Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].CCN(CC)CC.[Na+].[Cl-]>C(Cl)Cl>[CH3:24][S:25]([O:1][CH2:2][CH2:3][C@@H:4]([NH:16][C:17]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:23])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:11]=1)(=[O:27])=[O:26]
Reactant: CC(C)(C)OC(=O)N[C@H](CCO)Cc1ccc(C(F)(F)F)cc1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](CCOS(C)(=O)=O)Cc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
(S)-tert-Butyl 4-hydroxy-1-(4-(trifluoromethyl)phenyl)butan-2-ylcarbamate was dissolved in 60 mL DCM and cooled to 0° C. MsCl (773 mL, 10 mmol) and Et3N (1.67 mL, 12 mmol) were added and the reaction was stirred for 1.5 hours at 0° C. NaCl (saturated, aqueous) was added, and the mixture was extracted with DCM (3×100 mL), dried over MgSO4 and evaporated. The title compound was obtained as an off-white solid and used without further purification in the next step. LCMS (API-ES) m/z (%): 411.1 (100%, M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.O[CH:10]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:10]2[CH2:14][CH2:13][NH:12][CH2:11]2)=[N:6][CH:7]=1
Reactant: Oc1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Clc1ccc(OC2CCNC2)nc1
Reaction time: 8 h

Procedure:
To a stirred solution of 5-chloro-2-pyridinol (323.9 mg; 2.5 mmol), tert-butyl 3-hydroxy-1-pyrrolidinecarboxylate (468.0 mg, 2.5 mmol) and triphenylphosphine polymer bound (1 g, 3 mmol) in THF/CH2Cl2 (1:1, 5 ml) slowly was added diethyl azodicarboxylate (435.5 mg 2.5 mmol). The solution was slowly stirred overnight Resin was then removed by filtration and washed with THF. The combined filtrates were evaporated to dryness. The resulting residue was purified by RP-HPLC (10-40% CH3CN). The pure material was treated with 95% TFA/5% H2O, 30 min. The TFA phase was then evaporated to give the desired product as a solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11](=[O:32])[NH:12][C:13]1[S:14][CH2:15][C@@H:16]2[CH2:22][C@H:21]([CH2:23][OH:24])[O:20][CH2:19][C@:17]2([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[N:18]=1)([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][S:2]([O:24][CH2:23][C@@H:21]1[O:20][CH2:19][C@:17]2([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[N:18]=[C:13]([NH:12][C:11]([O:10][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:32])[S:14][CH2:15][C@@H:16]2[CH2:22]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3ccccc3F)CO[C@@H](CO)C[C@H]2CS1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3ccccc3F)CO[C@@H](COS(C)(=O)=O)C[C@H]2CS1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methanesulfonyl chloride (36.2 μL, 0.474 mmol) was added drop-wise to a 0° C. solution of tert-butyl[(4aR,6R,8aS)-8a-(2-fluorophenyl)-6-(hydroxymethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]carbamate (C18) (94 mg, 0.24 mmol) and triethylamine (0.198 mL, 1.42 mmol) in dichloromethane (1 mL). The reaction was allowed to warm to room temperature and stir for 18 hours. Saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted three times with dichloromethane. The combined organic layers were washed with water, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography (Gradient: 0% to 50% ethyl acetate in heptane) provided the product as a white solid. Yield: 86 mg, 0.18 mmol, 75%. LCMS m/z 475.4 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.53 (s, 9H), 1.60-1.68 (br m, 1H), 1.92-2.07 (br m, 1H), 2.56 (dd, J=12.9, 2.9 Hz, 1H), 2.93 (dd, J=12.7, 3.9 Hz, 1H), 3.07-3.19 (br m, 1H), 3.09 (s, 3H), 3.79 (d, J=12.1 Hz, 1H), 3.96-4.04 (m, 1H), 4.21 (dd, J=12.0, 1.5 Hz, 1H), 4.27 (dd, half of ABX pattern, J=11.3, 6.2 Hz, 1H), 4.32-4.38 (br m, 1H), 7.06-7.13 (m, 1H), 7.18-7.24 (m, 1H), 7.30-7.39 (br m, 2H).
Reaction SMILES: [CH3:1][NH:2][NH2:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH:19]3[CH2:20][CH2:21][CH2:22][CH:15]2[C:16](=[CH:24]O)[C:17](=O)[CH2:18]3)(=[O:13])=[O:12])=[CH:7][CH:6]=1>>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH:19]3[CH2:20][CH2:21][CH2:22][CH:15]2[C:16]2[CH:24]=[N:3][N:2]([CH3:1])[C:17]=2[CH2:18]3)(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)cc1
Reactant: CNN
Product: Cn1ncc2c1CC1CCCC2N1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
Prepared as described in Example 5 using methyl hydrazine and 9-(4-chlorophenylsulfonyl)-2-(hydroxymethylene)-9-azabicyclo[3.3.1]nonan-3-one which was prepared as described in Example 34.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[CH2:19][CH2:18][C:17]4([CH3:23])[C:20]([CH3:22])([CH3:21])[CH:13]3[CH2:14][C:15]3[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][C:16]=34)=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH2:30][OH:31]>C(O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[CH2:19][CH2:18][C:17]4([CH3:23])[C:20]([CH3:22])([CH3:21])[CH:13]3[CH2:14][C:15]3[CH:27]=[C:26]([C:28]([NH:30][OH:31])=[NH:29])[CH:25]=[CH:24][C:16]=34)=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC12CCN(C(=O)c3ccc4[nH]cnc4c3)C(Cc3cc(C#N)ccc31)C2(C)C
Reactant: NO
Solvent: CCO
Product: CC12CCN(C(=O)c3ccc4[nH]cnc4c3)C(Cc3cc(C(=N)NO)ccc31)C2(C)C
Temperature: 25 °C

Procedure:
A solution of 3-(1H-benzoimidazole-5-carbonyl)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-9-carbonitrile (0.30 g) and hydroxylamine (50% in water, 0.5 ml) in ethanol (5 mL) is stirred at reflux temperature for 2 h. After cooling to room temperature, the mixture is concentrated under reduced pressure to give the title compound as a white foam-like solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[N:3]=1.[NH2:24][CH3:25]>>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:4]1[N:3]=[C:2]([NH:24][CH3:25])[C:7]([C:8]#[N:9])=[CH:6][C:5]=1[C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nc1Cl
Reactant: CN
Product: CNc1nc(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)cc1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the product of Step C (300 mg) was added H2NCH3 (3.34 mL, 2 M solution in THF). The reaction stirred at room temperature overnight before concentrating. The product was dissolved in EtOAc and washed with saturated aqueous NaHCO3 solution. The solution was concentrated and purified via flash chromatography on silica gel with a gradient elution of 0% to 20% EtOAc in hexane affording the title compound. HPLC/MS: 353.9 (M+1), 355.9 (M+3); Rt=4.21 min.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:26])[C:7]([C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])=[C:8]([OH:14])[C:9]2([CH3:13])[CH3:12])=[CH:4][CH:3]=1.B1(/[CH:36]=[CH:37]/[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.CCOC(C)=O.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>[OH:14][C:8]1[C:9]([CH3:12])([CH3:13])[C:10]2[C:5]([C:6](=[O:26])[C:7]=1[C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])=[O:16])=[CH:4][CH:3]=[C:2](/[CH:36]=[CH:37]/[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH:11]=2
Reactant: CC1(C)OB(/C=C/c2ccccc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)C(C)(C)c2cc(Br)ccc2C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)C(C)(C)c2cc(/C=C/c3ccccc3)ccc2C1=O
Temperature: 80 °C
Reaction time: 4 h

Procedure:
Tert-butyl 2-(7-bromo-2-hydroxy-1,1-dimethyl-4-oxo-1,4-dihydronaphthalene-3-carboxamido)acetate (360 mg, 848 μmol, Example 53A-E) was dissolved in 1,4-dioxane (8485 μL) and then beta-styrylboronic acid pinacol ester (293 mg, 1273 mmol), potassium carbonate (2 M in water, 2121 μL, 4242 μmol) and tetrakis(triphenylphosphine)palladium (98.0 mg, 84.8 μmol) were added. The reaction was stirred at 80° C. for 4 hours. The reaction mixture was diluted with 100 mL of EtOAc, washed 2 times with 50 mL of sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated to give crude product. The title compound was obtained by flash chromatography.
Reaction SMILES: [NH:1]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[N:10][N:11]=[C:12]2[Cl:15])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(O)CCC>[ClH:15].[NH:1]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[N:10][N:11]=[C:12]2[NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)Nc1ccc2c(Cc3ccncc3)nnc(Cl)c2c1
Reactant: Nc1ccccc1
Solvent: CCCCO
Product: CC(=O)Nc1ccc2c(Cc3ccncc3)nnc(Nc3ccccc3)c2c1
Product: Cl

Procedure:
By analogy with Example 25, 250 mg (0.80 mmol) 7-acetamino-1-chloro-4-(4-pyridylmethyl)-phthalazine is reacted in 3.2 ml 1-butanol with 0.22 ml (2.4 mmol) aniline to obtain title compound: m.p.: 162-166° C.; HPLC: tRet(Grad5-40)=9.75; FAB MS (M+H)+=370.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7]O)(=[O:4])[CH:2]=[CH2:3].[N-:9]=C=O>>[C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[NH2:9][C:1]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: [N-]=C=O
Reactant: C=CC(=O)OCCO
Product: C=CC(=O)O
Product: CCOC(N)=O

Procedure:
A round bottomed flask was charged with one equivalent of the ethylenically unsaturated polyisocyanate from Example 1 and 0.01%, based on the weight of the final product, of dibutyltin dilaurate. The flask was equipped with an overhead stirrer, nitrogen inlet, thermocouple, temperature controller, heating mantle and condenser. One equivalent of hydroxyethyl acrylate was then incrementally added to the stirred flask under a nitrogen blanket such that the temperature did not exceed 60° C. After the addition was complete the temperature was maintained at 60° C. for two hours until the isocyanate content was less than 0.5% by weight as determined by titration. A urethane acrylate was obtained having the following properties:
Reaction SMILES: Cl.[NH2:2][C@H:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30](Cl)(=[O:32])=[O:31]>ClCCl>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([NH:2][C@H:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)(=[O:32])=[O:31]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: COC(=O)c1ccc2c(c1)CC[C@H]2N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)CC[C@H]2NS(=O)(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(R)-Methyl 1-amino-2,3-dihydro-1H-indene-5-carboxylate hydrochloride (A-02) (0.2 g, 0.881 mmol, 1 eq) was dissolved in dichloromethane and triethylamine (2.5 eq) under nitrogen, and 2-chlorobenzenesulfonic acid chloride (0.185 g, 0.881 mmol, 1 eq) was added at 0° C. The reaction mixture was stirred for 2 h at RT. Then concentration was carried out under reduced pressure, and the residue was diluted with ethyl acetate, washed with 10% ammonium chloride solution and sat. NaCl solution, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (silica gel, cyclohexane:EA 4:1) and the desired product (R)-methyl 1-(2-chlorophenylsulfonamido)-2,3-dihydro-1H-indene-5-carboxylate (C-01) was thus obtained. Yield: 87%
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:20]([F:23])([F:22])[F:21])=[N:4][N:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][C:13]3[NH:17][N:18]=[CH:19][C:12]2=3)=[O:10])[C:6]=1[CH3:7].[F:24][C:25]1[CH:26]=[CH:27][C:28](Br)=[N:29][CH:30]=1.CN[C@@H]1CCCC[C@H]1NC.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.O1CCOCC1>[Cl:1][C:2]1[C:3]([C:20]([F:23])([F:21])[F:22])=[N:4][N:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][C:13]3[N:17]([C:28]4[CH:27]=[CH:26][C:25]([F:24])=[CH:30][N:29]=4)[N:18]=[CH:19][C:12]2=3)=[O:10])[C:6]=1[CH3:7]
Reactant: Fc1ccc(Br)nc1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCCc2[nH]ncc21
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCCc2c1cnn2-c1ccc(F)cn1
Temperature: 120 °C

Procedure:
2-(4-Chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)-1-(6,7-dihydro-1H-pyrazolo[4,3-b]pyridin-4(5H)-yl)ethanone (104 mg, 0.3 mmol) was combined with 5-fluoro-2-bromopyridine (106 mg, 0.6 mmol), 0.3 mL of dioxane, Cu(I)I (11.4 mg, 0.06 mmol, 20%), (±)-trans-N,N′-dimethylcyclohexane-1,2-diamine (21.3 mg, 0.15 mmol, 50%), and K2CO3 (83 mg, 0.6 mmol). The slurry was heated to 120° C. until complete (approx 3 hours). The reaction mixture was diluted in 4 mL of EtOAc and washed with 2×H2O. The organic layer was concentrated and the residue was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to provide the title compound as a white solid. 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 8.91 (s, 0.8H), 8.33 (d, J=2.7 Hz, 0.2H), 8.28 (d, J=2.9 Hz, 0.8H), 7.87-7.94 (m, 1H), 7.68-7.77 (m, 1H), 5.42 (s, 1.6H), 5.41 (s, 0.4H), 3.93 (s, 1.6H), 3.88 (s, 0.4H), 2.88 (t, J=6.4 Hz, 2H), 2.29 (s, 0.6H), 2.28 (s, 2.4H), 2.18 (m, 2H); MS: (ES) m/z calculated for C18H16ClF4N6O [M+H]+ 443.1, found 443.0.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:15][N:16]3[CH2:20][CH:19]([CH2:21][CH2:22][CH3:23])[CH2:18][C:17]3=[O:24])=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=2)[N:7]=1.[CH3:25][S-:26].[Na+].O.C(OCC)(=O)C>C1COCC1>[CH3:25][S:26][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:15][N:16]3[CH2:20][CH:19]([CH2:21][CH2:22][CH3:23])[CH2:18][C:17]3=[O:24])=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=2)[N:7]=1
Reactant: C[S-]
Reactant: CCCC1CC(=O)N(Cc2c(C(F)(F)F)nc3ccc(Cl)nn23)C1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCCC1CC(=O)N(Cc2c(C(F)(F)F)nc3ccc(SC)nn23)C1
Temperature: 150 °C
Yield: 26 %

Procedure:
A mixture of 1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one 30 (400 mg, 1.11 mmol) and sodium methanethiolate (155 mg, 2.22 mmol, 2.2 eq) in THF is heated in a microwave apparatus (300 W, Tmax 150° C.) during 15 minutes. After cooling to room temperature, hydrolysis (15 ml of water), extraction (ethyl acetate, 3×15 ml), the cumulated organic layers are dried over MgSO4, filtered and condensed under reduce pressure to afford an oil which is purified under preparative chromatography over silicagel (Gradient: CH2Cl2 to CH2Cl2/MeOH/NH4OH 99/1/0.1 (v/v/v)). Recrystallization in diisopropyl ether affords 1-{[6-(methylthio)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one 46.
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[CH2:14][C:15]2[NH:19][CH:18]=[N:17][CH:16]=2)=[CH:5][CH:4]=1)#[N:2].CCN(C(C)C)C(C)C.Cl[C:32]([O:34][CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:33]>C(Cl)Cl>[CH3:37][C:36]([CH3:39])([CH3:38])[CH2:35][O:34][C:32]([N:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:21][CH:20]=2)[CH:9]([CH2:14][C:15]2[NH:19][CH:18]=[N:17][CH:16]=2)[CH2:10]1)=[O:33]
Reactant: N#Cc1ccc(CN2CCNCC2Cc2cnc[nH]2)cc1
Reactant: CC(C)(C)COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)COC(=O)N1CCN(Cc2ccc(C#N)cc2)C(Cc2cnc[nH]2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 1-(4′-Cyanobenzyl)imidazol-5-ylmethyl piperazine prepared as described in EXAMPLE 2 (0.416 mmol) in methylene chloride was added DIEA (0.832 mmol) and commercially available neopentyl chloroformate (0.499 mmol). This solution was stirred for 2 hours at 25° C. and then the title compound was purified on preparative hpic and isolated via lyophilization. FAB-MS: calc: 395.5 found: 396.2. 1H-NMR (CD3OD): 8.9 ppm (s, 1H); 7.8 ppm (d, 2H); 7.5 ppm (s, 1H); 7.45 ppm (d, 2H); 5.65 ppm (s, 2H); 3.8 ppm (s, 2H); 3.45 ppm (s, 2H); 3.3 ppm (m, 4H): 2.3 ppm (m, 4H); 0.95 ppm (m, 9H).
Reaction SMILES: Cl.COC.[C:5]([C:9]1[CH:16]=[CH:15][C:12]([CH2:13]O)=[CH:11][CH:10]=1)([O:7]C)=[O:6].[CH2:17]([C:21]1[N:22](CC2C=CC=CC=2Cl)[C:23](/[CH:26]=[C:27](\[CH2:31][C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)/[C:28]([OH:30])=[O:29])=[CH:24][N:25]=1)[CH2:18][CH2:19]C>>[CH2:17]([C:21]1[N:22]([CH2:13][C:12]2[CH:15]=[CH:16][C:9]([C:5]([OH:7])=[O:6])=[CH:10][CH:11]=2)[C:23](/[CH:26]=[C:27](\[CH2:31][C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)/[C:28]([OH:30])=[O:29])=[CH:24][N:25]=1)[CH2:18][CH3:19]
Reactant: COC(=O)c1ccc(CO)cc1
Reactant: CCCCc1ncc(/C=C(\Cc2cccs2)C(=O)O)n1Cc1ccccc1Cl
Agent: COC
Agent: Cl
Product: CCCc1ncc(/C=C(\Cc2cccs2)C(=O)O)n1Cc1ccc(C(=O)O)cc1

Procedure:
The title compound was prepared using the procedure of Example 1 replacing valermamidine methyl ether hydrochloride with butyramidine methyl ether hydrochloride and replacing 2-chlorbenzyl alcohol with 4-carbomethoxybenzyl alcohol; mp 250° C. (d).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C1C(=O)N([Br:18])C(=O)C1>>[Br:18][C:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[NH:8][CH:9]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: O=C1CCC(=O)N1Br
Product: Clc1ncnc2[nH]cc(Br)c12
Temperature: 25 °C
Yield: 80.7 %

Procedure:
To a suspension of 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (2.5 g, 16 mmol) in CDCl3 (65 mL) was added NBS (2.9 g, 16 mmol) and the reaction mixture stirred and heated at reflux for 2.5 hours. The mixture was cooled to room temperature, the solids isolated by vacuum filtration, rinsed with cold CHCl3 and air dried to give 5-Bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 79%.) LCMS (APCI+) m/z 232 and 234 [M+H]+; Rt: 2.32 min. 1H NMR (DMSO-d6, 400 MHz) δ 12.98 (1H, br. s), 8.63 (1H, s), 7.96 (1H, s.)
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[O:13][C:14]([CH3:17])(C)C)(C)(C)C.[C]=O.[CH2:20]([OH:22])C>[Pd](Cl)Cl>[C:1]1([CH2:7][C:20]([O:13][CH2:14][CH3:17])=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OOC(C)(C)C
Reactant: CCO
Reactant: Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [C]=O
Product: CCOC(=O)Cc1ccccc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 57.3 %

Procedure:
Toluene (1.38 g), ethanol (46 mg), di-tert-butyl peroxide (73 mg, 1 equivalent), and palladium chloride (0.9 mg, 1 mol %) were added into a reaction kettle, into which 10 atm carbon monoxide was introduced. The reaction was heated to 120° C., and stirred at this constant temperature for 16 h. After the reaction was completed, carbon monoxide was discharged, and 47 mg ethyl phenylacetate was obtained by column chromatography, in a yield of 57%. The ethyl phenylacetate obtained was dissolved in 1,4-dioxane. 6 N sodium hydroxide solution was added, and the reaction was heated to 60° C. After 2 h of reaction, the pH value was adjusted to 1 by adding 2 N hydrochloric acid. After removing the organic solvent under reduced pressure, 35 mg product phenylacetic acid was obtained by extraction with ethyl acetate, and the yield of hydrolysis was 90%.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.[ClH:11].[Cl:12]Cl.[N+](C1C=CC=CC=1O)([O-])=O>O>[Cl:11][C:4]1[CH:5]=[C:6]([N+:7]([O-:9])=[O:8])[CH:1]=[C:2]([Cl:12])[C:3]=1[OH:10]
Reactant: Cl
Reactant: ClCl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=[N+]([O-])c1ccccc1O
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)c(O)c(Cl)c1
Reaction time: 4.33 h
Yield: 96 %

Procedure:
139 parts of p-nitrophenol are suspended in 292 parts of water and the suspension is ground. A reactor is then charged with 1250 parts of 20 % hydrochloric acid which has been used as reaction medium for a previous batch and recycled to the reactor after isolation of the product. Then 156 parts of chlorine and the suspension of p-nitrophenol are added simultaneously at 25° C. to the hydrochloric acid. The suspension of nitrophenol is added over 240 minutes, whereas the simultaneous addition of chlorine is made for 20 minutes longer over 260 minutes. The batch is then allowed to react for 30 minutes and excess chlorine is expelled over a further 30 minutes. The product is isolated by filtration, washed until neutral and dried, affording 200 parts of 2,6-dichloro-4-nitrophenol (corresponding to a yield of 96 %). Melting point: 119°-120° C. (lit.: 125° C.).
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].[O:5]=[C:6]1[NH:14][C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[N:7]1[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C@H:24]2[C:30]3=[N:31][C:32](N)=[CH:33][CH:34]=[C:29]3[CH2:28][C@H:27]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:37]=3[F:43])[CH2:26][CH2:25]2)=[O:22])[CH2:17][CH2:16]1.C=O.[C:46](O)(=O)C>C(#N)C>[O:5]=[C:6]1[NH:14][C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[N:7]1[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C@H:24]2[C:30]3=[N:31][C:32]([N:2]([CH3:1])[CH3:46])=[CH:33][CH:34]=[C:29]3[CH2:28][C@H:27]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:37]=3[F:43])[CH2:26][CH2:25]2)=[O:22])[CH2:17][CH2:16]1
Reactant: CC(=O)O
Reactant: Nc1ccc2c(n1)[C@H](OC(=O)N1CCC(n3c(=O)[nH]c4ncccc43)CC1)CC[C@@H](c1cccc(F)c1F)C2
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: CN(C)c1ccc2c(n1)[C@H](OC(=O)N1CCC(n3c(=O)[nH]c4ncccc43)CC1)CC[C@@H](c1cccc(F)c1F)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.9 %

Procedure:
SODIUM CYANOBOROHYDRIDE (108 mg, 1.721 mmol) was added to the Acetonitrile (2 mL) solution of (6R,9R)-2-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (46 mg, 0.086 mmol) and FORMALDEHYDE (1 mL, 13.43 mmol) at rt. The reaction was stirred at room temperature for 4 hours. ACETIC ACID (0.5 mL, 8.73 mmol) was added to the reaction mixture and the reaction was stirred overnight. Volatile was removed mostly via vacuum and the crude was added NaOH (1N) and stirred at room temperature for 1 hour before extract with ethyl acetate. The ethyl acetate layer was dried (Na2SO4), filtered and concentrated. Flash column by methanol in CH2Cl2 from 0 to 4% to 8% gave the desired product (19.8 mg, 39%). MS (ESI)[M+H+]=563.42.
Reaction SMILES: [CH2:1]([C:3](=[CH2:6])[CH:4]=[O:5])[CH3:2].[SH:7][C:8]1[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11].C(N(CC)CC)C>C1COCC1.CCOCC>[C:10]([C:9]1[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=1[S:7][CH2:6][CH:3]([CH2:1][CH3:2])[CH:4]=[O:5])(=[O:11])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(c1ccccc1)c1ccccc1S
Reactant: C=C(C=O)CC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(C=O)CSc1ccccc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 63.6 %

Procedure:
To an ice bath cooled solution of 9.76 g (0.116 mole) of 2-ethylacrolein in 40 mL of dry THF was added 24.6 g (0.116 mole) of 2-mercaptobenzophenone in 40 mL of THF followed by 13 g (0.128 mole) of triethylamine. The reaction mixture was stirred at room temperature for 3 days, diluted with ether, and was washed successively with dilute HCl, brine, and 1 M potassium carbonate. The ether layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by HPLC (10% EtOAc-hexane) to give 22 g (64%) of 11 in the second fraction. An attempt to further purifiy this material by kugelrohr distillation at 0.5 torr (160-190° C.) gave a fraction (12.2 g) which contained starting material indicating a reversed reaction during distillation. This material was dissolved in ether (100 mL) and was washed with 50 mL of 1 M potassium carbonate three times to give 6.0 g of a syrup which was purified by HPLC (10% EtOAc-hexane) to give 5.6 g of pure 11.