Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH3:35])([CH3:34])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([NH:18][C:19]3[N:24]=[C:23]([NH:25][C:26]4[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=4)[C:22]([Cl:32])=[CH:21][N:20]=3)=[CH:13][C:12]=2[CH3:33])[CH2:7][CH2:6]1)=[O:4].C([O-])([O-])=O.[K+].[K+].[CH2:42](I)[CH3:43].[NH4+].[Cl-]>CC(C)=O>[Cl:32][C:22]1[C:23]([NH:25][C:26]2[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=2)=[N:24][C:19]([NH:18][C:14]2[C:15]([CH3:17])=[CH:16][C:11]([CH:8]3[CH2:7][CH2:6][N:5]([C:3](=[O:4])[C:2]([NH:1][CH2:42][CH3:43])([CH3:35])[CH3:34])[CH2:10][CH2:9]3)=[C:12]([CH3:33])[CH:13]=2)=[N:20][CH:21]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(C(=O)C(C)(C)N)CC4)cc3C)ncc2Cl)n[nH]1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCNC(C)(C)C(=O)N1CCC(c2cc(C)c(Nc3ncc(Cl)c(Nc4cc(C)[nH]n4)n3)cc2C)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 2-amino-1-(4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)piperidin-1-yl)-2-methylpropan-1-one (6 mg, 0.012 mmol) in acetone (0.5 mL) was added K2CO3 (11 mg, 0.079 mmol). The mixture was stirred at room temperature for 10 min. before the addition of EtI (6 mg, 0.038 mmol). The resulting mixture was then stirred at room temperature for 14 h before it was treated with saturated aqueous NH4Cl (1 mL) and extracted with EtOAc (3×2 mL). The organic layers were combined, concentrated, and the residue was purified by preparative thin layer chromatography (silica gel, 8% MeOH/DCM/NH3) followed by further purification with preparative RP-HPLC to provide 1-(4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)piperidin-1-yl)-2-(ethylamino)-2-methylpropan-1-one; ESMS m/z 525.3 (M+H+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].CCN(C(C)C)C(C)C.[O:33]1[CH2:38][CH2:37][CH:36]([CH2:39][NH2:40])[CH2:35][CH2:34]1>CN1C(=O)CCC1.O>[CH3:20][C:15]1[C:14]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([NH:40][CH2:39][CH:36]4[CH2:37][CH2:38][O:33][CH2:34][CH2:35]4)=[C:3]([N+:21]([O-:23])=[O:22])[CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])=[C:18]([CH3:19])[O:17][N:16]=1
Reactant: NCC1CCOCC1
Reactant: COc1cc2c(Cl)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc2c(NCC3CCOCC3)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Reaction time: 0.08 h
Yield: 93 %

Procedure:
4-Chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-nitroquinoline (for a preparation see Intermediate 8) (1.06 g, 3.18 mmol) was dissolved in NMP (5 ml), then DIPEA (0.56 ml, 3.18 mmol) and (tetrahydro-2H-pyran-4-yl)methanamine (0.75 g, 6.51 mmol) were added at room temperature. The reaction mixture immediately changed colour and within 5 minutes, a thick yellow precipitate was formed. The mixture was stirred for 20 min, then diluted with water (30 ml) and stirred for 10 min. The precipitate was collected by filtration and washed with water (2×20 ml), then dried in vacuo to give 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-3-nitro-N-((tetrahydro-2H-pyran-4-yl)methyl)quinolin-4-amine (1.22 g, 2.96 mmol, 93% yield) as a bright yellow solid. LCMS (formate) Rt 0.88 min, MH+ 413
Reaction SMILES: CI.[C:3]([O-])([O-])=O.[K+].[K+].[Br:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[NH:18][C:17](=[S:20])[N:16]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]2=[O:27].O>C1COCC1>[Br:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[C:17]([S:20][CH3:3])[N:16]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]2=[O:27]
Reactant: O=C([O-])[O-]
Reactant: O=c1c2cccc(Br)c2[nH]c(=S)n1-c1ccccc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: CSc1nc2c(Br)cccc2c(=O)n1-c1ccccc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of MeI (1.68 mL, 27.0 mmol), K2CO3 (2.49 g, 18.01 mmol), 8-bromo-3-phenyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (402a; 3.00 g, 9.00 mmol) in 30 mL THF was fitted with a water cooled reflux condenser and heated to reflux (80° C. oil bath) overnight under N2. Additional 1.5 equiv MeI was added and heating continued. After 2 h, water was added, and the reaction was partitioned between water and EtOAc. The aqueous layer was washed 1× brine, and the organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 8-bromo-2-(methylthio)-3-phenylquinazolin-4(3H)-one as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.16 (1H, dd, J=7.8, 1.4 Hz), 8.07 (1H, dd, J=7.8, 1.4 Hz), 7.53-7.61 (3H, m), 7.44-7.51 (2H, m), 7.37 (1H, t, J=7.8 Hz), 2.56 (3H, s). m/z (ESI, +ve) 346.9/349.0 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]12[CH2:22][C:12]3([C:23](OCC)=[O:24])[CH2:13][C:14]([C:17](OCC)=[O:18])([CH2:16][C:10]([CH3:28])([CH2:11]3)[CH2:9]1)[CH2:15]2.CCOC(C)=O.OS(O)(=O)=O>CCOCC>[CH3:28][C:10]12[CH2:16][C:14]3([CH2:17][OH:18])[CH2:13][C:12]([CH2:23][OH:24])([CH2:22][C:8]([CH3:7])([CH2:15]3)[CH2:9]1)[CH2:11]2
Reactant: CCOC(=O)C12CC3(C)CC(C)(C1)CC(C(=O)OCC)(C3)C2
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC12CC3(C)CC(CO)(C1)CC(CO)(C2)C3
Reaction time: 2 h
Yield: 87.4 %

Procedure:
Six grams of lithium-aluminum hydride (0.158 mole) was stirred with 200 ml of absolute ether and to this was added dropwise 24.15 g (0.078 mole) of diethyl 1,3-dimethyladamantane-5,7-dicarboxylate in 50 ml of absolute ether at a rate such as to maintain gentle refluxing of the solvent. Refluxing was continued for two hours. Then the excess LiAlH4 was decomposed with moist AcOEt. The reaction mixture was acidified with 20% H2SO4 which gave, by crystallization, 15.3 g of 1,3-dimethyl-5,7-bis (hydroxymethyl)-adamantane (IIb) which was collected by filtration. Another 1.8 g crop was obtained from the filtrate after separating the water phase and evaporating the organic layer. Yield was 17.1 g (97%). MP was 158°-161° C. Recrystallization from ethyl acetate afforded a product MP 160°-162° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:20])C=1>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[CH:4][N+:3]=1[O-:20]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(C(F)(F)F)ccn1
Solvent: ClCCl
Product: Cc1cc(C(F)(F)F)cc[n+]1[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-methyl-4-(trifluoromethyl)pyridine (3.9 g, 24 mmol) in methylene chloride (50 mL) was added m-chloroperbenzoic acid (7.0 g, 31 mmol). After being stirred at room temperature overnight, the solution was washed with 50 mL of 1 N NaOH. The water phase was back-extracted with methylene chloride. The combined organic phases were dried over Na2SO4 and concentrated under vacuum to give the title compound. MS (M+H) 178.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31].C(OCC)(=O)C>C1COCC1.O>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH2:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)C(=O)CBr
Reactant: O=C(Cc1ccnc(F)c1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)CC(C(=O)c1ccccc1)c1ccnc(F)c1
Reaction time: 0.17 h
Yield: 87.2 %

Procedure:
To a solution of 2-(2-fluoropyridin-4-yl)-1-phenylethanone (450 mg, 2.1 mmol) in dry THF (10 mL) at 0° C. was added a solution of sodium bis(trimethylsilyl)amide (2.1 mL, 1M). After 10 min. 1-bromopinacolone (309 μL, 2.3 mmol) was added dropwise and the solution stirred for 2 h. The solution was poured into ethyl acetate (25 mL) and H2O (25 mL) and the layers allowed to separate. The organic layer was collected and the aqueous layer extracted with ethyl acetate (30 mL). The combined organic layers were washed with H2O and brine, dried (MgSO4) and concentrated. The product was purified by flash chromatography using EtOAc-Pet. spirit (20:80) as eluant to give the pure product as a pale yellow oil (574 mg, 87%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH2:14]([O:13][C:11](=[O:12])[NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH2:5][OH:6])[CH:3]=1)[CH3:15]
Reactant: Nc1cccc(CO)c1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)Nc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
50 g (406 mmol) of 3-aminobenzyl alcohol are suspended in 750 ml of dichloromethane under a nitrogen atmosphere, the mixture is stirred at room temperature for 30 min and subsequently cooled to 0° C. 49 g (452 mmol) of ethyl chloroformate are slowly added dropwise. After the addition, the reaction mixture is stirred for 20 h and at the same time slowly warmed to room temperature. 300 ml of 1M potassium carbonate solution are added to the suspension formed (evolution of gas!). The organic phase is separated off, the aqueous phase is extracted with 200 ml of dichloromethane, the combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate, and the solvent is removed by distillation.
Reaction SMILES: [Cl:1][C:2]1[N+:7]([O-:8])=[C:6]([CH2:9][C:10]([O:12]C2C=CC([N+]([O-])=O)=CC=2)=O)[C:5]([C:22]#[N:23])=[CH:4][CH:3]=1.[C:24]([O:28][C:29](=[O:42])[NH:30][C:31]1[C:35]2[CH:36]=[C:37]([CH2:40][NH2:41])[CH:38]=[CH:39][C:34]=2[O:33][N:32]=1)([CH3:27])([CH3:26])[CH3:25].CO>CCOC(C)=O.CCCCCC>[C:22]([C:5]1[C:6]([CH2:9][C:10]([NH:41][CH2:40][C:37]2[CH:38]=[CH:39][C:34]3[O:33][N:32]=[C:31]([NH:30][C:29]([O:28][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:42])[C:35]=3[CH:36]=2)=[O:12])=[N+:7]([O-:8])[C:2]([Cl:1])=[CH:3][CH:4]=1)#[N:23]
Reactant: CC(C)(C)OC(=O)Nc1noc2ccc(CN)cc12
Reactant: N#Cc1ccc(Cl)[n+]([O-])c1CC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1noc2ccc(CNC(=O)Cc3c(C#N)ccc(Cl)[n+]3[O-])cc12
Reaction time: 8 h

Procedure:
A mixture of 6-chloro-3-cyano-2-(4-nitro-phenoxycarbonylmethyl)-pyridine 1-oxide (83.6 mg, 0.25 mmol), as prepared in Example 6f, and (5-aminomethyl-benzo[d]isoxazol-3-yl)-carbamic acid tert-butyl ester (78.8 mg, 0.3 mmol) in CDCl3 (3 mL) was stirred in an ice-water bath which was allowed to rise to rt overnight. A lot of precipitate formed. TLC showed the disappearance of 6-chloro-3-cyano-2-(4-nitro-phenoxycarbonylmethyl)-pyridine 1-oxide. A small amount of methanol was added to dissolve the solid. The solution was applied onto a prep TLC (2 mm, 20×20 cm) and developed with EtOAc/Hexane (4:1). A white solid was obtained (103 mg). LC/MS (ESI) (M+H+ 458.1)
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:18])=[C:4]([NH2:17])[CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:7]=1.C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N+:31]([O-])(OCCC(C)C)=O>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[C:4]2[C:3]=1[CH:18]=[N:31][NH:17]2
Reactant: Cc1c(N)cc(Oc2ccc(F)cc2F)cc1Br
Reactant: CC(C)CCO[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: Fc1ccc(Oc2cc(Br)c3cn[nH]c3c2)c(F)c1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 57.9 %

Procedure:
3-Bromo-5-(2,4-difluoro-phenoxy)-2-methyl-phenylamine (5.31 g, 16.9 mmol) was dissolved in 50 mL dry benzene, and acetic anhydride (5.17 g, 50.7 mmol) and potassium acetate (1.69 g, 17.2 mmol) were added. The reaction mixture was placed under nitrogen atmosphere and heated to 80° C. with stirring for 10 minutes. Isoamyl nitrate (3.39 mL, 25.4 mmol) was added dropwise over 30 minutes, after which the reaction mixture was stirred at 80° C. under nitrogen for 17 hours. The reaction mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure. Water (8 mL) and concentrated HCl (16 mL of 6N aqueous solution) were added, and the mixture was heated to 55° C. Methanol (100 mL) was added, and the mixture was heated to 80° C. The mixture was cooled and concentrated under reduced pressure, and the residue was partitioned between water and ethyl acetate. The organic layer was separated and concentrated under reduced pressure. The residue was partitioned betwee methylene chloride and saturated sodium bicarbonate. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was chromatographed through silica (0%-25% EtOAc in hexanes) to give 3.18 g of 4-bromo-6-(2,4-difluoro-phenoxy)-1H-indazole.
Reaction SMILES: Cl[C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][CH2:39][NH2:40].C(N(CC)CC)C>CN1C(=O)CCC1>[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][CH2:39][NH:40][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(Cl)nc2c1-c1cccc(C(F)(F)F)c1
Reactant: CN(C)CCCN
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NCCCN(C)C)nc2c1-c1cccc(C(F)(F)F)c1
Temperature: 220 °C
Yield: 69.5 %

Procedure:
To a solution of 4-{5-[2-chloro-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Int. 19, 68 mg, 0.14 mmol) in NMP (2.5 mL) was added N,N-dimethyl-propane-1,3-diamine (54 μL, 0.43 mmol) followed by triethylamine (39 μL, 0.28 mmol). The reaction mixture was heated to 220° C. for 5 hrs using microwave irradiation. The cooled reaction mixture was concentrated in vacuo then loaded onto a SCX-2 cartridge (2 g) in MeOH. After washing with DCM/MeOH, the crude product was eluted with 2 M NH3 in MeOH and following concentration in vacuo gave a brown oil (53 mg). The oil thus obtained was purified using preparative TLC (20×20 cm×1 mm) eluting with 20% MeOH in DCM to give the title compound as a pale yellow oil, which solidified on standing (14 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=2)[C:10]2[N:14]([CH3:15])[C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.O.[NH:31]1[C:35]([NH2:36])=[N:34][N:33]=[N:32]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([NH:36][C:35]3[NH:34][N:33]=[N:32][N:31]=3)=[O:27])=[CH:23][CH:22]=2)[C:10]2[N:14]([CH3:15])[C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cn1c(N(Cc2ccc(C(=O)O)cc2)c2cc(Cl)cc(Cl)c2)nc2ccccc21
Reactant: Nc1nnn[nH]1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cn1c(N(Cc2ccc(C(=O)Nc3nnn[nH]3)cc2)c2cc(Cl)cc(Cl)c2)nc2ccccc21
Temperature: 40 °C

Procedure:
To a solution of the title compound of Example 223 Step C (0.16 mmol, 68 mg), 1H-tetraazol-5-amine monohydrate (0.48 mmol, 49 mg), HOBt (0.32 mmol, 49 mg) and EDC (0.32 mmol, 61 mg) in 1 mL of DMF was added DIEA (0.48 mmol, 83 μL). The reaction mixture was warmed to 40° C. for 2 h, then concentrated under reduced pressure. The residue was purified by reverse-phase chromatography (Condition B). The product was lyophilized, affording a white solid. 1H NMR (500 MHz, d6-DMSO) δ 12.38 (s, 1H), 8.07 (d, 2H), 7.73 (d, 2H), 7.63 (m, 1H), 7.56 (m, 1H), 7.24-7.33 (overlapping m, 2H), 7.15 (t, 1H), 6.90 (d, 2H), 5.31 (s, 2H), 3.53 (s, 3H). MS (ESI): m/z 493 (M+H). HPLC A: 1.69 min.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([NH:8][CH2:9][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:22][C:23]([O:26][C:27]([N:29]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[N:30]([C:38]1[C:43]([F:44])=[C:42](Cl)[N:41]=[C:40]([Cl:46])[N:39]=1)[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:28])([CH3:25])[CH3:24].CS(C)=O>C1COCC1>[Cl:46][C:40]1[N:39]=[C:38]([N:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[N:29]([C:27]([O:26][C:23]([CH3:22])([CH3:24])[CH3:25])=[O:28])[C:47]([O:49][C:50]([CH3:51])([CH3:52])[CH3:53])=[O:48])[C:43]([F:44])=[C:42]([N:8]([N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)[CH2:9][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[N:41]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(Cl)c1F
Reactant: CN1CCN(NCc2nccs2)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN1CCN(N(Cc2nccs2)c2nc(Cl)nc(N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2F)CC1
Reaction time: 8 h
Yield: 3.8 %

Procedure:
4-Methyl-N-(1,3-thiazol-2-ylmethyl)-1-piperazinamine (2.2169 g, 10.44 mmol) was dissolved in THF (30 mL) and triethylamine (4.37 ml, 31.3 mmol). Then tris(1,1-dimethylethyl)2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate (3.89 g, 7.83 mmol) and DMSO (5 mL) were added. The reaction was left to stir overnight. The THF was evaporated away, and the mixture was diluted with water. The aqueous layer was extracted with ethyl acetate, and the organics were dried (Na2SO4) and evaporated. Purification by silica gel chromatography and RP-HPLC provided tris(1,1-dimethylethyl) 2-{2-chloro-5-fluoro-6-[(4-methyl-1-piperazinyl)(1,3-thiazol-2-ylmethyl)amino]-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (0.2014 g, 3%). LCMS: (M+H)+=674.6.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:11][CH:10]=[C:9]([C:12](OCC)=[O:13])[CH:8]=1.[H-].C([Al+]CC(C)C)C(C)C.O.S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1.C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:11][CH:10]=[C:9]([CH2:12][OH:13])[CH:8]=1
Reactant: CCOC(=O)c1c[nH]c(-c2ccccn2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: OCc1c[nH]c(-c2ccccn2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
A solution (30 mL) of ethyl 5-(pyridin-2-yl)-1H-pyrrole-3-carboxylate (1.62 g) in tetrahydrofuran was cooled to −50° C., and a 1.5 mol/L solution (15 mL) of diisobutylaluminum hydride in toluene was added dropwise by small portions. The mixture was further stirred at 0° C. for 1 hr, water (3 mL) was added to the reaction mixture and the mixture was stirred at room temperature for 1 hr. Celite and anhydrous magnesium sulfate were added and the mixture was further stirred for 15 min and filtrated. The obtained filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1→1:3) to give the title compound as colorless crystals (yield 1.15 g, 88%).
Reaction SMILES: [SH2:1].[O:2]=[C:3]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:7]2[S:15][C:16]([C:24]#[N:25])=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:5]=[CH:4]1>N1C=CC=CC=1.C(N(CC)CC)C>[O:2]=[C:3]1[N:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:7]2[S:15][C:16]([C:24](=[S:1])[NH2:25])=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:5]=[CH:4]1
Reactant: S
Reactant: N#Cc1sc2c(ccc(=O)n2-c2ccccc2)c1-c1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: NC(=S)c1sc2c(ccc(=O)n2-c2ccccc2)c1-c1ccccc1
Reaction time: 60 h
Yield: 40 %

Procedure:
Hydrogen sulphide was bubbled through a solution of the compound of Example 77 (539 mg, 1.64 mmol) in pyridine (1 0 mL) and triethylamine (0.5 mL) for 30 minutes. The reaction was left to stand for 60 h at r.t. and then nitrogen bubbled through the mixture to ensure the solution was purged of H2S. The solution was diluted with DCM and washed with water (×2), 2M HCl(aq) (×2) and brine. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The crude product was recrystallised from DCM-hexane to give the title compound as a solid (327 mg, 40%). δH (DMSO-d6) 9.70 (1H, s), 7.70–7.47 (9H, m), 7.45 (2H, m), 7.38 (1H, d J 9.6 Hz), 6.52 (1H, d, J 9.6 Hz). LCMS (ES+) RT 3.33 minutes, 385 (M+Na)+, 363 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#N)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C1C[O:36]CC1>CCCCCC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[CH:18]=[O:36])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: N#Cc1cccc(-c2cccc(OCc3ccccc3)c2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Product: O=Cc1cccc(-c2cccc(OCc3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a stirred solution of 75 (0.12 g, 0.42 mmol) in anhydrous THF (10 mL) at −78° C., under a nitrogen atmosphere was added diisobutylaluminum hydride (0.5 mL, 0-5 mmol, using a 1M solution in hexane) dropwise. The reaction mixture was stirred at the same temperature for 1 hour and then quenched by dropwise addition of potassium sodium tartrate (10% solution in water). The resulting mixture was warmed to room temperature, diluted with diethyl ether (20 mL) and stirred vigorously for 1 h. The organic phase was separated and the aqueous phase was extracted with diethyl ether. The combined organic layer was washed with brine, dried (MgSO4) and evaporated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel (20% diethyl ether-hexane) to give 76 (0.091 g, 75% yield) as a viscous liquid.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[CH:3]=1.[NH:10]1[CH:14]=[N:13][CH:12]=[N:11]1.CNC1CCCCC1NC.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[Cu]I>[CH3:9][C:4]1[CH:3]=[C:2]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH:7]=[C:6]([CH3:8])[CH:5]=1
Reactant: Cc1cc(C)cc(I)c1
Reactant: c1nc[nH]n1
Agent: [Cu]I
Agent: CNC1CCCCC1NC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(-n2cncn2)c1
Temperature: 25 °C
Yield: 80.4 %

Procedure:
A solution of 1-iodo-3,5-dimethylbenzene (6.25 mL, 43.1 mmol), 1H-1,2,4-triazole (5.95 g, 86 mmol), CuI (0.410 g, 2.155 mmol), N1,N2-dimethylcyclohexane-1,2-diamine (0.681 mL, 4.31 mmol) and K2CO3 (21.04 g, 99 mmol) in DMF (200 mL) was heated at 140° C. overnight. After cooling to room temperature, it was filtered through a short plug of Celite®. Upon evaporation of the solvent, the residue was purified by column chromatography on silica gel with DCM/EtOAc (4/1) (v/v) as eluent to yield 1-(3,5-dimethylphenyl)-1H-1,2,4-triazole (6 g, 80%) as a liquid.