Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:12][N:13]([O:16]C2CCCCO2)[CH:14]=[O:15])[C:5]([F:30])=[C:4]([N:31]([CH3:39])[CH2:32][C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[N:3]=1>C(O)(=O)C.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)[CH2:12][N:13]([OH:16])[CH:14]=[O:15])[C:5]([F:30])=[C:4]([N:31]([CH3:39])[CH2:32][C:33]2[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=2)[N:3]=1
Reactant: CN(Cc1ccncc1)c1nc(Cl)nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)c1F
Solvent: CC(=O)O
Solvent: O
Product: CN(Cc1ccncc1)c1nc(Cl)nc(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)c1F
Reaction time: 8 h
Yield: 30.5 %

Procedure:
[(2R)-3-(2-{2-Chloro-5-fluoro-6-[methyl(4-pyridinylmethyl)amino]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (0.0958 g, 0.1701 mmol) was dissolved in acetic acid (8 mL) and water (2 mL). This reaction mixture was left to stir overnight. The volatiles were evaporated, and the resulting material was purified by RP-HPLC to provide [(2R)-3-(2-{2-chloro-5-fluoro-6-[methyl(4-pyridinylmethyl)amino]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide as a beige solid (0.0249 g, 31%). LCMS: (M+H)+=480.1.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[N:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.C[N:17](C=O)C>ClCCl>[Br:1][C:2]1[S:6][C:5]([C:7]([NH2:17])=[O:9])=[N:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1ncc(Br)s1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NC(=O)c1ncc(Br)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
To 5-bromo-thiazole-2-carboxylic acid (0.267 g, 0.128 mmol) suspended in dry dichloromethane (30 mL) are added oxalyl chloride (0.22 mL, 0.257 mmol) and a drop of DMF. The reaction is stirred for 1 hour at room temperature. The solvent is evaporated and the resultant crude is dissolved in 7M NH3 in MeOH. The reaction mixture is stirred overnight at room temperature. After evaporation of the solvent, the residue is dissolved in dichloromethane and washed with 1M NaOH. The organic phase is dried over MgSO4, filtered and evaporated. The residue is purified by silica gel column chromatography eluting with 95:5 DCM:MeOH to give the title compound (33.8 mg, 25%).
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[C:12]([CH2:14][O:15]C2CCCCO2)[CH:11]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CO>[CH2:1]([C:8]1[N:13]=[C:12]([CH2:14][OH:15])[CH:11]=[C:10]([C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=2)[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2cc(COC3CCCCO3)nc(Cc3ccccc3)n2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: Cc1ccc(-c2cc(CO)nc(Cc3ccccc3)n2)cc1
Reaction time: 18 h
Yield: 98.7 %

Procedure:
To a solution of the product from Step A (2.0 g, 5.3 g) in MeOH (30 mL) was added p-TsOH.H2O. After 18 h, the reaction was diluted with satd. aq. NaHCO3 and extracted with EtOAc (2×). The combined organic layers were dried and concentrated to give the 1.53 g (99%) of the title compound. MS (ESI): exact mass calcd. for C19H18N2O, 290.14; m/z found, 291.4 [M+H]+. 1H NMR (CDCl3): 8.00-7.98 (m, 2H), 7.45-7.43 (m, 3H), 7.32-7.28 (m, 4H), 7.23-7.20 (m, 1H), 4.74 (d, J=4.8, 2H), 4.33 (s, 2H), 3.62 (t, J=5.1, 1H), 2.42 (s, 3H).
Reaction SMILES: [CH:1]([N:4]([CH:20]([CH3:22])[CH3:21])[CH2:5][CH2:6][CH:7]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)[C:8]#[N:9])([CH3:3])[CH3:2].Cl[CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:28][CH2:27]1.C1(C2C=CC=CC=2)C=CC(C(CCN(C(C)C)C(C)C)C#N)=CC=1.ClCCN(C(C)C)C(C)C>>[CH:20]([N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6][C:7]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)([CH2:24][CH2:25][N:26]1[CH2:27][CH2:28][CH:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:30][CH2:31]1)[C:8]#[N:9])([CH3:22])[CH3:21]
Reactant: CC(C)N(CCC(C#N)c1cccc2ccccc12)C(C)C
Reactant: ClCCN1CCC(c2ccccc2)CC1
Agent: CC(C)N(CCC(C#N)c1ccc(-c2ccccc2)cc1)C(C)C
Agent: CC(C)N(CCCl)C(C)C
Product: CC(C)N(CCC(C#N)(CCN1CCC(c2ccccc2)CC1)c1cccc2ccccc12)C(C)C

Procedure:
Substitution of equivalent quantities of α-[2-(diisopropylamino)ethyl]-α-(1-naphthyl)acetonitrile and 1-(2-chloroethyl)-4-phenylpiperidine for α-(4-biphenylyl)-α-[2-(diisopropylamino)ethyl]acetonitrile and 2-chloro-N,N-diisopropylethylamine called for in Example 2, Method B, respectively and substantial repetition of the procedure detailed therein, affords α-[2-(diisopropylamino)ethyl]-α-(1-naphthyl)-α-[2-(4-phenyl-1-piperidinyl)ethyl]acetonitrile.
Reaction SMILES: [NH2:1][C:2]1[N:6]2[N:7]=[C:8]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[C:5]2=[N:4][N:3]=1.CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>ClC(Cl)C>[N:15]1([C:8]2[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[C:5]3=[N:4][N:3]=[C:2]([NH:1][C:37](=[O:39])[CH3:38])[N:6]3[N:7]=2)[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1
Reactant: CC(=O)Cl
Reactant: Nc1nnc2c3c(c(N4CCOCC4)nn12)CCCC3
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CC(=O)Nc1nnc2c3c(c(N4CCOCC4)nn12)CCCC3

Procedure:
A 5.80 gm (0.0211 mole) quantity of the compound of Example 15 was dissolved in 100 ml of dichloroethane, and 380 mg (0.003 mole) of dimethylaminopyridine and 3.1 gm (0.03 mole) of triethylamine were added, followed by 2.38 gm (0.030 mole) of acetyl chloride. This mixture was refluxed overnight and evaporated. The resulting mixture was partioned between dilute aqueous NaHCO3 and CH2Cl2. The organic layer was dried and evaporated. The residue was triturated with ether and the resulting solid was collected to give 4.40 g of N-(7,8,9,10-tetrahydro-6-(4-morpholinyl)-1, 2,4-triazolo[3,4-a]phthalazin-3yl)acetamide; mp 147-149° C. (toluene-hexane).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][N:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]([F:32])([CH:29]([F:31])[F:30])[CH2:20]OS(C(F)(F)F)(=O)=O>CC(C)=O.C(OCC)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:20][C:19]([F:32])([F:18])[CH:29]([F:31])[F:30])=[CH:7][N:6]=1)=[O:4]
Reactant: O=S(=O)(OCC(F)(F)C(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: COC(=O)c1ccc(OCC(F)(F)C(F)F)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 5-hydroxy-pyridine-2-carboxylic acid methyl ester (2.0 g, 13.1 mmol) in acetone (40 ml) was treated with potassium carbonate (5.415 g, 39.2 mmol) and trifluoro-methanesulphonic acid 2,2,3,3-tetrafluoropropyl ester. After 4 hours stirring at room temperature the suspension was diluted with diethylether. After filtration the solution was evaporated and the yellow solid purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 30:70 as the eluent. The 5-(2,2,3,3-tetrafluoro-propoxy)-pyridine-2-carboxylic acid methyl ester was obtained as a light yellow solid (3.49 g, 76% of theory). MS (ISP): m/z=468.1 [M+H]+.
Reaction SMILES: [OH-].[Na+].Cl[C:4]([C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[C:10]([Cl:15])[CH:9]=1)=[CH:5]C=O.ClCCl>O.O1CCOCC1>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C:4]#[CH:5])=[CH:9][C:10]=1[Cl:15]
Reactant: O=CC=C(Cl)c1ccc(Br)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: C#Cc1ccc(Br)c(Cl)c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
40 g of sodium hydroxide are dissolved, under an inert atmosphere, in 230 ml of water, 120 ml of 1,4-dioxane are added and the reaction mixture is heated to 80° C. 17.5 g of 3-chloro-3-(4-bromo-3-chlorophenyl)propenal dissolved in 400 ml of 1,4-dioxane are added and the reaction mixture is stirred for 30 minutes at 80° C. The reaction mixture is allowed to cool to room temperature and 2300 ml of dichloromethane are then added. The phases are separated after settling has taken place and the organic phase is washed with water and dried over magnesium sulphate. The compound dissolved in a dichloromethane/1,4-dioxane mixture is used in its current form in the next step.
Reaction SMILES: [OH:1][CH2:2][CH:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([O:13][CH3:14])[CH:6]=1)[CH3:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:14][O:13][C:7]1[CH:6]=[C:5]([CH:3]([CH3:4])[CH:2]=[O:1])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10]
Reactant: COc1cc(C(C)CO)ccc1C#N
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1cc(C(C)C=O)ccc1C#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 4-(1-hydroxypropan-2-yl)-2-methoxybenzonitrile (0.12 g, 0.63 mmol) in dry CH2Cl2 (30 mL) at 0° C. was added Dess-Martin periodinane (0.35 g, 0.82 mmol) in one portion. The mixture was stirred for 12 h at rt and quenched with a 1:1 mixture of saturated Na2S2O3 (20 mL) and saturated NaHCO3 (20 mL). The resulting mixture was diluted with CH2Cl2 (50 mL) and the layers were separated. The aqueous phase was extracted with CH2Cl2 (2×50 mL). The combined organic phases were washed with brine, dried (Na2SO4), and concentrated in vacuo to give crude 2-methoxy-4-(1-oxopropan-2-yl)benzonitrile. The crude residue was used in subsequent reactions without further purification.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH3:24])[N:5]2[C:10]3[CH:11]=[CH:12][N:13](S(C4C=CC(C)=CC=4)(=O)=O)[C:9]=3[N:8]=[CH:7][C:6]=12.[CH:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)=[O:26].CCO.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.[Pd]>[CH3:24][C:4]1[N:5]2[C:10]3[CH:11]=[CH:12][NH:13][C:9]=3[N:8]=[CH:7][C:6]2=[C:2]([C:30]2[CH:31]=[CH:32][C:27]([CH:25]=[O:26])=[CH:28][CH:29]=2)[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2c(Br)nc(C)n23)cc1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCO
Product: Cc1nc(-c2ccc(C=O)cc2)c2cnc3[nH]ccc3n12
Temperature: 150 °C
Yield: 76.2 %

Procedure:
To a microwave reaction vial containing 3-bromo-1-methyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.100 g, 0.247 mmol, Preparation #AB.1), 4-formylphenylboronic acid (0.074 g, 0.493 mmol, Lancaster) and SiliaCat® DPP-Pd (0.031 g, 0.025 mmol, Silicycle) in 1,4-dioxane (1.0 mL) and EtOH (1.0 mL) was added a solution of Cs2CO3 (0.177 g, 0.543 mmol) in water (0.3 mL). The mixture was heated in a microwave at 150° C. for 30 min. The mixture was filtered through a filtration tube with a polyethylene frit, and the resulting solid was rinsed with EtOAc (5 mL). The solid was dissolved in a 9:1 DCM/MeOH solution and filtered. The filtrate was concentrated under reduced pressure followed by drying overnight in a vacuum oven at about 65° C. to give the title compound (0.052 g, 76%): LC/MS (Table 2, Method c) Rf=1.67 min.; MS m/z: 277 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:7]1[C:14]2[C@H:13]3[CH2:15][C@H:12]3[CH2:11][C:10]=2[C:9]([C:16]([OH:18])=O)=[N:8]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:50][C@@H:51]([C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:52][OH:53]>CN(C=O)C>[OH:53][CH2:52][C@@H:51]([NH:50][C:16]([C:9]1[C:10]2[CH2:11][C@@H:12]3[CH2:15][C@@H:13]3[C:14]=2[N:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[N:8]=1)=[O:18])[C:54]([CH3:57])([CH3:56])[CH3:55]
Reactant: CC(C)(C)[C@H](N)CO
Reactant: O=C(O)c1nn(-c2cnccn2)c2c1C[C@@H]1C[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[C@@H](CO)NC(=O)c1nn(-c2cnccn2)c2c1C[C@@H]1C[C@H]21
Temperature: 23 °C
Reaction time: 0.08 h
Yield: 99.8 %

Procedure:
To a solution of Intermediate 4 (1.4 g, 5.78 mmol) and triethylamine (1.611 mL, 11.56 mmol) in DMF (15 mL) was added HATU (2.242 g, 5.90 mmol). The reaction was stirred at 23° C. for 5 min, then (S)-2-amino-3,3-dimethylbutan-1-ol (0.711 g, 6.07 mmol) was added. The reaction was stirred at 23° C. for 15 min then concentrated. The residue was purified by silica gel column chromatography to give the title compound (1.97 g) as a white solid. LCMS m/z=342.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 0.48 (td, J=4.6, 3.4 Hz, 1H), 1.05 (s, 9H), 1.24 (td, J=8.0, 4.7 Hz, 1H), 2.26-2.32 (m, 1H), 2.74-2.78 (m, 1H), 2.94 (d, J=16.8 Hz, 1H), 3.01 (dd, J=16.7, 6.1 Hz, 1H), 3.67-3.72 (m, 1H), 3.93-3.98 (m, 2H), 7.08 (d, J=8.5 Hz, 1H), 8.42 (dd, J=1.4, 0.9 Hz, 1H), 8.51 (d, J=2.7 Hz, 1H), 9.26 (d, J=1.1 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[H-].[Na+].Cl[CH2:10][CH2:11][CH2:12][OH:13]>CN(C=O)C>[CH3:1][C:2]1[N:3]([CH2:10][CH2:11][CH2:12][OH:13])[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: OCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nccn1CCCO

Procedure:
The starting material may be prepared as follows. A mixture of 2-methylimidazole (6.15 g.), a 50% w/w dispersion of sodium hydride in oil (5.4 g.) and DMF (20 ml.) was treated with 3-chloropropanol (10.6 g.) and the mixture heated at 100° for 24 hours and then evaporated to dryness. The residue was treated with concentrated aqueous hydrochloric acid (8 ml.) and the solution washed with chloroform, and then basified with potassium carbonate. The mixture was extracted with chloroform, and the extract was dried and evaporated to dryness to give 2-methyl-1-(3-hydroxypropyl)imidazole which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].F[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24].N1C=CC=CC=1>BrC1C=CC=CC=1>[CH3:15][N:13]([CH3:14])[CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N+:23]([O-:25])=[O:24])[CH:3]=2)[NH:7][CH:6]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CN(C)CCc1c[nH]c2ccc(N)cc12
Solvent: Brc1ccccc1
Solvent: c1ccncc1
Product: CN(C)CCc1c[nH]c2ccc(Nc3ccccc3[N+](=O)[O-])cc12
Temperature: 156 °C
Yield: 82 %

Procedure:
5-Amino-3-(2-dimethylaminoethyl)indole and 2-fluoronitrobenzene were used. Pyridine was used as base, bromobenzene was used as solvent, and the reaction was heated at reflux (156° C.) for 11 hours. Chromatography afforded the title compound (82%) as a dark red solid: mp, 116.0°-117.0° C.; 13C NMR (CD3OD) δ146.7, 136.7, 133.2, 131.0, 129.5, 127.2, 124.7, 121.3, 117.3, 117.2, 117.0, 114.1,113.4, 61.4, 45.4, 24.2; HRMS calculated for C18H20N4O2 324.1588, found 324.1564. Anal. calcd. for C18H20N4O2 1/3H2O: C, 65.44; H, 6.31; N, 16.96. Found: 65.44; H, 5.92; N, 16.69.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=[CH:18][C:19]=1[C:20](O)=[O:21]>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=[CH:18][C:19]=1[C:20]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1)=[O:21]
Reactant: Nc1ccc2cccnc2c1
Reactant: COc1cc(-c2ccccc2)ccc1C(=O)O
Product: COc1cc(-c2ccccc2)ccc1C(=O)Nc1ccc2cccnc2c1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-aminoquinoline (D55) (26 mg, 0.18 mmol) and 3-methoxy-1,1′-biphenyl-4-carboxylic acid (D59) (50 mg, 0.22 mmol) as an off-white solid. MS (ES): MH+ 355.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1.[Cu]C#N.[C:17]([O:22][CH3:23])(=[O:21])[C@H:18]1[O:20][CH2:19]1.[Cl-].[NH4+]>COC(C)(C)C>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:19][C@H:18]([OH:20])[C:17]([O:22][CH3:23])=[O:21])=[CH:8][CH:9]=1
Reactant: Brc1ccc(Br)cc1
Reactant: COC(=O)[C@@H]1CO1
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: COC(C)(C)C
Product: COC(=O)[C@@H](O)Cc1ccc(Br)cc1
Temperature: -30 °C
Reaction time: 0.17 h
Yield: 56.7 %

Procedure:
72 ml (0.122 mol, 2.5 eq) of tert-butyllithium (1.7M/pentane) are added slowly using a needle to a suspension of 35 g (0.148 mol, 3 eq) of 1,4-dibromobenzene in 100 ml of tert-butyl methyl ether at −30° C. The mixture is stirred at −30° C. for 10 min and then 5.3 g (0.059 mol) of copper(I) cyanide are introduced into the above solution. The reaction mixture is stirred at −30° C. for 20 min. A solution of 5 g (0.049 mol) of methyl (S)-glycidate in 10 ml of tert-butyl methyl ether is added while keeping the temperature below −20° C. The mixture is stirred at −30° C. for 20 min and then the reaction is halted by the addition of a saturated ammonium chloride solution. The mixture is extracted with 3×300 ml of ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated and then the residue is chromatographed on silica gel (heptane 100% up to heptane/ethyl acetate 60/40). 7.2 g of methyl (S)-3-(4-bromophenyl)-2-hydroxypropionate are obtained in the form of a solid. Yield=56%.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[NH:21][C:20]3[C:19](=[O:22])[N:18]([CH2:23][CH2:24][CH3:25])[C:17](Cl)=[N:16][C:15]=3[N:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.C(N(C(C)C)CC)(C)C.CN1CCCC1=O>O>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[NH:21][C:20]3[C:19](=[O:22])[N:18]([CH2:23][CH2:24][CH3:25])[C:17]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[N:16][C:15]=3[N:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: CCCn1c(Cl)nc2nc(-c3cnn(Cc4ccccc4)c3)[nH]c2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCn1c(N2CCCC2)nc2nc(-c3cnn(Cc4ccccc4)c3)[nH]c2c1=O
Temperature: 85 °C

Procedure:
A mixture of 8-(1-benzyl-1H-pyrazol-4-yl)-2-chloro-1-propyl-1,7-dihydro-purin-6-one (prepared as given in Example 1) (1.2 g, 3.2 mmol), pyrrolidine (0.34 g, 4.8 mmol), Diisopropyl ethyl amine (0.826 g, 6.4 mmol) and N-methylpyrrolidone (12 ml) were heated at 80-90° C. for 20 hours. Reaction mixture was cooled to 20-25° C. and water (20 ml) was added, solid separated out. The solid material was filtered off and purified by column chromatography to get pure 8-(1-Benzyl-1H-pyrazol-4-yl)-1-propyl-2-pyrrolidin-1-yl-1,7-dihydro-purin-6-one as off white solid (0.83 g, 64%).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH2:13][C@H:14]([C:20]([OH:22])=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][NH2:19]>[Ni].[Pd]>[OH:4][CH:3]([CH:5]([OH:6])[CH:7]([OH:8])[CH:9]([OH:10])[CH2:11][OH:12])[CH2:2][NH:13][C@H:14]([C:20]([OH:22])=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:2][CH:3]([OH:4])[CH:5]([OH:6])[CH:7]([OH:8])[CH:9]([OH:10])[CH2:11][OH:12]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Ni]
Agent: [Pd]
Product: O=C(O)[C@H](CCCCNCC(O)C(O)C(O)C(O)CO)NCC(O)C(O)C(O)C(O)CO

Procedure:
The starting materials were D-glucose and L-(+)-lysine in a molar ratio 2:1. The reductive amination took place using Raney nickel or palladium/activated carbon (10%) as a catalyst and heating for 2 hours to 50° C. and 4 hours to 70° C., a yellowish resin-like product being obtained.
Reaction SMILES: [CH3:1]/[C:2](=[CH:8]\[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)/[C:3]([O:5][CH2:6][CH3:7])=[O:4].[H][H]>C(O)C.[Pd]>[NH2:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:14][CH:13]=1
Reactant: CCOC(=O)/C(C)=C/c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (E)-ethyl 2-methyl-3-(4-nitrophenyl)acrylate (645) (2.49 g, 10.6 mmol) in ethanol (100 mL) was added Pd/C (250 mg, 10% Degussa type). A balloon of hydrogen gas was added and the reaction was evacuated and back-filled with hydrogen three times. The reaction was stirred overnight at room temperature, was filtered through a pad of celite and concentrated in vacuo to give ethyl 3-(4-aminophenyl)-2-methylpropanoate (646).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15](Cl)=[O:16])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18](P(CCCC)CCCC)[CH2:19][CH2:20]C.C([Mg]Cl)CC>O1CCCC1>[C:1]([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15](=[O:16])[CH2:18][CH2:19][CH3:20])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCP(CCCC)CCCC
Reactant: O=C(Cl)C1CCCN(C(=O)c2ccccc2)C1
Agent: CCC[Mg]Cl
Solvent: C1CCOC1
Product: CCCC(=O)C1CCCN(C(=O)c2ccccc2)C1
Temperature: -20 °C
Yield: 38.5 %

Procedure:
1-benzoyl-3-piperidinecarbonyl chloride (1.01 g; 4.02 mmol) was dissolved in dry tetrahydrofuran (30 ml) under a nitrogen atmosphere, and cooled to −20° C. Tributylphosphine (1.1 ml; 4.4 mmol) was then added and after 20 minutes of stirring at −20° C., propylmagnesium chloride (2 ml; 4.0 mmol; 2 M in ether) was added. After stirring for 5 minutes, the reaction was quenched by addition of 1 N HCl (5 ml), and the mixture was allowed to warm to ambient temperature. It was then diluted with 1 N HCl and extracted with diethyl ether. The ether was washed with saturated sodium bicarbonate solution, and then brine. It was then dried with anhydrous magnesium sulfate and evaporated at ambient temperature under reduced pressure. The crude product was purified by chromatography on silica eluting with 50% ethyl acetate in hexane, giving 1-benzoyl-3-butyrylpiperidine (401.7 mg) as a colorless oil. MS m/z (positive ion) 260 (MH+; 100).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=1)#[CH:12].N>>[F:19][C:17]1[CH:18]=[C:13]([C:11]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[CH:12]=2)[CH:14]=[C:15]([F:20])[CH:16]=1
Reactant: ON=C(Cl)c1cccnc1
Reactant: C#Cc1cc(F)cc(F)c1
Agent: N
Product: Fc1cc(F)cc(-c2cc(-c3cccnc3)no2)c1

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 1A (78 mg, 0.5 mmol) and 1-ethynyl-3,5-difluorobenzene (Apollo, 69 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.50 (tt, J=9.3, 2.4 Hz, 1H), 7.60-7.78 (m, 3H), 7.89 (s, 1H), 8.32 (dt, J=7.8, 2.2 Hz, 1H), 8.76 (d, J=3.4 Hz, 1H), 9.11 (d, J=1.7 Hz, 1H) ppm; MS (DCI/NH3) m/z 259 (M+H)+.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1)(=O)=O.[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[N:34]1[CH2:40][CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[N:34]1[CH2:40][CH2:39][CH2:38][N:37]([CH2:6][CH2:7][N:8]2[C:16]3[N:15]=[C:14]([NH2:17])[N:13]4[N:18]=[C:19]([C:21]5[O:22][CH:23]=[CH:24][CH:25]=5)[N:20]=[C:12]4[C:11]=3[CH:10]=[CH:9]2)[CH2:36][CH2:35]1
Reactant: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Reactant: Fc1ccc(N2CCCNCC2)c(F)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc2c(ccn2CCN2CCCN(c3ccc(F)cc3F)CC2)c2nc(-c3ccco3)nn12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of the title D compound of Example 1, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate (0.06 g, 0.165 mmol) in dry DMF (5 mL), the title A compound, 1-(2,4-difluorophenyl)-1,4-diazepane (0.33 mmol) and 0.06 mL of DIEA are added, and the solution is stirred at 100° C. for 5 h. The reaction mixture is cooled to RT, and the solvent is removed under reduced pressure. The crude product is purified by flash chromatography using a 95/5.0/0.5-mixture of DCM/MeOH/NH4OH as eluent to give 7-(2-(4-(2,4-difluorophenyl)-1,4-diazepan-1-yl)ethyl)-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine: LC/MS (M+1=479.01). 1H NMR (DMSO-d6, 400 MHz) δ 1.82 (m, 2H), 2.71 (m, 2H), 2.82 (m, 2H), 2.88 (t, 2H, J=6.4 Hz), 3.24 (m, 4H), 4.22 (t, 2H, J=6.4 Hz), 6.57 (d, 1H, J=3.6 Hz), 6.71 (m, 1H), 6.85-6.94 (m, 2H), 7.09 (m, 1H), 7.14 (d, 1H, J=3.6 Hz), 7.19 (d, 1H, J=3.2 Hz), 7.51 (br s, 2H, NH2), 7.92 (s, 1H).