Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([N:17](CC)CC)C.C[Si](C#N)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:17][CH2:15][C:11]1([OH:14])[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1
Reactant: CCN(CC)CC
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: C[Si](C)(C)C#N
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: NCC1(O)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 450.5 %

Procedure:
To a pre-cooled solution (20° C.) of 1-benzyl-4-piperidone (35.0 mL, 196 mmol) and triethylamine (5.5 mL, 40 mmol) was added trimethylsilylcyanide (32.0 mL, 240 mmol), portionwise over 10 minutes. Once the addition was complete, the reaction mixture was stirred at room temperature for 3 hours. This reaction mixture was then cautiously added (10 mL portions over 12 minutes) to a stirring mixture of lithium aluminum hydride (8.5 g, 224 mmol) in tetrahydrofuran (420 mL). Once the addition was complete the reaction mixture was refluxed for 1.5 hours. After cooling to room temperature, the reaction was quenched with water (8.5 mL), followed by 1N NaOH (8.5 mL), and then water (2×8.5 mL). The resulting mixture was allowed to stir at room temperature overnight. The solids were filtered off and rinsed with DCM and ethanol. The filtrate was concentrated down to a solid and then purified by flash chromatography (0-20% methanol in DCM with 1% NH4OH) to give compound 397 as a yellow solid (39.7 g, 92%). LCMS-ESI (POS), M/Z, M+1: Found 221.2, Calculated 221.2.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13][C:14]1[S:15][CH2:16][CH2:17][N:18]=1)C.O.[OH-].[Li+]>C1COCC1.O>[S:15]1[CH2:16][CH2:17][N:18]=[C:14]1[S:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:6][CH2:5][C:4]([OH:19])=[O:3]
Reactant: CCOC(=O)CCc1ccccc1SC1=NCCS1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCc1ccccc1SC1=NCCS1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 250 mg of 2-(2-thiazolinylthio)hydrocinnamic acid ethyl ester, 36 mg of lithium hydroxide monohydrate and 5 ml of THF/water 9:1 is stirred at room temperature for 5 days and then concentrated to dryness by evaporation. The residue is taken up in water, washed with ethyl acetate, adjusted to pH 5 with 0.5N HCl and extracted with ethyl acetate. The extracts are washed with water, dried with sodium sulphate, concentrated by evaporation and chromatographed on silica gel with eluant R. Rf (R)=0.22.
Reaction SMILES: [CH2:1]([CH:3]1[C:8](=[O:9])[NH:7][C:5](=[O:6])[CH2:4]1)[CH3:2].[H-].[Na+].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[CH2:1]([CH:3]1[C:8](=[O:9])[N:7]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:5](=[O:6])[CH2:4]1)[CH3:2]
Reactant: CCC1CC(=O)NC1=O
Reactant: CCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Product: CCCCCCCCCN1C(=O)CC(CC)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-ethyl succinimide (4.72 mM) in dimethylformanide (10 ml) was treated with sodium hydride (5.20 mM) and nonyl bromide (5.20 mM). The reaction mixture was stirred at room temperature for two hours and then quenched with saturated aqueous ammonium chloride. The organic layer was separated and the aqueous layer extracted with ethyl acetate(3×25 ml). The combined organic layers were washed with 10% aqueous sodium thiosulfate, brine, dried over sodium sulfate and concentrated in vacuo. Chromatography over silica gel afforded the desired product, pure 3-ethylN-nonyl succinimide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Cl-].[CH3:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[CH:16]=[N+:17]([CH3:19])[CH3:18].CC1C=C(C=CC=1)C=O.CNC>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:16]([N:17]([CH3:18])[CH3:19])[C:15]1[CH:14]=[C:13]([CH3:12])[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1cccc(C=[N+](C)C)c1
Reactant: Clc1ccc2[nH]ccc2c1
Agent: CNC
Agent: Cc1cccc(C=O)c1
Agent: [Cl-]
Product: Cc1cccc(C(c2c[nH]c3ccc(Cl)cc23)N(C)C)c1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 5-chloro-1H-indole and (3-methyl-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 3-methyl-benzaldehyde and dimethylamine.
Reaction SMILES: C(Br)C1C=CC=CC=1.[N:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:11][CH:10]=1>C(#N)C>[NH:9]1[CH2:10][CH2:11][CH:12]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:13][CH2:14]1
Reactant: c1ccc2oc(-c3ccncc3)nc2c1
Agent: BrCc1ccccc1
Solvent: CC#N
Product: c1ccc2oc(C3CCNCC3)nc2c1
Reaction time: 0.17 h
Yield: 69.3 %

Procedure:
A solution of 1.71 g of benzyl bromide in 10 ml of acetonitrile is added to a solution of 1.96 g of 2-(4-pyridinyl)benzoxazole in 25 ml of hot acetonitrile. After 10 minutes the product begins to crystallize out of solution. The mixture is heated on the steam bath for 2 hours and then diluted with ether and filtered. The crude solid is dissolved in 50 ml of 1:1 methanol-water and treated portionwise with 2 g of sodium borohydride. The mixture is diluted with water and 2.4 g of the solid product is collected. The 2.4 g of solid is dissolved in 150 ml of ethanol, 2 g of 5% paladium on carbon is added, and the mixture is placed on the Parr hydrogenator under 50 psi hydrogen. The mixture is filtered, and the filtrate evaporated in vacuo to give 1.4 g of the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.NC1C=CC=CC=1O.[CH3:18][C:19]1[CH:20]=[CH:21][C:22](C(O)=O)=[CH:23][CH:24]=1>>[C:19]1([CH3:18])[CH:20]=[CH:21][C:22]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[CH:23][CH:24]=1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: c1ccc2ocnc2c1
Agent: Nc1ccccc1O
Product: Cc1ccc(-c2nc3ccccc3o2)cc1

Procedure:
Preparation of the above benzoxazole reactant is as follows: o-aminophenol is reacted with p-toluic acid to yield 2-(p-tolyl)benzoxazole; this intermediate is then brominated with N-bromosuccinimide to obtain 2-4-bromomethylphenyl)-benzoxazole.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:12](Cl)(Cl)=[S:13]>O.Cl>[N:11]([C:8]1[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=1)=[C:12]=[S:13]
Reactant: S=C(Cl)Cl
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: Cl
Solvent: O
Product: CS(=O)(=O)c1ccc(N=C=S)cc1
Reaction time: 1 h
Yield: 85.2 %

Procedure:
A solution of 4-methanesulfonylphenylamine (2.4 g, 14 mmol) was dissolved in a mixture of water (30 mL) and hydrochloric acid (9 mL, 37%). This was treated drop wise at room temperature with thiophosgene (1.5 g, 13.2 mmol) with good stirring. After 1 h, the suspension was filtered, washed with water and dried over P2O5 to give 2.4 g (85% yield) of 1-isothiocyanato4-methanesulfonylbenzene. 1H NMR (CDCl3), 300 MHz δ3.09 (s, 3H, CH3), 7.41(d, 2H, Aromatic), 7.98 (d, 2H, Aromatic).
Reaction SMILES: Cl.[CH3:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])=[CH:10][CH:9]=2)[N:4]=1.[Cl:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[C:28]([S:33](Cl)(=[O:35])=[O:34])[CH:27]=[CH:26]2>O1CCOCC1.ClCCl.CN(C)C1C=CN=CC=1>[Cl:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[C:28]([S:33]([N:19]1[CH2:20][CH2:21][N:16]([C:14]([C:11]3[CH:12]=[CH:13][C:8]([C:5]4[N:4]=[C:3]([CH3:2])[O:7][N:6]=4)=[CH:9][CH:10]=3)=[O:15])[CH2:17][CH2:18]1)(=[O:35])=[O:34])[CH:27]=[CH:26]2
Reactant: O=S(=O)(Cl)c1ccc2cc(Cl)ccc2c1
Reactant: Cc1nc(-c2ccc(C(=O)N3CCNCC3)cc2)no1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1nc(-c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2)no1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The BOC group is cleaved off using 4N HCl in dioxane. A solution of 100 mg of the resulting [4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl]piperazin-1-ylmethanone (“A”) and 120 mg of 6-chloronaphthalene-2-sulphonyl chloride in 5 ml of dichloromethane is admixed with 400 mg of 4-dimethylaminopyridine on polystyrene, and the mixture is stirred at room temperature For 18 hours. Filtration and removal of the solvent gives [4-(6-chloronaphthalene-2-sulphonyl)piperazin-1-yl][4-(5-methyl[1,2,4]oxadiazol-3-yl)phenyl]methanone, FAB 497.
Reaction SMILES: OC1C=CC(C[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([O:24][C:25](=[O:39])[NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:20][CH2:19]2)=[O:15])=CC=1.[CH2:42]=[O:43].C([BH3-])#N.[Na+].CO>[Cl-].[Zn+2].[Cl-]>[OH:43][C:42]1[CH:30]=[CH:29][C:28]([CH2:33][CH2:34][NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([O:24][C:25](=[O:39])[NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:20][CH2:19]2)=[O:15])=[CH:27][CH:32]=1
Reactant: O=C(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)NCCCCCNCc1ccc(O)cc1
Reactant: C=O
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: O=C(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)NCCCCCNCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the product of Example 2 (300 mg, 0.38mmol) in 4 mL of MeOH was added zinc chloride (26 mg, 0.19 mmol, 0.5 eq), followed by formaldehyde (37% aqueous solution, 141 μL, 1.9 mmol, 10 eq). The solution was stirred at room temperature for 30 minutes and then sodium cyanoborohydride (24 mg, 0.38 mmol, 1 eq) was added. The reaction mixture was stirred at room temperature for 2 hours. and then the solvent was removed in vacuo. The crude product was purified by reverse phase HPLC to afford the title compound as a bis(trifluoroacetate) salt. MS m/z [M+H+] calc'd for C34H44N4O4 573.3; found 573.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:18]=[CH:17][C:16]2[C:11](=[C:12]([O:19]C)[CH:13]=[CH:14][CH:15]=2)[N:10]=1.B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:18]=[CH:17][C:16]2[C:11](=[C:12]([OH:19])[CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: COc1cccc2cnc(-c3c(F)cccc3F)nc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc2cnc(-c3c(F)cccc3F)nc12
Reaction time: 8 h
Yield: 94 %

Procedure:
To a solution of the 2-(2,6-difluorophenyl)-8-methoxyquinazoline (1.0 eq) in methylene chloride (0.23M) was added BBr3 (2.0 eq) at room temperature. The reaction mixture was stirred overnight. The solvents were removed under reduced pressure. The residue was dissolved in ethyl acetate (150 mL), and washed with NaHCO3, brine, then dried over MgSO4, filtered, and evaporated under reduced pressure to give crude product, which was purified by column (ethyl acetate:hexanes=1:2) to yield 2-(2,6-difluorophenyl)quinazolin-8-ol (94%). LC/MS (m/z): 259.0 (MH+), Rt=0.82.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25]N=[C:23](OC)[CH:22]=4)[CH2:15][CH2:14]3)[S:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[Cl:29][C:30]1SN=C(C2C=CN=C(Cl)C=2)N=1.BrCCC1C=CC(Cl)=CC=1>>[Cl:29][C:30]1[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][N:16]2[CH2:17][CH2:18][N:13]([C:11]3[S:10][N:9]=[C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=4)[N:12]=3)[CH2:14][CH2:15]2)=[CH:22][CH:23]=1
Reactant: COc1cc(CCN2CCN(c3nc(-c4ccnc(Cl)c4)ns3)CC2)ccn1
Reactant: Clc1cc(-c2nsc(Cl)n2)ccn1
Agent: Clc1ccc(CCBr)cc1
Product: Clc1ccc(CCN2CCN(c3nc(-c4ccnc(Cl)c4)ns3)CC2)cc1

Procedure:
In analogy to the procedure described for the synthesis of 3-(2-chloropyridin-4-yl)-5-(4-(2-(2-methoxypyridin-4-yl)ethyl)piperazin-1-yl)-1,2,4-thiadiazole (Example 168), the tile compound was prepared from 5-chloro-3-(2-chloropyridin-4-yl)-1,2,4-thiadiazole and 1-(2-bromoethyl)-4-chlorobenzene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:11][CH:12]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:11][CH:12]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[C:13]2[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=2)[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: C[C@@H](NC(c1ccc(F)cc1)c1cccc([N+](=O)[O-])c1)c1cc(F)cc(F)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: C[C@@H](NC(c1ccc(F)cc1)c1cccc(N)c1)c1cc(F)cc(F)c1

Procedure:
Following a reaction and purification procedure similar to those described in Example (59b), 4.40 g of N-[(R)-1-(3,5-difluorophenyl)ethyl]-N-[(4-fluorophenyl)-(3-nitrophenyl)methyl]amine [prepared as described in step (a) above], 6.54 g of nickel chloride hexahydrate and 1.81 g of sodium borohydride were reacted, to obtain 1.24 g of isomer A and 1.66 g of isomer B of the title compound as yellow oils, respectively.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4]([OH:11])[C:3]=1[S:12][C:13]#[N:14].O>CN(C)C=O>[NH2:14][C:13]1[S:12][C:3]2[C:4]([OH:11])=[N:5][C:6]([CH:8]3[CH2:10][CH2:9]3)=[N:7][C:2]=2[N:1]=1
Reactant: N#CSc1c(N)nc(C2CC2)nc1O
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc2nc(C3CC3)nc(O)c2s1
Temperature: 135 °C
Yield: 75 %

Procedure:
A solution of the compound (0.20 g) obtained in Step 2 in N,N-dimethylformamide (7.0 ml) was stirred overnight under heating at 135° C. The reaction mixture was cooled to room temperature, and water (7.0 ml) was added under ice-cooling. The precipitated solid was collected by filtration, washed with water and dried to give the title compound (0.15 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[O:19][C:18](C=CC4C=CC(C#N)=CC=4)=[N:17][CH:16]=3)[CH:12]=[CH:11][CH:10]=2)[CH:3]=1.CC1C=CN=C(NC2C=CC=C(C3OC=NC=3)N=2)C=1.Br[C:50]1[CH:51]=[C:52]([S:56]([N:59]([CH2:61][CH2:62][OH:63])[CH3:60])(=[O:58])=[O:57])[CH:53]=[CH:54][CH:55]=1.O(C(C)(C)C)[Li]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[OH:63][CH2:62][CH2:61][N:59]([CH3:60])[S:56]([C:52]1[CH:53]=[CH:54][CH:55]=[C:50]([C:18]2[O:19][C:15]([C:13]3[CH:12]=[CH:11][CH:10]=[C:9]([NH:8][C:4]4[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=4)[N:14]=3)=[CH:16][N:17]=2)[CH:51]=1)(=[O:58])=[O:57]
Reactant: CN(CCO)S(=O)(=O)c1cccc(Br)c1
Reactant: Cc1ccnc(Nc2cccc(-c3cnc(C=Cc4ccc(C#N)cc4)o3)n2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccnc(Nc2cccc(-c3cnco3)n2)c1
Agent: [Li]OC(C)(C)C
Solvent: C1COCCO1
Product: Cc1ccnc(Nc2cccc(-c3cnc(-c4cccc(S(=O)(=O)N(C)CCO)c4)o3)n2)c1
Yield: 24 %

Procedure:
Prepared as for 4-(2-{5-[6-(4-methyl-pyridin-2-ylamino)-pyridin-2-yl]-oxazol-2-yl}-vinyl)-benzonitrile above using (4-methyl-pyridin-2-yl)-(6-oxazol-5-yl-pyridin-2-yl)-amine, 3-bromo-N-(2-hydroxy-ethyl)-N-methyl-benzenesulfonamide, Pd(PPh3)4, LiOtBu and anhydrous 1,4-dioxane to afford the title compound as a pale yellow solid (24%). 1H NMR (400 MHz, CDCl3) δ 9.81 (s, 1H), 8.45-8.34 (m, 2H), 8.12 (d, J=5.0 Hz, 1H), 8.01-7.77 (m, 5H), 7.66 (d, J=8.4 Hz, 1H), 7.46 (d, J=7.4 Hz, 1H), 6.79 (d, J=5.0 Hz, 1H), 4.83 (t, J=5.5 Hz, 1H), 3.55 (q, J=5.8 Hz, 2H), 3.11 (t, J=5.9 Hz, 2H), 2.81 (d, J=8.0 Hz, 3H), 2.36 (s, 3H). (ESI+) m/z 466 (M+H)+. Retention time=2.45 mins (method 1).
Reaction SMILES: [CH:1]1([N:4]([CH:26]2[CH2:28][CH2:27]2)[C:5]([C:7]2[N:23]([CH2:24][CH3:25])[C:10]3=[N:11][C:12]([NH:19][C:20]([NH2:22])=[S:21])=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.CO[CH:31](OC)[N:32](C)C.C1(C)C=C(C)C=C(C)C=1S(ON)(=O)=O>O>[S:21]1[C:20]([NH:19][C:12]2[N:11]=[C:10]3[N:23]([CH2:24][CH3:25])[C:7]([C:5]([N:4]([CH:1]4[CH2:2][CH2:3]4)[CH:26]4[CH2:27][CH2:28]4)=[O:6])=[CH:8][C:9]3=[C:14]3[N:15]([CH3:18])[CH:16]=[N:17][C:13]=23)=[N:22][CH:31]=[N:32]1
Reactant: COC(OC)N(C)C
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(NC(N)=S)nc21
Agent: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Solvent: O
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3ncns3)nc21
Temperature: 50 °C
Reaction time: 3 h
Yield: 22.1 %

Procedure:
A mixture of N,N-dicyclopropyl-6-ethyl-1-methyl-4-thioureido-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 2B, 30 mg, 0.075 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (1 g, 8.39 mmol) was heated at 50° C. for 2 h. Excess 1,1-dimethoxy-N,N-dimethylmethanamine was evaporated in vacuo and the crude example was dissolved in dichloromethane (1 mL) and O-(mesitylsulfonyl)hydroxylamine (24.4 mg, 0.113 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. Water was added and the layers were separated. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by preparative HPLC to give 4-(1,2,4-thiadiazol-5-ylamino)-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (7 mg, 19.20% yield) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.C(N(CC)CC)C.[C:22](O)([CH3:25])([CH3:24])[CH3:23]>ClCCl.O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)O
Reactant: Nc1ccc(C(=O)O)cn1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(N)nc1
Temperature: 80 °C

Procedure:
A mixture of 6-amino pyridine 3-carboxylic acid (2.0 g, 14.48 mmol) and thionyl chloride (10 mL) was reflux for 3.5 h under anhydrous atmosphere. Acid chloride formation was confirmed by TLC. Excess of thionyl chloride was removed under reduced pressure on rotavapour. Triethyl amine (5 mL, 36.2 mmol) and tert-butanol (5 mL) was added to acid chloride at 0° C. under inner atmosphere and reaction mixture was heated at 80° C. for 2 h. completion of reaction was confirmed by TLC. The reaction mixture was diluted with dichloromethane (50 mL) and water (50 mL), layers were separated and aqueous layer was extracted with DCM (2×30 mL) combined organic layers were washed with water (50 mL), brine (50 mL) and dried over anhydrous sodium sulphate (50 g). The solvent was removed under reduced pressure and the residue was purified by column chromatography using 20-30% ethyl acetate in hexane. Removal of solvent from appropriate fractions under reduced pressure using rotavapour gave pure product (0.7 g).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20](=[O:23])[CH2:21]N)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C.C(OC(NC1C=CC(C(F)(F)F)=CC=1C(O)=O)=O)(C)(C)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C.CCOC(C)=O>[CH2:12]([O:19][C:20](=[O:23])[CH3:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCC(=O)OCc1ccccc1
Agent: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 96 h
Yield: 215.4 %

Procedure:
Glycine benzyl ester p-toluenesulfonate salt (6.03 g) was dissolved in DMF prior to the addition of Hunig's base (12.4 mL) and 2-(tert-butoxycarbonyl)amino-5-trifluoromethylbenzoic acid (6 g) (Takagishi et al., Synlett 1992, 360). After cooling to 0° C., BOP Reagent (8.69 g) was added. The resulting mixture was warmed to rt and was stirred 96 h. EtOAc was added along with 1 N HCl solution. The EtOAc layer was washed with 1 N HCl (aq), NaHCO3 solution (aq), and brine. The EtOAc was dried (MgSO4), filtered, and concentrated. Flash chromatography of the resulting residue gave 2-tert-butoxycarbonylamino-5-trifluoromethyl-benzoylamino)-acetic acid benzyl ester (5.78 g). MS found: (M+Na)+=475.3.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH2:9][N:10]2[C:19](=[O:20])[C:18]3[N:17]([CH2:21][C:22]#[C:23][CH3:24])[C:16](Br)=[N:15][C:14]=3[N:13]([CH3:26])[C:11]2=[O:12])=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].C([C@H]([C@@H](C(O)=O)O)O)(O)=O.[C:37]1(=[O:53])[N:41]([CH:42]2[CH2:47][CH2:46][CH2:45][NH:44][CH2:43]2)[C:40](=[O:48])[C:39]2=[CH:49][CH:50]=[CH:51][CH:52]=[C:38]12.CN1CCCC1=O.C(N(C(C)C)CC)(C)C>CO.O>[C:1]([C:3]1[C:4]([CH2:9][N:10]2[C:19](=[O:20])[C:18]3[N:17]([CH2:21][C:22]#[C:23][CH3:24])[C:16]([N:44]4[CH2:45][CH2:46][CH2:47][C@@H:42]([N:41]5[C:40](=[O:48])[C:39]6=[CH:49][CH:50]=[CH:51][CH:52]=[C:38]6[C:37]5=[O:53])[CH2:43]4)=[N:15][C:14]=3[N:13]([CH3:26])[C:11]2=[O:12])=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CC#CCn1c(Br)nc2c1c(=O)n(Cc1ncccc1C#N)c(=O)n2C
Reactant: O=C1c2ccccc2C(=O)N1C1CCCNC1
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: O
Solvent: CO
Solvent: CN1CCCC1=O
Product: CC#CCn1c(N2CCC[C@@H](N3C(=O)c4ccccc4C3=O)C2)nc2c1c(=O)n(Cc1ncccc1C#N)c(=O)n2C
Temperature: 140 °C
Reaction time: 2 h

Procedure:
230 g (0.557 mol) of 1-[(3-cyanopyridin-2-yl)methyl]-3-methyl-7-(2-butin-1-yl)-8-bromoxanthine, 318 g (0.835 mol) of 3-(phthalimido)piperidine D-tartrate and 1.15 litres of N-methyl-2-pyrrolidone are initially charged in the reactor. The reactor contents are heated to 140° C. After the temperature has been attained, 478 ml (2.78 mol) of diisopropylethylamine are metered in within 20 minutes and the reaction mixture is subsequently stirred at 140° C. for 2 hours. Subsequently, the reaction mixture is cooled to 75° C. and diluted with 720 ml of methanol. Afterwards, 2.7 litres of water are added at 68-60° C. and the mixture is cooled to 25° C. The product is filtered off and washed with 2 litres of water. Drying is effected at 70° C. in a drying cabinet under inertization.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH2:12][CH2:11][C:10](C(OCC)=O)([C:13]([O:15][C:16](C)(C)[CH3:17])=[O:14])[C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]2[CH2:12][CH2:11][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C1(C(=O)OC(C)(C)C)CCc2cc([N+](=O)[O-])cnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CCc2cc([N+](=O)[O-])cnc21
Temperature: 35 °C
Reaction time: 3 h

Procedure:
A mixture of 7-tert-butyl 7-ethyl 3-nitro-5,6-dihydro-7H-cyclopenta[b]pyridine-7,7-dicarboxylate (6.2 g, 18.4 mmol) in 30 mL of TFA and 30 mL DCM was stirred at 35° C. for 3 hours then concentrated to dryness. The residue was dissolved in 200 mL of EtOAc and washed with saturated NaHCO3 (2×25 mL) and brine (25 mL), dried over anhydrous Na2SO4 and concentrated to afford the title compound.
Reaction SMILES: [CH:1](=[N:9][CH2:10]C(N=CC1C(=CC=CC=1)O)C)C1C(=CC=CC=1)O.[C:22]1(C)[C:23](C)=[CH:24][CH:25]=[CH:26][CH:27]=1>>[CH:22]1([N:9]([CH3:10])[CH3:1])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CC(CN=Cc1ccccc1O)N=Cc1ccccc1O
Reactant: Cc1ccccc1C
Product: CN(C)C1CCCCC1

Procedure:
1.6% N,N'-disalicylidene-1,2-propanediamine as an 80% solution in xylene; and