC[C@@H](n2c(NC(=O)c3ccc(F)cc3)nc3ccc(CO)cc32)CC1

Procedure:
The title compound was prepared in 6 steps from cis-ethyl 4-aminocyclohexanecarboxylate using a method analogous to the preparation of cis-methyl 4-((E)-2-(4-fluorobenzoylimino)-6-(hydroxymethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate. MS m/z=440.2 [M+H]. Calc'd for C24H26FN3O4: 439.2.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[NH2:17][C:18]1[CH:25]=[C:24](F)[C:21]([C:22]#[N:23])=[CH:20][N:19]=1>C1COCC1>[NH2:17][C:18]1[CH:25]=[C:24]([O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])[C:21]([C:22]#[N:23])=[CH:20][N:19]=1
Reactant: N#Cc1cnc(N)cc1F
Reactant: CN(C)CCO
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)CCOc1cc(N)ncc1C#N
Reaction time: 0.03 h

Procedure:
2-(dimethylamino)ethanol (0.293 ml, 2.92 mmol) was treated at room temperature with KHMDS (1 M in THF, 2.19 ml, 2.19 mmol). The reaction mixture was stirred for 2 min and then added to a solution of 6-amino-4-fluoronicotinonitrile (intermediate 21, 100 mg, 0.729 mmol) in THF (2 ml). The resulting dark brown solution was stirred at room temperature for 60 min, quenched with sat. aq. NH4Cl, directly absorbed on isolate and dried under vacuum. The crude material was purified by reverse phase chromatography (13 g C18 cartridge, 0.1% TFA in water/acetonitrile 100:0 to 0:100). The product containing fractions were concentrated. The residue was treated with a small amount sat. aq. NaHCO3 and NaCl (s) and extracted with CH2Cl2 (5×). The combined organic layers were dried over Na2SO4 and concentrated to give the title compound as a white solid. (UPLC-MS 3) tR 0.45 min; ESI-MS 207.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][N:3]=1.Cl.[F:13][C:14]([F:19])([F:18])[C@@H:15]([NH2:17])[CH3:16]>N1C=CC=CC=1.C(OCC)(=O)C>[F:13][C:14]([F:19])([F:18])[C@@H:15]([NH:17][S:8]([C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9])[CH3:16]
Reactant: C[C@H](N)C(F)(F)F
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C[C@H](NS(=O)(=O)c1ccc(Cl)nc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.1 %

Procedure:
2-chloropyridine-5-sulfonyl chloride (12 g, 56.6 mmol) was added to a solution of (S)-1,1,1-trifluoropropan-2-amine hydrochloride (7.8 g, 51.2 mmol) in pyridine (15 mL) at 0° C. The mixture was stirred at room temperature for 10 minutes and diluted with ethyl acetate (200 ml) and washed with 3 N aq. HCl (2×100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The solid was triturated with hexane (2×40 mL) and filtered to provide (S)-6-chloro-pyridine-3-sulfonic acid (2,2,2-trifluoro-1-methyl-ethyl)-amide as an off-white solid (11.84 g, 75%). 1H NMR (500 MHz, CDCl3): δ0.81 (1H, d, J=2.4 Hz), 8.18 (1H, dd, J=2.5 Hz, 2.6 Hz), 7.51 (1H, d, J=8.8 Hz), 4.92 (1H, br s), 4.08 (1H, m), 1.45 (3H, d, J=7.0 Hz).
Reaction SMILES: Cl[C:2]1[C:3](=[O:19])[N:4]([CH2:15][CH2:16][O:17][CH3:18])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N:20]1([C:26]2[N:30]=[C:29]([NH2:31])[NH:28][N:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH3:18][O:17][CH2:16][CH2:15][N:4]1[C:3](=[O:19])[C:2]([NH:31][C:29]2[NH:28][N:27]=[C:26]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[N:30]=2)=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13]
Reactant: COCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: Nc1nc(N2CCOCC2)n[nH]1
Product: COCCN1C(=O)C(Nc2nc(N3CCOCC3)n[nH]2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 4-chloro-2-(2-methoxyethyl)-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 3-morpholin-4-yl-1H-1,2,4-triazol-5-amine in a similar manner as described for Example 13. 1H NMR (400 MHz, CD3CN): δ 7.49-7.61 (m, 5H), 5.71 (bs, 2H), 3.94 (t, 2H), 3.71 (t, 2H), 3.58-3.62 (m, 4H), 3.37 (s, 3H), 3.10-3.14 (m, 4H); Mass Spectrum: M+H+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:28][CH2:29][CH2:30][CH2:31][NH:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37][CH2:38][CH2:39][CH2:40][NH2:41]>COCCOC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([NH:41][CH2:40][CH2:39][CH2:38][NH:37][CH2:36][CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30][CH2:29][NH2:28])=[O:12]
Reactant: COc1ccccc1CC(=O)O
Reactant: NCCCNCCCCNCCCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: COCCOC
Product: COc1ccccc1CC(=O)NCCCNCCCCNCCCN
Reaction time: 48 h

Procedure:
According to the General Procedure using 2-methoxyphenylacetic acid (81 mg. 0.49 mMol), dicyclohexylcarbodiimide (53 mg, 0.26 mMol), and spermine (201 mg, 0.99 mMol) in DME (4 ml), activation during 2.5 h and coupling over 48 h. The produce was eluted over silica gel with the lower layer of dichloromethane/methanol/0.880 ammonia solution (2:1:1). The desired amide was in fractions 6-10 and was homogeneous when monitored by tlc on silica (CH2Cl2 /MeOH/NH4OH lower layer, 2:1:1), Rf =0.25, (28 mg, 31%), lyophilisation gave 16 mg of a colourless, viscous oil whose spectroscopic data include: pmr (90 MHz, 2H2O) 1.35-1.85 (m, 8H, 4×CH2 --CH2), 2.4-2.9 (m, 10H, 5×CH2 --N), 3.25 (t, J=7, 2H, CON2H--CH2 --CH2), 3.5 (s, 2H, Ar--CH2 --CO), 3.83(s, 3H, OCH3), 6.75-7.05 (m, 2H, 2×ArH 3,5), and 7.15-7.35 (m, 2H, 2×ArH 4,6)ppm.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([Br:10])=[C:5]([Br:9])[C:6]=1[C:7]#[N:8].CC(C)([O-])C.[K+].Cl[C:18]([O:20][CH3:21])=[O:19].O>O1CCCC1>[Br:10][C:4]1[N:3]([C:18]([O:20][CH3:21])=[O:19])[C:2]([Br:1])=[C:6]([C:7]#[N:8])[C:5]=1[Br:9]
Reactant: N#Cc1c(Br)[nH]c(Br)c1Br
Reactant: COC(=O)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)n1c(Br)c(Br)c(C#N)c1Br
Reaction time: 0.33 h

Procedure:
A solution of 2,4,5-tribromopyrrole-3-carbonitrile (3.0 g, 0.091 mol) in tetrahydrofuran is treated portionwise with potassium t-butoxide (1.33 g, 0.012 mol) at room temperature, stirred for 20 minutes, treated dropwise with a solution of methyl chloroformate (1.29 g, 0.014 mol) in tetrahydrofuran, stirred for 21/2 days, poured into water and extracted with ether. The combined ether extracts are washed with brine, dried over MgSO4 and concentrated in vacuo to give a brown solid residue. The residue is recrystallized from ethyl acetate/hexanes to afford the title compound as a tan solid, 1.4 g (39.5%) mp 119.5° to 122.0° C.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([F:27])([F:26])[CH2:6][N:7]([C:16]1[C:21]([N+:22]([O-])=O)=[CH:20][N:19]=[C:18]([Cl:25])[N:17]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)C>C(O)(=O)C.[Fe]>[Cl:25][C:18]1[N:19]=[CH:20][C:21]2[NH:22][C:4](=[O:3])[C:5]([F:27])([F:26])[CH2:6][N:7]([CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]=2[N:17]=1
Reactant: CCOC(=O)C(F)(F)CN(CCc1ccccc1)c1nc(Cl)ncc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: O=C1Nc2cnc(Cl)nc2N(CCc2ccccc2)CC1(F)F
Reaction time: 0.17 h
Yield: 64 %

Procedure:
To a solution of 1.22 g (0.003 mole) of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-phenethyl-amino]-2,2-difluoro-propionic acid ethyl ester (IV-275) in 20 mL of acetic acid was added 1.3 g (0.023 g-atom) of iron powder. The mixture was heated to 80 degrees for 2 hours and then filtered while hot. Water and ethyl acetate were added to the filtrate and the mixture was stirred for 10 minutes and then filtered. The layers were separated. The organic layer was washed successively with ammonium hydroxide and water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Recrystallization of the residue with ethyl acetate and hexane gave 0.65 g of 2-chloro-7,7-difluoro-9-phenethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-275).
Reaction SMILES: [N:1]1[C:2]([C:10]([OH:12])=O)=[CH:3][N:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=12.[NH2:13][C@@H:14]([CH3:30])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[CH:22]=2)=[N:17]1>>[Cl:29][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:10]([C:2]3[N:1]=[C:5]4[CH:6]=[N:7][CH:8]=[CH:9][N:4]4[CH:3]=3)=[O:12])[CH3:30])[N:17]=2)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1cn2ccncc2n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cn2ccncc2n1
Yield: 90 %

Procedure:
The title compound was prepared as described in Example 34(d), starting from imidazo[1,2-a]pyrazine-2-carboxylic acid (0.163 g, 0.997 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.2 g, 0.767 mmol). The product was purified with flash-chromatography. Yield 90%. 1H-NMR (400 MHz; CDCl3): δ 1.18 (d, 3H), 4.35 (dd, 1H), 4.43 (dd, 1H), 4.47-4.57 (m, 1H), 6.93 (d, 1H), 7.85 (d, 1H), 7.94-8.00 (m, 3H), 8.03-8.06 (m, 1H), 8.47 (d, 1H), 8.60 (dd, 1H), 8.73 (d, 1H), 9.14-9.16 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[CH2:11][CH2:10]1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[F:8][C:5]1[CH:4]=[N:3][C:2]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[CH2:11][CH2:10]2)=[N:7][CH:6]=1
Reactant: OCC1CCNCC1
Reactant: Fc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: OCC1CCN(c2ncc(F)cn2)CC1
Temperature: 100 °C
Yield: 95.3 %

Procedure:
A solution of 2-chloro-5-fluoropyrimidine (1.1 g, 8.05 mmol) and 4-piperidinemethanol (1.14 g, 9.66 mmol) in DMSO (20 mL) was treated with K2CO3 (2.23 g, 16.10 mmol). The reaction mixture was heated at 100° C. overnight. The mixture was cooled to ambient temperature and poured into water and extracted with CH2Cl2 (60 mL×3). The organic extracts were combined and washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give crude product as a brown oil. The crude product was purified by chromatography on an ISCO silica gel column using 0 to 40% EtOAc/hexanes to give 1.62 g (95%) of [1-(5-fluoro-2-pyrimidinyl)-4-piperidinyl]methanol as a white solid upon standing. 1H NMR (400 MHz, CDCl3): δ 8.18 (s, 2H), 4.75-4.65 (m, 2H), 3.51 (d, 2H, J=6.1 Hz), 2.95-2.80 (m, 2H), 1.85-1.70 (m, 3H), 1.30-1.15 (m, 2H); LRMS (ESI), m/z 212 (M+H).
Reaction SMILES: CS[C:3]1[N:13]2[C:14]3[N:9]([C:10]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=4)=[CH:11][CH2:12]2)[N:8]=[CH:7][C:6]=3[C:5](=[O:25])[N:4]=1.[CH:26]([NH2:29])([CH3:28])[CH3:27].C(O)C>C(O)(=O)C>[CH3:27][CH:26]([NH:29][C:3]1[N:13]2[C:14]3[N:9]([C:10]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=4)=[CH:11][CH2:12]2)[N:8]=[CH:7][C:6]=3[C:5](=[O:25])[N:4]=1)[CH3:28]
Reactant: CC(C)N
Reactant: CSc1nc(=O)c2cnn3c2n1CC=C3c1cccc(C(F)(F)F)c1
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)Nc1nc(=O)c2cnn3c2n1CC=C3c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
To a suspension of 5.0 g of 5-(methylthio)-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,5a,8a-tetraazaacenaphthylen-3-one in 35 ml of acetic acid is added 2.64 g of isopropylamine. The reaction mixture is heated on a steambath for 18 hours. The resulting solution is cooled to room temperature and 17 ml of ethanol added. The mixture is cooled to 10° C. and 35 ml of ethanol and 20 g of ice added. The mixture is stirred for an additional 30 minutes at -10° C. The product is collected by filtration, washed with ethanol (2×20 ml) and air-dried to give 3.2 g (62.3%) of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[F:50][C:51]([F:57])([F:56])[C:52]1([NH2:55])[CH2:54][CH2:53]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([NH:55][C:52]4([C:51]([F:57])([F:56])[F:50])[CH2:54][CH2:53]4)=[O:24])=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Reactant: NC1(C(F)(F)F)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1(C(F)(F)F)CC1)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 23 %

Procedure:
To a DMF (0.4 mL) solution of (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation I, 50 mg, 0.15 mmol) and HATU (87 mg, 0.23 mmol) was charged 1-(trifluoromethyl)cyclopropanamine hydrochloride (37 mg, 0.23 mmol), followed by drop-wise addition of DIEA (0.080 mL, 0.46 mmol). After stirring first at ambient temperature for 15 minutes and then at 85° C. overnight, the reaction was cooled and directly purified by reverse-phase chromatography (5 to 60% acetonitrile/water) to yield the final product as off-white solid (15 mg, 23%). LCMS (apci) m/z=435.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1.[I:11]N1C(=O)CCC1=O>CC(C)=O>[Br:1][C:2]1[N:7]=[C:6]2[C:8]([I:11])=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1
Reactant: Brc1cnc2[nH]ccc2n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(C)=O
Product: Brc1cnc2[nH]cc(I)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.9 %

Procedure:
To a solution of 2-bromo-5H-pyrrolo[3,2-b]pyrazine [Intermediate AS] (0.68 g, 3.4 mmol) in acetone (17 mL) was added N-iodosuccinimide (0.82 g, 3.6 mmol) and the resulting mixture was stirred for 4 h at rt. The mixture was evaporated in vacuo to yield a residue that was purified via silica gel chromatography eluting with 40% THF in hexanes to give the title compound as a yellow solid (0.99 g, 89%). 1H NMR (DMSO-d6, 300 MHz): δ 12.82 (s, 1H), 8.42 (s, 1H), 8.20 (s, 1H). HPLC retention time: 2.23 minutes. MS ESI (m/z): 324.0, 326.0 (M+H)+, calc. 323.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].Cl.[C:12]1([C:18]2[N:22]=[C:21]([CH:23]3[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]3)[O:20][N:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl.CO>[F:1][C:2]1[CH:3]=[C:4]([C:5]([N:25]2[CH2:26][CH2:27][CH2:28][CH:23]([C:21]3[O:20][N:19]=[C:18]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:22]=3)[CH2:24]2)=[O:6])[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: c1ccc(-c2noc(C3CCCNC3)n2)cc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: O=C(c1cccc(F)c1)N1CCCC(c2nc(-c3ccccc3)no2)C1
Yield: 53 %

Procedure:
The compound was prepared following the procedure described in the Example 3 (D), using 3-Fluoro-benzoyl chloride as the acyl chloride of choice and the 3-(3-Phenyl-[1,2,4]oxadiazol-5-yl)-piperidine hydrochloride (already prepared before in the Example 7). Yield: 53% (yellow oil); Rf=0.25 (DCM/MeOH:98/2); LCMS (Tr): 4.77 min (Method C); MS (ES+) gave m/z: 352.3.
Reaction SMILES: [Br-].[CH2:2]([N+:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Br:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:16][C:17]1[NH:18][CH:19]=[C:20]([CH3:24])[C:21]=1[C:22]#[N:23].N1C(C)=CC=CC=1C>C(Cl)Cl>[Br-:15].[NH2:16][C:17]1[NH:18][C:19]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][N+:9]=2[CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[C:20]([CH3:24])[C:21]=1[C:22]#[N:23]
Reactant: Brc1cccc[n+]1Cc1ccccc1
Reactant: Cc1c[nH]c(N)c1C#N
Agent: [Br-]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: Cc1c(-c2cccc[n+]2Cc2ccccc2)[nH]c(N)c1C#N
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
Under an argon atmosphere, 1.81 g (5.5 mmol) of N-benzyl-2-bromo-pyridinium bromide [for preparation see J. Heterocyclic Chem. 28,1083 (1991)] are added to 605.5 mg (5.0 mmol) of 2-amino-3-cyano-4-methyl-pyrrole [for preparation see Synthesis (1976), 51] in 40 ml of methylene chloride and 639 μl (5.5 mmol) of lutidine. After 5.5 hours' stirring at RT, the reaction mixture is concentrated by evaporation to approximately half its original volume. Filtering the suspension and washing with methylene chloride/ethyl acetate (1:1) and ethyl acetate/hexane (1:1) yield the title compound; 1H-NMR (300 MHz, DMSO-d6): 10.83 (s, 1H), 9.10 (d, J=7, 1H), 8.49 (t, J=7, 1H), 7.96 (m, 2H), 7.30 (m, 3H), 6.95 (m, 2H), 6.57 and 5.80 (2s, each 2H), 1.76 (s, 3H); FAB-MS: (M+H)+ =289.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([CH:24]([F:26])[F:25])([C:14]2[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:15]=2[F:23])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C1COCC1.[Pd]>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:14]2[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:15]=2[F:23])([CH:24]([F:26])[F:25])[N:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1=NC(c2cc([N+](=O)[O-])ccc2F)(C(F)F)COC1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1=NC(c2cc(N)ccc2F)(C(F)F)COC1
Yield: 94.9 %

Procedure:
[5-Difluoromethyl-5-(2-fluoro-5-nitro-phenyl)-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (180 g, 462 mmol) and 17.61 g Pd—C 10% were suspended in 1760 mL THF. The mixture was shaken in a Parr apparatus in an atmosphere of hydrogen at rt. After 6 h the reaction mixture was filtered over celite and evaporated. The residue was crystallized from DCM/heptanes to provide 157.6 g of the title compound as beige crystals.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][CH:3]=1.[C:13]([O-])(=O)/C=C/C([O-])=O>>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH2:8][N:9]([CH3:13])[CH2:10][CH2:11][CH:12]=2)=[N:4][CH:3]=1
Reactant: O=C([O-])/C=C/C(=O)[O-]
Reactant: Cc1cnc(-c2cccnc2)s1
Product: Cc1cnc(C2=CCCN(C)C2)s1

Procedure:
The title compound was prepared from 88 (2.2 g, 0.013 mol) by the procedure described in Example 49. The crude free base obtained, 89, was converted to the title fumarate, 90. Yield: 0.8 g (0.0032 mol, 25%). M.P. 159°-160° C. Anal. (C12H16N2O2S) C, H, N.