Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([O:11][C:12](=[O:16])[C@H:13]([CH3:15])[NH2:14])[CH3:10].Cl[CH2:18][C:19]1[C:20]([N+:26]([O-:28])=[O:27])=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=1>C(O)C>[CH2:9]([O:11][C:12](=[O:16])[C@H:13]([CH3:15])[NH:14][CH2:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([CH3:18])[C:20]=1[N+:26]([O-:28])=[O:27])[CH3:10]
Reactant: Cc1cccc(CCl)c1[N+](=O)[O-]
Reactant: CCOC(=O)[C@H](C)N
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](C)NCc1cccc(C)c1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of 120 ml of triethylamine in 200 ml of absolute ethanol was added dropwise over a period of 30 minutes to a solution of 91.8 g of L-alanine ethyl ester hydrochloride in 300 ml of absolute ethanol. The mixture was warmed to 60° C., a clear solution resulting. To this solution was added dropwise within 1 hour a solution of 55.5 g of 3-(chloromethyl)-2-nitrotoluene in 300 ml of absolute ethanol. Thereafter, the temperature was increased to 80° C. and the mixture was stirred at this temperature overnight. Thereafter, the mixture was evaporated to dryness under reduced pressure and the residue was dissolved in 600 ml of water. The solution was extracted three times with methylene chloride and the extracts were washed successively with water and with saturated sodium chloride solution, dried and evaporated. The thus-obtained crude product was purified by chromatography on silica gel using methylene chloride/5% methanol for the elution. There was obtained N-(3-methyl-2-nitrobenzyl)-L-alanine ethyl ester in the form of a yellow oil; [α]D =-36° (c=1% in methanol).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[N:18]=[C:17]2[CH:19]=[CH:20][C:21]([CH3:24])=[C:22]([CH3:23])[C:16]2=[N:15]1)[CH2:11][C:12]#[CH:13]>>[F:9][CH2:8][C:4]1[N:3]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][N:14]2[N:18]=[C:17]3[CH:19]=[CH:20][C:21]([CH3:24])=[C:22]([CH3:23])[C:16]3=[N:15]2)[CH:7]=[CH:6][CH:5]=1
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCn1nc2ccc(C)c(C)c2n1
Product: Cc1ccc2nn(CCC#Cc3cccc(CF)n3)nc2c1C
Yield: 39.5 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (79 mg, 0.41 mmol) and 2-but-3-ynyl-4,5-dimethyl-2H-benzo[d][1,2,3]triazole (75 mg, 0.38 mmol, 177(B)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 98:2) to yield 46 mg (0.15 mmol, 40%) of 2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-4,5-dimethyl-2H-benzo[d][1,2,3]triazole as an orange oil.
Reaction SMILES: [CH:1](Br)=[CH2:2].[Mg].Cl[C:6]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:7]=1[O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:14](=[O:15])[O:13][C:12]2(O)[CH3:19].[ClH:29]>C1COCC1>[Cl:29][C:6]1[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[CH:21][C:7]=1[O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:14](=[O:15])[O:13][C:12]2([CH3:19])[CH:1]=[CH2:2]
Reactant: C=CBr
Reactant: CC1(O)OC(=O)c2ccc(Oc3ccc(C(F)(F)F)cc3Cl)cc21
Reactant: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CC1(C)OC(=O)c2ccc(Oc3ccc(C(F)(F)F)cc3Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Vinyl bromide (112.4 g, 1.05 mol) in THF (500 ml) was added to magnesium (24 g, 1.0 mol) in THF (500 ml) under a nitrogen blanket over 1 hour. The temperature was maintained below 60° during addition and stirring continued for a further 30 minutes during which all the magnesium dissolved. The reaction mixture was cooled to 0° C. and then a solution of 5-(2-chloro-4-trifluoromethylphenoxy)-3-hydroxy-3-methylphthalide, prepared as described in Example 2, (119.5 g, 0.33 mol) in THF (500 ml) was run in while maintaining a temperature of 0° to 5° C. After stirring for a further 1 hour, during which the temperature rose to 20° C., dilute hydrochloric acid (1.1 mol in 250 ml) was added very cautiously over 30 minutes. The solution separated into two layers and the aqueous layer was run off. Toluene (500 ml) was added and the solution washed twice with water. The solvent was stripped and the residual oil dissolved in ethyl acetate/60°-80° petroleum spirit and eluted over silica. The desired product, 5-(2-chloro-4-trifluoromethylphenoxy)-3-methyl-3-vinyl phthalide, was crystallised from hexane, m.p.=71°-73° C. Yield=122.2 g (96%).
Reaction SMILES: [N:1]1[C:10]2C(=CC=C[CH:9]=2)N=[CH:3][CH:2]=1.Cl[C:12]1[C:13]2[N:14]([CH:22]=[N:23][N:24]=2)[C:15]2[C:20]([N:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2.[CH2:25](NCC)[CH3:26].C(NCCC)CC>>[CH2:2]([N:1]([CH2:10][CH3:9])[C:12]1[C:13]2[N:14]([C:22]([CH2:25][CH3:26])=[N:23][N:24]=2)[C:15]2[C:20]([N:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:3]
Reactant: Clc1nc2ccccc2n2cnnc12
Reactant: c1ccc2nccnc2c1
Reactant: CCNCC
Solvent: CCCNCCC
Product: CCc1nnc2c(N(CC)CC)nc3ccccc3n12
Yield: 69 %

Procedure:
This compound was prepared by the method of Example 11, utilizing 4-chloro-1-ethyl-[1,2,4]triazolo4,3-a]quinoxaline (the product of Example 4) as starting material in place of 4-chloro-[1,2,4]triazolo[4,3-a]quinoxaline (the product of Example 2) and diethylamine as reagent in place of di-n-propylamine. The crude product was recrystallized from cyclohexane to afford 3.54 g. (69% yield) of pure 4-diethylamino-1-ethyl-[1,2,4]triazolo[4,3-a]quinoxaline as a white solid (m.p. 98°-100° C.). Mass spectrum: m/e, 269 (P).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.C(O)(=[O:11])C.OO>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N+:3]=1[O-:11]
Reactant: CC(=O)O
Reactant: Cc1ccc(O)cn1
Agent: OO
Solvent: O
Product: Cc1ccc(O)c[n+]1[O-]
Reaction time: 18 h

Procedure:
A mixture of 100.0 g of 2-methyl-5-hydroxy-pyridine, 600 ml of acetic acid and 200 ml of 30-35% hydrogen peroxide is heated on a steam bath with occasional swirling for 18 hours. Then to the mixture is added 500 ml of water and the resulting solution is evaporated to leave a residue. The last traces of water from the residue are removed azeotropically with isopropanol to give a yellow solid. This solid is recrystallized from ethanol to give 2-methyl-5-hydroxy-pyridine-1-oxide melting at 185°-187°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([CH:17]=[O:18])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:19](=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][C:40]([O:42][CH3:43])=[O:41])=[CH:35][CH:34]=2)O1>O1CCOCC1.[Pd](Cl)Cl.C1(P(C2C3C(=CC=CC=3)C=CC=2)C2C3C(=CC=CC=3)C=CC=2)C2C(=CC=CC=2)C=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([CH:17]([OH:18])[C:33]3[CH:34]=[CH:35][C:36]([CH2:39][C:40]([O:42][CH2:43][CH3:19])=[O:41])=[CH:37][CH:38]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(-c2cccc(Cl)c2)nc2c1CCC2
Reactant: COC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: [K+]
Agent: c1ccc2c(P(c3cccc4ccccc34)c3cccc4ccccc34)cccc2c1
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc(C(O)c2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 100 °C
Yield: 73.2 %

Procedure:
To a suspension of 2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-4-carbaldehyde (0.210 g, 0.81 mmol) in dioxane (10 mL) was added palladium chloride (0.007 g, 0.040 mmol), trinaphthyl phosphine (0.017 g, 0.040 mmol), potassium carbonate 0.336 g, 2.43 mmol), and methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (0.200 g, 0.97 mmol). The mixture was purged with nitrogen and then heated to 100° C. under sealed conditions for 16 h. After this time, the mixture was diluted with water and extracted with ethyl acetate. The organic layer were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (0.250 g, 75%) as a white foam. MW=421.9. 1H NMR (CDCl3, 500 MHz) δ 8.01-7.97 (m, 1H), 7.87-7.83 (m, 1H), 7.76 (s, 1H), 7.40-7.23 (m, 6H), 5.81 (s, 1H), 4.13 (q, J=7.0 Hz, 2H), 3.59 (s, 2H), 3.07-2.98 (m, 2H), 2.87-2.79 (m, 1H), 2.64-2.49 (m, 1H), 2.08 (quin, J=7.5 Hz, 2H), 1.30-1.21 (m, 3H); APCI MS m/z 422 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:30])[CH:3]([N:19]1C(=O)C2=CC=CC=C2C1=O)[CH2:4][C:5](=[CH2:18])[CH2:6][N:7]1C(=O)C2=CC=CC=C2C1=O.O.NN.O.[ClH:35]>C(O)C>[ClH:35].[ClH:35].[F:1][CH:2]([F:30])[CH:3]([NH2:19])[CH2:4][C:5](=[CH2:18])[CH2:6][NH2:7]
Reactant: C=C(CC(C(F)F)N1C(=O)c2ccccc2C1=O)CN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: C=C(CN)CC(N)C(F)F
Temperature: 90 °C

Procedure:
A mixture of 1,1-difluoro-2,5-diphthalimido-4-methylene-pentane (7.77 g, 19 mmoles) prepared as in Step D above, and hydrazine hydrate (38 mL of a 1 M solution in ethanol) is heated for 5 hours at 90° C. After addition of water (30 mL) and concentrated hydrochloric acid (60 mL) heating is continued for one more hour at 90° C. After filtration, and evaporation to dryness, the residue is dissolved in water, and the remaining phthalhydrazide is elimated by filtration. Concentration under vacuum affords an oil which is used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH3:19])([CH3:18])[C:10](=[O:20])[NH:9]2)=[CH:4][CH:3]=1.[Cl:21][CH2:22][C:23](Cl)=[O:24].C(N(CC)CC)C>C(O)(=O)C>[Cl:21][CH2:22][C:23]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH3:18])([CH3:19])[C:10](=[O:20])[NH:9]2)=[CH:6][CH:7]=1)=[O:24]
Reactant: O=C(Cl)CCl
Reactant: CC1(C)C(=O)NC(c2ccc(N)cc2)c2ccccc21
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CC1(C)C(=O)NC(c2ccc(NC(=O)CCl)cc2)c2ccccc21

Procedure:
30.0 g. (0.1125 moles) of 1-(4'-aminophenyl)-1,4-dihydro-4,4-dimethyl-3(2H)-isoquinolinone are reacted in 280 ml. of glacial acetic acid with 14.7 g. (0.13 moles) of chloroacetyl chloride, in the presence of 13.5 g. (0.13 moles) of triethylamine. The reaction conditions are the same as described in Example 1. The crude product is recrystallized from ethanol to yield 25.15 g. of the title compound; m.p.: 218°-219°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:13]([C:14]([OH:16])=O)=[C:12]([CH3:17])[O:11][N:10]=1.[NH2:18][C:19]1[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[C:24]([Cl:33])=[CH:23][C:20]=1[C:21]#[N:22].C(O)(C(F)(F)F)=O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[NH2:18][C:19]1[CH:26]=[C:25]([N:27]2[CH2:28][CH2:29][N:30]([C:14]([C:13]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[N:10][O:11][C:12]=3[CH3:17])=[O:16])[CH2:31][CH2:32]2)[C:24]([Cl:33])=[CH:23][C:20]=1[C:21]#[N:22]
Reactant: N#Cc1cc(Cl)c(N2CCNCC2)cc1N
Reactant: COc1ccccc1-c1noc(C)c1C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1-c1noc(C)c1C(=O)N1CCN(c2cc(N)c(C#N)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
The reaction mixture of 3-(2-methoxyphenyl)-5-methylisoxazole-4-carboxylic acid (10.00 mg, 0.043 mmol), 2-amino-5-chloro-4-(piperazin-1-yl)benzonitrile, 2 TFA (16.6 mg, 0.036 mmol), EDC (9.59 mg, 0.050 mmol) and DMAP (8.73 mg, 0.071 mmol) in DCM (1 mL) was stirred at room temperature overnight. The product was purified by preparative HPLC (0.1% TFA MeOH/H2O) to give 11 mg (52% yield) of the title compound. 1H-NMR (CDCl3, 400 MHz): δ 7.59 (1H, dd, J1=7.5 Hz, J2=1.8 Hz), 7.52-7.46 (1H, m), 7.33 (1H, s), 7.13-6.97 (2H, m), 6.06 (1H, s), 3.84 (2H, s), 3.80 (3H, s), 3.25 (2H, s), 2.98 (2H, s), 2.57 (3H, s), 2.43 (2H, s).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[O:7][CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=1)(=[O:4])=[O:3].[C:16](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[CH3:16][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[C:6]1[O:7][CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=1
Reactant: CCOC(=O)c1coc(NS(C)(=O)=O)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CCOC(=O)c1coc(N(C)S(C)(=O)=O)n1
Reaction time: 3 h

Procedure:
To a 25 ml round bottom flask under N2 was added (101.8 mg, 0.4346 mmoles) ethyl 2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxylate, (180.2 mg, 1.3038 mmoles, 3.0 eq.) potassium carbonate, and (5 ml) acetonitrile. The mixture was then agitated at ambient temperature while (33.8 μl, 0.5429 mmoles, 1.25 eq.) iodomethane was added. The reaction was allowed to run at ambient temperature for 3 hours. An electrospray mass spec indicated mostly starting material. The N2 line was removed and an additional (40 μl, 0.6425 mmoles, 1.5 eq.) iodomethane were added. The reaction was left at ambient temperature overnight. The reaction was quenched with (5 ml) 1N HCl and was extracted with dichloromethane. The organic layer was washed with water and then evaporated to dryness. The resulting oil was purified by preparative HPLC, yielding (70 mg) of ethyl 2-[methyl(methylsulfonyl)amino]-1,3-oxazole-4-carboxylate.
Reaction SMILES: BrC1C=CC=C2C=1CC[NH:6]C2CC(OC)=O.S(=O)(=O)(O)O.[C:22]([N:25]1[CH2:34][CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][C:31]=2[Br:35])[CH:26]1[CH2:36][C:37]([O:39]C)=O)(=[O:24])[CH3:23].C([O-])(O)=O.[Na+]>O.CO>[Br:35][C:31]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:32]=1[CH2:33][CH2:34][N:25]1[C:22](=[O:24])[CH2:23][NH:6][C:37](=[O:39])[CH:36]=[C:26]12
Reactant: COC(=O)CC1c2cccc(Br)c2CCN1C(C)=O
Reactant: COC(=O)CC1NCCc2c(Br)cccc21
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1C=C2c3cccc(Br)c3CCN2C(=O)CN1
Temperature: 25 °C

Procedure:
methyl 2-(5-bromo-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate. MeOH (1280 mL) was cooled to −15° C. and conc. Sulfuric acid (147 mL, 2759 mmol) was added slowly (exotherm) under cooling. To this solution, methyl 2-(2-acetyl-5-bromo-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (90 g, 276 mmol) was added and the reaction mixture was stirred under reflux for 96 h. The reaction mixture was cooled to RT and slowly added to a solution of NaHCO3 (540 g) in water (1.35 L). The slightly basic aqueous solution was extracted with AcOEt (3×500 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (300 mL) and brine (300 mL). The organic layer was dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was dried under high vacuo to yield the title compound as yellow foam (76 g) which was used without further purification. UPLC-MS: MS 284.1/286.1 (M+H+); UPLC rt 0.50 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10]O)=[NH:9])=[N:6][CH:7]=1.[C:12]([C:18]([O:20][CH3:21])=[O:19])#[C:13][C:14](OC)=[O:15].C[OH:23]>[OH-].[Na+]>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:10]=[C:12]([C:18]([O:20][CH3:21])=[O:19])[C:13]([OH:23])=[C:14]([OH:15])[N:9]=2)=[N:6][CH:7]=1
Reactant: N=C(NO)c1ccc(N)cn1
Reactant: CO
Reactant: COC(=O)C#CC(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1nc(-c2ccc(N)cn2)nc(O)c1O
Temperature: 60 °C

Procedure:
To a stirred solution of compound of example 1 (0.30 g, 1.97 mmol) in methanol (10 mL) was added dimethyl acetylenedicarboxylate (0.34 g, 2.36 mmol) and the reaction mixture was heated at 60° C. for 4 hours. Methanol was removed under reduced pressure and xylene (20 mL) was added to the reaction mixture and heated at 140° C. for 12 hours. The reaction mixture was then concentrated, and residue obtained was dissolved in 5% aqueous NaOH (20 mL) and was washed with ethyl acetate (2×50 mL) to remove unreacted organic impurities. Aqueous layer was then acidified with dilute 10% acetic acid, extracted with ethyl acetate (3×50 mL), dried over anhydrous sodium sulfate and concentrated to obtain the title compound.
Reaction SMILES: [CH2:1]([C:4]1[S:5][C:6]([C:10]([OH:12])=O)=[C:7]([CH3:9])[N:8]=1)[CH2:2][CH3:3].CN(C)C=O.C(Cl)([Cl:20])=O>C1(C)C(C)=CC=CC=1>[CH2:1]([C:4]1[S:5][C:6]([C:10]([Cl:20])=[O:12])=[C:7]([CH3:9])[N:8]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc(C)c(C(=O)O)s1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1C
Solvent: CN(C)C=O
Product: CCCc1nc(C)c(C(=O)Cl)s1

Procedure:
In a 200-ml three-neck flask, 15.0 g (0.08 mole) of 2-propyl-4-methylthiazole-5-carboxylic acid were suspended in 100 ml of xylene, followed by the addition of 0.05 g of N,N-dimethylformamide. Under heating and reflux, phosgene was blown at a flow rate of 1.5 l/hr for 3 hours (0.20 mole). After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to obtain 16.2 g of 2-propyl-4 -methylthiazole-5-carboxylic acid chloride. Its purity and yield were 97.3% and 98.2%, respectively.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([N:19]5[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]5)=[CH:15][CH:14]=4)=[N:11][N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:7]=3[C:8]=2[CH:9]=1.CC1(C)C(C)(C)OB([C:42]2[CH:43]=[CH:44][C:45]([NH2:48])=[N:46][CH:47]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:25][N:22]1[CH2:23][CH2:24][N:19]([C:16]2[CH:17]=[CH:18][C:13]([C:12]3[C:6]4[CH2:5][C:4]5[S:3][C:2]([C:42]6[CH:43]=[CH:44][C:45]([NH2:48])=[N:46][CH:47]=6)=[CH:9][C:8]=5[C:7]=4[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:31])[CH3:33])[N:11]=3)=[CH:14][CH:15]=2)[CH2:20][CH2:21]1
Reactant: CN1CCN(c2ccc(-c3nn(COCC[Si](C)(C)C)c4c3Cc3sc(Br)cc3-4)cc2)CC1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN1CCN(c2ccc(-c3nn(COCC[Si](C)(C)C)c4c3Cc3sc(-c5ccc(N)nc5)cc3-4)cc2)CC1
Temperature: 100 °C
Yield: 75 %

Procedure:
A mixture of the corresponding 2-Bromo-6-[4-(4-methyl-piperazin-1-yl)-phenyl]-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (1.25 g, 2.3 mmol), 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (0.75 g, 3.4 mmol), Na2CO3 (2 M, 5.4 mL), and Pd(PPh3)2Cl2 (260 mg, 0.23 mmol) in toluene/ethanol (1:1, 15 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (50% EtOAc in hexane) to give the corresponding intermediate 5-[6-[4-(4-Methyl-piperazin-1-yl)-phenyl]-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-2-yl]-pyridin-2-ylamine as brown solid in 75% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7](C1C=CC=C(O)C=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1.[C:35](=[O:38])([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([O:5][C:6]([NH:7][CH:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:10]1[CH:11]=[C:35]([CH:13]=[CH:14][CH:9]=1)[O:38][CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)=[O:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)c1cccc(O)c1
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(COc2cccc(C(NC(=O)OC(C)(C)C)c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 135.7 %

Procedure:
A mixture of tert-butyl(3-hydroxyphenyl)(phenyl)methylcarbamate (3.20 g, 10.7 mmol), methyl 4-(bromomethyl)benzoate (2.70 g, 11.8 mmol), and potassium carbonate (2.20 g, 16.1 mmol) in acetonitrile (54 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated at reduced pressure, and the residue partitioned between ethyl acetate and water. The aqueous phase was extracted with further ethyl acetate, and the combined organic extracts combined, dried with anhydrous magnesium sulfate, filtered and the solvent evaporated at reduced pressure. The residue was re-crystallised from ethyl acetate and iso-hexane to afford the title compound (3.25 g, 68%).
Reaction SMILES: [CH:1]1([C@H:7]2[C:47](=[O:48])[N:46]3[CH2:49][C@@H:43]([CH2:44][C@H:45]3[C:50](=[O:67])[NH:51][C@:52]3([C:57](=[O:66])[NH:58][S:59]([C:62]4([CH3:65])[CH2:64][CH2:63]4)(=[O:61])=[O:60])[CH2:54][C@H:53]3[CH:55]=[CH2:56])[O:42][C:19]3=[N:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[C:27]([O:28][CH:29]4[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]4)=[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]3[CH2:68][C@H:11]3[O:10][C:9](=[O:69])[NH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:70][C:71]([F:76])([F:75])[C:72]([OH:74])=[O:73]>ClCCl>[F:70][C:71]([F:76])([F:75])[C:72]([O-:74])=[O:73].[CH:1]1([C@H:7]2[C:47](=[O:48])[N:46]3[CH2:49][C@@H:43]([CH2:44][C@H:45]3[C:50](=[O:67])[NH:51][C@:52]3([C:57](=[O:66])[NH:58][S:59]([C:62]4([CH3:65])[CH2:63][CH2:64]4)(=[O:61])=[O:60])[CH2:54][C@H:53]3[CH:55]=[CH2:56])[O:42][C:19]3=[N:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[C:27]([O:28][CH:29]4[CH2:30][CH2:31][NH2+:32][CH2:33][CH2:34]4)=[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]3[CH2:68][C@H:11]3[O:10][C:9](=[O:69])[NH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(F)(F)F
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCCC1)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1OC1CCN(C(=O)OC(C)(C)C)CC1)O2)C(=O)NS(=O)(=O)C1(C)CC1
Solvent: ClCCl
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCCC1)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1OC1CC[NH2+]CC1)O2)C(=O)NS(=O)(=O)C1(C)CC1
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Example 235 (100 mg, 0.103 mmol) in dichloromethane (5 ml) was added trifluoroacetic acid (1.025 ml, 0.103 mmol). The reaction was stirred at room temperature for 2 hours at which stage LCMS indicated complete hydrolysis of the NBoc group. The volatiles were evaporated under reduced pressure and the residue was diluted with DCM and azeotroped twice with toluene. The resulting residue (˜101 mg) was dried under vacuum and used for the next step without purification.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][NH:9][C:10]1[N:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:19]3[CH:24]=[C:23]([CH2:25][N:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[S:22][C:20]=3[N:21]=2)=[CH:12][N:11]=1.[C:38](O)(=[O:42])[C@H:39]([CH3:41])[OH:40]>>[OH:40][C@@H:39]([CH3:41])[C:38]([N:29]1[CH2:30][CH2:31][N:26]([CH2:25][C:23]2[S:22][C:20]3[N:21]=[C:16]([C:13]4[CH:14]=[N:15][C:10]([NH:9][CH3:8])=[N:11][CH:12]=4)[N:17]=[C:18]([N:32]4[CH2:33][CH2:34][O:35][CH2:36][CH2:37]4)[C:19]=3[CH:24]=2)[CH2:27][CH2:28]1)=[O:42]
Reactant: CNc1ncc(-c2nc(N3CCOCC3)c3cc(CN4CCNCC4)sc3n2)cn1
Reactant: C[C@H](O)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CNc1ncc(-c2nc(N3CCOCC3)c3cc(CN4CCN(C(=O)[C@H](C)O)CC4)sc3n2)cn1

Procedure:
The crude TFA salt of N-methyl-5-(4-morpholino-6-((piperazin-1-yl)methyl)thieno[2,3-d]pyrimidin-2-yl)pyrimidin-2-amine was reacted with L-lactic acid via General Procedure B to give 28.3 mg of 388 after reverse phase HPLC purification. MS (Q1) 499.3 (M)+
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:14][CH2:15][CH:16]2[CH2:18][O:17]2)=[CH:5][C:6]2[O:11][C:10](=[O:12])[CH:9]=[CH:8][C:7]=2[CH:13]=1.[C:19]1([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>C(O)C.C(O)(C)C>[OH:17][CH:16]([CH2:18][N:28]1[CH2:29][CH2:30][CH:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:26][CH2:27]1)[CH2:15][O:14][C:4]1[C:3]([O:2][CH3:1])=[CH:13][C:7]2[CH:8]=[CH:9][C:10](=[O:12])[O:11][C:6]=2[CH:5]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: COc1cc2ccc(=O)oc2cc1OCC1CO1
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Product: COc1cc2ccc(=O)oc2cc1OCC(O)CN1CCC(c2ccccc2)CC1
Yield: 69 %

Procedure:
Method C (27 h at 45° C.); starting materials; 6-methoxy-7-(oxiranylmethoxy)-2H-1-benzopyran-2-one (example 86) and 4-phenylpiperidine; yield 69%; fusion point 114°-115° C. (from isopropanol and ethanol). Hydrochloride: method G; yield 82%; fusion point 202°-205° C. (from isopropanol and ethanol).