Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CN(P(N(C)C)(N(C)C)=[O:17])C.[F:24][C:25]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:26]=1[C:27]#[N:28].C1[CH2:38][O:37]CC1>>[C:27]([C:26]1[CH:29]=[CH:30][C:31]([CH2:33][C:38]([OH:37])=[O:17])=[CH:32][C:25]=1[F:24])#[N:28]
Reactant: C1CCOC1
Reactant: Cc1ccc(C#N)c(F)c1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: N#Cc1ccc(CC(=O)O)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of dry diisopropylamine (16.5 g, 163 mmol) in dry THF (150 mL) under nitrogen was cooled with a −78° C. dry ice/acetone bath, and n-butyl lithium (2.50 M in hexane, 65.2 mL) was added slowly. The resulting solution was warmed to ambient temperature for 10 min and then cooled to −78° C. again. HMPA (30.0 mL, 168 mmol) was added, followed by a solution of 2-fluoro-4-methylbenzonitrile (20.0 g, 148 mmol) in 50 mL of dry THF. After stirring at −78° C. for 2 hours, CO2 was bubbled through the solution for 20 min, and then the mixture was warmed slowly to 0° C. Then 1 N HCl was added until pH=2 and the mixture was extracted with EtOAc. The organic layers were washed with brine and dried over anhydrous sodium sulphate and concentrated to afford title compound.
Reaction SMILES: [C:1](#[N:4])[CH2:2][OH:3].[C:5]([C:7]1[CH:8]=[C:9]([N:14]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:21][C:20]=3[CH3:34])[S:16][CH2:15]2)[CH:10]=[CH:11][C:12]=1F)#[N:6].[H-].[Na+]>C1COCC1.CCOC(C)=O>[C:5]([C:7]1[CH:8]=[C:9]([N:14]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])=[CH:21][C:20]=3[CH3:34])[S:16][CH2:15]2)[CH:10]=[CH:11][C:12]=1[O:3][CH2:2][C:1]#[N:4])#[N:6]
Reactant: Cc1cc(CCC(=O)OC(C)(C)C)ccc1C1=NN(c2ccc(F)c(C#N)c2)CS1
Reactant: N#CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(CCC(=O)OC(C)(C)C)ccc1C1=NN(c2ccc(OCC#N)c(C#N)c2)CS1
Temperature: 75 °C

Procedure:
Glycolonitrile (0.013 mmol, 0.1 mL) was added to a solution of tert-butyl 3-(4-(3-(3-cyano-4-fluorophenyl)-1,3,4-thiadiazol-5-yl)-3-methylphenyl)propanoate (0.012 mmol, 0.005 g, from Step B) in THF (1 mL). Sodium hydride (95%, 5 mg) was added to the reaction mixture which was heated at 75° C. for 16 h. The reaction was diluted with EtOAc (20 mL) and washed with water (20 mL). The organics were dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel chromatography eluting with 25% EtOAc/hexanes yielded the title compound: ESI-MS (m/z) 461.2; HPLC A: 3.94 min.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[C:4]([O:11][CH3:12])[C:5]([Cl:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:14]OS(OC)(=O)=O>C1COCC1>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([O:11][CH3:12])[C:5]([Cl:10])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: COc1c(O)c(Br)cc(C=O)c1Cl
Reactant: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: COc1c(Br)cc(C=O)c(Cl)c1OC
Temperature: 65 °C
Reaction time: 3 h
Yield: 70.3 %

Procedure:
To the mixture of aldehyde 156 (15.0 g, 56.5 mmol) in THF (300 mL) were added dimethylsulfate (7.0 mL, 73.5 mmol) and LiOH monohydrate (3.1 g, 73.5 mmol). The mixture was stirred for 3 hours at 65° C. The mixture was cooled to r.t. and filtered to remove insoluble materials through celite. The filtrate was extracted with EtOAc/aq. 50% NaCl solution (200 mL/500 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the compound 157 (11.1 g, 70%).
Reaction SMILES: Cl.Cl.[N:3]1([CH2:8][CH2:9][O:10][C:11]2[CH:40]=[CH:39][C:14]([CH2:15][C:16]3[C:17]4[CH:38]=[CH:37][CH:36]=[CH:35][C:18]=4[S:19][C:20]=3[C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]4[N:31]=CN[CH:34]=4)=[O:29])=[CH:23][CH:22]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.[O:41]1[C:45]([C:46]([OH:48])=[O:47])=CC=N1.CO.[NH4+].[OH-]>C(Cl)(Cl)Cl>[C:46]([OH:48])(=[O:47])[C:45]([OH:10])=[O:41].[N:3]1([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:15][C:16]3[C:17]4[CH:38]=[CH:37][CH:36]=[CH:35][C:18]=4[S:19][C:20]=3[C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]4[CH:34]=[CH:45][O:41][N:31]=4)=[O:29])=[CH:23][CH:22]=3)=[CH:39][CH:40]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C(O)c1ccno1
Reactant: O=C(Nc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1)c1c[nH]cn1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(Nc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1)c1ccon1
Product: O=C(O)C(=O)O
Yield: 95 %

Procedure:
By essentially following the conditions described in Example 1, Part F, the free base of the title compound was prepared as a foam from 2-(4-aminophenyl)-3-[4-[2-(1-pyrrolidinyl)ethoxy]benzyl]benzo[b]thiophene (Example 16; Part D) and 5-isoxazolecarboxylic acid in 95% yield following radial chromatography (SiO2; 1% then 2% then 3% MeOH in CHCl3 sat'd with NH4OH). The product was converted to the oxalate salt according to the proceedure described in Example 1, Part G.
Reaction SMILES: [CH3:1][O-:2].[Na+].[C:4]1([CH3:18])[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14](Cl)[CH:13]=[C:12](Cl)[N:11]=2)=[CH:6][CH:5]=1.[CH3:19][OH:20]>>[C:4]1([CH3:18])[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([O:2][CH3:1])[CH:13]=[C:12]([O:20][CH3:19])[N:11]=2)=[CH:6][CH:5]=1
Reactant: Cc1ccc(-c2nc(Cl)cc(Cl)n2)cc1
Reactant: C[O-]
Reactant: CO
Agent: [Na+]
Product: COc1cc(OC)nc(-c2ccc(C)cc2)n1
Reaction time: 4 h

Procedure:
156.1 g of a 30.5% solution of sodium methylate are stirred with 700 ml of anhydrous methanol. To the solution are then added, over 10 minutes and with gentle cooling, 95.64 g of 2-p-tolyl-4,6-dichloropyrimidine. The mixture is then heated to reflux and kept at the boil for 4 hours. The solvent is removed by distillation and the residue is charged into 1000 ml of water. The product is triturated with water to remove sodium chloride, isolated by filtration, washed with water and dried in the air, affording 90.4 g of the title compound with a melting point of 61°-62° C.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C1(P([N:24]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[N-:24]=[C:7]=[O:9].[CH2:5]1[CH2:4][CH2:3][CH:2]=[CH:1][CH2:6]1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)C1CC=CCC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C1=CCCCC1
Product: [N-]=C=O

Procedure:
A solution of 3-cyclohexenylcarboxylic acid (1 mmol), diphenylphosphoryl azide (1.2 mmol) and triethylamine (2.5 mmol) in toluene was heated at 100° C. for 9 hours.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[C:11]=2[OH:17])=[CH:8][CH:9]=1)=[O:4].[N:18]([O-])=O.[Na+].[CH3:22][C:23]1[CH2:24][C:25](=[O:38])[N:26]([C:28]2[CH:37]=[CH:36][C:35]3[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=3[CH:29]=2)[N:27]=1.C(=O)(O)[O-].[Na+]>Cl>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][N:18]=[C:24]3[C:25](=[O:38])[N:26]([C:28]4[CH:37]=[CH:36][C:35]5[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=5[CH:29]=4)[N:27]=[C:23]3[CH3:22])[C:11]=2[OH:17])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(-c2cccc(N)c2O)o1
Reactant: O=N[O-]
Reactant: CC1=NN(c2ccc3c(c2)CCCC3)C(=O)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)c1ccc(-c2cccc(NN=C3C(=O)N(c4ccc5c(c4)CCCC5)N=C3C)c2O)o1
Yield: 23.6 %

Procedure:
5-(3-Amino-2-hydroxy-phenyl)-furan-2-carboxylic acid methyl ester 54c (110 mg, 0.47 mmol) was dissolved in hydrochloric acid (1.6 mL, 1 mol/L) upon cooling by an ice-water bath, followed by dropwise addition of 0.6 mL of aqueous sodium nitrite (36 mg, 0.52 mmol). After the mixture was reacted for 10 minutes, 5-methyl-2-(5,6,7,8-tetrahydro-naphthalen-2-yl)-2,4-dihydro-pyrazol-3-one 3i (97 mg, 0.43 mmol) was added. The mixture was adjusted to pH 8˜9 with saturated aqueous sodium bicarbonate. The reaction mixture was reacted at room temperature for 24 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered and the filter cake was dissolved in 15 mL of water. The mixture was adjusted to pH 3˜4 with concentrated hydrochloric acid upon cooling by an ice-water bath. The mixture was filtered and the filter cake was purified by silica gel column chromatography to obtain the title compound 5-(2-hydroxy-3-{N′-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydro-naphthalen-2-yl)-1,5-dihydro-pyrazol-4-ylidene]-hydrazino}-phenyl)-furan-2-carboxylic acid methyl ester 54 (48 mg, yield 23.9%) as a red solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[C:21]([F:24])([F:23])[F:22])[CH:5]=1.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:12]=2[C:21]([F:24])([F:23])[F:22])[CH:5]=1
Reactant: COC(=O)c1cccc(Sc2c(C(F)(F)F)[nH]c3cc(Cl)ccc23)c1
Reactant: BrCc1ccccc1
Product: COC(=O)c1cccc(Sc2c(C(F)(F)F)n(Cc3ccccc3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 10, Step 3, using the following starting materials: 3-(6-chloro-2-trifluoromethyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester and benzyl bromide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].Br[CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[CH:4][C:3]=1[O:12][CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc(C(F)(F)F)cc1Cl

Procedure:
10.00 g (50.87 mmol) of 2-chloro-4-trifluoromethyl-phenol, 7.11 mL (55.00 mmol) of ethyl 2-bromopropionate and 7.60 g (55 mmol) of potassium carbonate in 100 mL DMF was stirred for 16 hours at 50° C. and then filtered. The filtrate was evaporated down i. vac., combined with water and exhaustively extracted with EtOAc. The combined org. extracts were washed with 10% aqueous sodium carbonate solution and water, dried over sodium sulphate and evaporated down i. vac.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[N:9][N:10]([C:12]2[N:17]=[CH:16][C:15]([NH:18][CH:19]([C:23]3[CH:33]=[CH:32][C:26]([C:27](OCC)=[O:28])=[CH:25][CH:24]=3)[CH2:20][CH2:21][CH3:22])=[CH:14][CH:13]=2)[CH:11]=1.[C:34]([OH:40])([C:36](F)(F)F)=[O:35].C[C:42]#[N:43]>O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[N:9][N:10]([C:12]2[N:17]=[CH:16][C:15]([NH:18][CH:19]([C:23]3[CH:24]=[CH:25][C:26]([C:27]([NH:43][CH2:42][CH2:36][C:34]([OH:40])=[O:35])=[O:28])=[CH:32][CH:33]=3)[CH2:20][CH2:21][CH3:22])=[CH:14][CH:13]=2)[CH:11]=1
Reactant: CCCC(Nc1ccc(-n2cc(-c3ccccn3)cn2)nc1)c1ccc(C(=O)OCC)cc1
Reactant: O=C(O)C(F)(F)F
Reactant: CC#N
Solvent: O
Product: CCCC(Nc1ccc(-n2cc(-c3ccccn3)cn2)nc1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
The title compound was prepared by a method analogous to that described for Example 163, Steps B-D, using (+/−)-ethyl 4-(1-(6-(4-(pyridin-2-yl)-1H-pyrazol-1-yl)pyridin-3-ylamino)butyl)benzoate. Column: Waters Atlantis dC18 4.6×50 mm, 5 μm. Modifier: TFA 0.05%. Gradient: 95% H2O/5% MeCN linear to 5% H20/95% MeCN over 4.0 min, Hold at 5% H2O/95% MeCN to 5.0 min. Flow: 2.0 mL/min. Retention time: 2.20 min. MS (M+1): 485.0.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5](Cl)=[CH:4][C:3]=1[CH:9]1[CH2:11][CH2:10]1.[CH2:12]([C:16]1[CH:21]=[CH:20][C:19]([C:22]#[CH:23])=[CH:18][CH:17]=1)[CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)[C:37]2[CH:42]=[CH:41]C=C[C:38]=2[C:43]2[C:48](C(C)C)=[CH:47][C:46]([CH:52](C)[CH3:53])=[CH:45][C:44]=2C(C)C)CCCCC1>O1CCOCC1.CC#N.CC#N.Cl[Pd]Cl.O>[CH2:12]([C:16]1[CH:17]=[CH:18][C:19]([C:22]#[C:23][C:2]2[CH:7]=[CH:6][C:5]([C:53]#[C:52][C:46]3[CH:47]=[CH:48][C:43]([CH2:38][CH2:37][CH2:42][CH3:41])=[CH:44][CH:45]=3)=[CH:4][C:3]=2[CH:9]2[CH2:11][CH2:10]2)=[CH:20][CH:21]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Reactant: C#Cc1ccc(CCCC)cc1
Reactant: Clc1ccc(Cl)c(C2CC2)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: CC#N
Product: CCCCc1ccc(C#Cc2ccc(C#Cc3ccc(CCCC)cc3)c(C3CC3)c2)cc1
Temperature: 100 °C

Procedure:
5 g (26 mmol) of 1,4-dichloro-2-cyclopropylbenzene, 9.4 g (58 mmol) of 1-n-butyl-4-ethynylbenzene, 19 g (58 mmol) of caesium carbonate, 69 mg (0.3 mmol) of bis(acetonitrile)palladium(II) chloride and 382 mg (0.8 mmol) of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl are dissolved in 80 ml of dioxane under nitrogen and heated at 100° C. overnight. 100 ml of water are added to the cooled solution, and the mixture is extracted twice with methyl t-butyl ether (100 ml). The combined organic phases are washed with water, dried over sodium sulfate and evaporated in vacuo. The residue is purified by column chromatography and recrystallised from ethanol, giving the title compound 1 as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:18])=[C:8]2[C:13](Cl)=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2].[O:19]([C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][C:27]=1[CH2:33][O:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.COC(C1C(C)=C2C(NC3C=CC(OC4C=CC=CC=4OC(C(OC(C)(C)C)=O)(C)C)=CC=3)=C(C#N)C=NN2C=1)=O.C(O)(C(F)(F)F)=O.O.C(O)(C(F)(F)F)=O.CC#N>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:18])=[C:8]2[C:13]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([O:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[C:27]([CH2:33][O:34][CH:35]4[CH2:40][CH2:39][CH2:38][CH2:37][O:36]4)[CH:28]=3)=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2]
Reactant: Nc1ccc(Oc2ccccc2)c(COC2CCCCO2)c1
Reactant: CCOC(=O)c1cn2ncc(C#N)c(Cl)c2c1C
Agent: COC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4OC(C)(C)C(=O)OC(C)(C)C)cc3)c2c1C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)c(COC4CCCCO4)c3)c2c1C
Reaction time: 0.13 h

Procedure:
Compound 394 was prepared from 4-chloro-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylic acid ethyl ester (Example 1D) (160 mg, 0.61 mmol) and 394D (180 mg, 0.60 mmol) by a route analogous to that used for the preparation of compound 388D. It has a retention time 7.69 min. (Column: HTS, 5 u, 4.6×50 mm; Gradient: 5-100% B in 8.0 min; A=0.1% TFA/H2O; B=0.1% TFA/CH3CN; Run time 10 min; Det: 215 nM; FR: 1.2 ml/min); MS Found: (M−H)+=525.4
Reaction SMILES: [CH3:1][N:2]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=[O:6])[C:3]1=[O:4].[N+:13]([CH3:16])([O-:15])=[O:14]>O>[OH:6][C:5]1([CH2:16][N+:13]([O-:15])=[O:14])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:2]([CH3:1])[C:3]1=[O:4]
Reactant: C[N+](=O)[O-]
Reactant: CN1C(=O)C(=O)c2ccccc21
Solvent: O
Product: CN1C(=O)C(O)(C[N+](=O)[O-])c2ccccc21
Temperature: 30 °C
Reaction time: 24 h

Procedure:
N-methyl isatin (0.08 g) and nitromethane (0.15 ml) were added to water and the reaction mixture was vigorously stirred at a temperature of 30° C. for 24 hours. The obtained product was extracted with ethyl acetate and purified by silica gel column chromatography using ethyl acetate/hexane as eluents to afford pure product.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([O:20]CC)=[O:19])[CH2:14][C@H:13]1[NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].Cl>O1CCCC1>[C:18]([C@H:15]1[CH2:16][CH2:17][C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[C@H:13]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:14]1)([OH:20])=[O:19]
Reactant: CCOC(=O)[C@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@@H](C(=O)O)CC[C@@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.2 %

Procedure:
(1S,2R,4S)-N1-Benzyloxycarbonyl-N2-(tert-butoxy-carbonyl)-4-ethoxycarbonyl-1,2-cyclohexanediamine (620 mg) was dissolved in tetrahydrofuran (10 ml), and an aqueous solution (5.0 ml) of lithium hydroxide monohydrate (93 mg) was added to stir the mixture at room temperature for 16 hours. After lithium hydroxide monohydrate (221 mg) was additionally added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours, the reaction mixture was neutralized with 1N hydrochloric acid and extracted with methylene chloride. An organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (580 mg) as a colorless foamy substance.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]1[N:19]=[C:18]([F:20])[N:17]=[C:16]2[C:12]=1[N:13]=[CH:14][NH:15]2.C([O-])([O-])=O.[K+].[K+].Br[CH:28]([CH3:30])[CH3:29].C(Cl)(Cl)Cl>CN(C=O)C.CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]1[N:19]=[C:18]([F:20])[N:17]=[C:16]2[C:12]=1[N:13]=[CH:14][N:15]2[CH:28]([CH3:30])[CH3:29]
Reactant: CC(C)Br
Reactant: Cc1cc(C)c(CNc2nc(F)nc3[nH]cnc23)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)c(CNc2nc(F)nc3c2ncn3C(C)C)cn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of (4, 6-dimethyl-pyridin-3-ylmethyl)-(2-fluoro-9H-purin-6-yl)-amine (0.6 g, 1.9 mmol) in DMF (10 ml) under an argon atmosphere, at RT, was added K2CO3 (powdered, anhydrous, 1.77 g, 5 eq, 13 mmol) followed by 2-bromopropane (1.8 ml, 10 eq, 19 mmol). The reaction mixture was stirred at RT for 24 h, when TLC (CHCl3: MeOH; 90:10) indicated that the reaction had gone to completion. The solvent was evaporated in vacuo and the residue partitioned between water (50 ml) and ethyl acetate (50 ml), the aqueous phase was separated and extracted with more EtOAc (2×50 ml). The bulked organic phase was washed with brine (50 ml), dried (MgSO4) and evaporated in vacuo, and the residue was purified by gradient column chromatography on silica gel, eluted with CHCl3:MeOH (100:0→95:5), to provide the product as a yellow film (0.4 g, 59%). δH (250 MHz, CDCl3) 1.52 [6 H, d, J 7.5 CH(CH3)2] 2.27 (3 H, s, CH3), 2.45 (3 H, s, CH3), 4.73-4.62 (3 H, m, NHCH2 and CH[CH3]2), 6.91 (1 H, s, ArH), 7.12 (1 H, NH), 7.47 (1 H, s, ArH), 8.32 (1 H, s, ArH); δC (250 MHz, CDCl3) 160.77 (C), 157.89 (C), 157.43 (C), 156.12 (C), 155.79 (C), 149.14 (CH), 137.7 (CH), 128.7 (C), 129.76 (C), 124.83 (CH), 47.2 (CH), 40.14 (CH2), 23.9 (CH3), 22.47 (2×CH3), 18.54 (CH3); m/z 315.3 (M+H)
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]2=[N:16][C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:19]=[C:14]2[CH:13]=[C:12]1[CH:32]1[CH2:34][CH2:33]1)C.[Li+].[OH-]>C1COCC1.O>[CH:32]1([C:12]2[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:35])=[O:3])[C:15]3=[N:16][C:17]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:19]=[C:14]3[CH:13]=2)[CH2:33][CH2:34]1
Reactant: CCOC(=O)CCCCCCn1c(C2CC2)cc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCCCCn1c(C2CC2)cc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 60 °C

Procedure:
7-(6-Cyclopropyl-2,3-diphenyl-pyrrolo[2,3-b]pyrazin-5-yl)-heptanoic acid ethyl ester (step 1)(250 mg, 0.535 mmol) in THF (6 ml) and water (2 ml) was treated with LiOH.monohydrate (45 mg, 1.069 mmol) and stirred at room temperature for 12 hours followed by heating at 60° C. for 10 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in water and washed with diethyl ether (×1). The aqueous was acidfied using citric acid, and extracted with EtOAc. The organic solvent was dried (Na2SO4) and the solvent was removed under reduced pressure. Purification of the product by chromatography on silica eluting with 1% MeOH in DCM, followed by further purification using preparative HPLC according to the following conditions to afforded the titled compound;
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C(N(CC)CC)C.[C:16]([O:20][C:21]([NH:23][C@H:24]([C:27](O)=[O:28])[CH2:25][Cl:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:27](=[O:28])[C@H:24]([CH2:25][Cl:26])[NH:23][C:21]([O:20][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:22])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCl)C(=O)O
Reactant: CCOC(=O)CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)[C@H](CCl)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.2 %

Procedure:
To a solution of 0.28 g (2 mmol) of glycine ethyl ester hydrochloride and 0.28 mL (2 mmol) of triethylamine in 10 mL of chloroform, 0.52 g (2 mmol) of N-(tert-butoxycarbonyl)-3-chloro-L-alanine in 6 mL of chloroform and 0.42 g (2 mmol) of dicyclohexylcarbodiimide were added at 0° C. The reaction mixture was stirred for 16 hours at room temperature. The resultant precipitate was removed by filtration and the filtrate was washed successively with 0.5N hydrochloric acid, water and 3% aqueous sodium bicarbonate, then was dried over anhydrous sodium sulfate. Removal of the solvent left a crystalline residue which was recrystallized from a mixture of ethyl acetate and n-hexane to give 0.415 g (60%) of the pure product melting at 71.5-72.0° C. The identity of the product, which has the structural formula ##STR73## was confirmed by IR and NMR analyses.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([C:13]1[C:18]([F:19])=[CH:17][N:16]=[CH:15][N:14]=1)[CH3:12].[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C:28](=[O:35])[CH2:29][N:30]1[CH:34]=[N:33][CH:32]=[N:31]1.C(O)(=O)C>C1COCC1>[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C:28]([OH:35])([CH:11]([C:13]1[C:18]([F:19])=[CH:17][N:16]=[CH:15][N:14]=1)[CH3:12])[CH2:29][N:30]1[CH:34]=[N:33][CH:32]=[N:31]1
Reactant: O=C(Cn1cncn1)c1ccc(F)cc1F
Reactant: CCc1ncncc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(c1ncncc1F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: -65 °C
Reaction time: 3 h

Procedure:
To THF (200 ml) was added sodium bis(trimethylsilyl)amide (79 ml of a 1.0M solution in THF) and the solution cooled to -65° C. under nitrogen. A solution of 4-ethyl-5-fluoropyrimidine (10 g) (see Preparation 8) in THF (100 ml) was added over 30 minutes. After stirring for 3 hours at -65° C. the thin slurry was treated with a solution of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (17.7 g) in THF (100 ml), dropwise over 30 minutes. The solution was stirred for a further 1 hour at -65° C. and then treated with acetic acid (20 ml). After warming to -20° C. the solution was washed with water (200 ml) and the organic layer separated and combined with an ethyl acetate (200 ml) back extract of the aqueous phase. The combined organic layers were concentrated under reduced pressure to provide a solid that was triturated with diethyl ether (230 ml) and filtered. The filtrate was concentrated under reduced pressure and chromatographed on silica with 1:1 diethyl ether/ethyl acetate as the eluent. The fractions containing the title compound were combined, concentrated under reduced pressure and the residue chromatographed on silica with 1:1 ethyl acetate/hexane as the eluent. The appropriate fractions were combined and evaporated under reduced pressure to provide the purified title compound (0.82 g), m.p. 125°-127° C. Found: C,54.89; N,19.66; C16H14F3N5O requires: C,55.01; H,4.01; N,20.05%.