Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[C:11]2[CH:12]=[C:13]([C:16]([OH:18])=O)[CH:14]=[CH:15][C:10]=2[O:9][CH:8]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[N-:32]=[N+:33]=[N-:34].[Na+]>CC(C)=O.O>[C:1]([NH:4][CH2:5][CH2:6][C:7]1[C:11]2[CH:12]=[C:13]([C:16]([N:32]=[N+:33]=[N-:34])=[O:18])[CH:14]=[CH:15][C:10]=2[O:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)NCCc1coc2ccc(C(=O)O)cc12
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(=O)NCCc1coc2ccc(C(=O)N=[N+]=[N-])cc12
Reaction time: 0.25 h

Procedure:
The acid (1 mmol) obtained in Step A is dissolved in acetone. The temperature of the reaction mixture is lowered with the aid of an ice bath, and triethylamine (1.5 mmol) and then ethyl chloroformate (1.5 mmol) are added. After stirring for 15 minutes, sodium azide (1.5 mmol), previously dissolved in water (1 ml of water per 400 mg of sodium azide), is added and stirring is again carried out for 10 minutes. The mixture is extracted with ethyl acetate, and the organic phase is then washed with water, dried over magnesium sulphate and evaporated to dryness. The azide obtained is used, without additional purification, in the following Step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6](B(O)O)[CH:7]=1.Br[C:14]1[CH:19]=[CH:18][C:17](/[C:20](/[CH3:27])=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][CH:15]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([C:14]2[CH:19]=[CH:18][C:17](/[C:20](/[CH3:27])=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][CH:15]=2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1B(O)O
Reactant: CCOC(=O)/C=C(\C)c1ccc(Br)cc1
Product: CCOC(=O)/C=C(\C)c1ccc(-c2cc(Cl)ccc2OC)cc1
Yield: 90.6 %

Procedure:
(E)-Ethyl 3-(5′-chloro-2′-methoxy-biphenyl-4-yl)-but-2-enoate (1.07 g, 91% yield) was prepared from 5-chloro-2-methoxyphenylboronic acid (1.0 g, 5.36 mmol) and (E)-ethyl 3-(4-bromophenyl)-but-2-enoate (0.96 g, 3.57 mmol) by a procedure analogous to that described in example 52a.
Reaction SMILES: [C:1]([OH:8])(=O)[CH2:2][CH2:3][CH:4]=[CH:5][CH3:6].C(N(CC)CC)C.[C:16](Cl)(=O)[C:17](C)(C)[CH3:18].[C:23]1([CH2:29][C@@H:30]2[O:34][C-:33]=[N:32][C:31]2=[O:35])C=CC=[CH:25][CH:24]=1.C1(C(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([Li])CCC>C1COCC1>[C:31]([N:32]1[C@@H:2]([CH2:3][C:4]2[CH:5]=[CH:6][CH:18]=[CH:17][CH:16]=2)[CH2:1][O:8][C:33]1=[O:34])(=[O:35])[CH:30]=[CH:29][CH2:23][CH2:24][CH3:25]
Reactant: O=C1N=[C-]O[C@H]1Cc1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC=CCCC(=O)O
Agent: [Li]CCCC
Solvent: CCN(CC)CC
Solvent: c1ccc(C(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC=CC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a mechanically stirred solution of 9.50 g (83.2 mmol, 1.10 equiv.) of 4-hexenoic acid (commericially available from Lancaster, Catalog #252-427-6) and 13.9 mL (10.1 g, 99.7 mmol, 1.33 equiv.) of triethylamine in 150 mL of dry THF, cooled to −78° C. under dry N2, was added 10.71 mL (10.49 g, 87.0 mmol, 1.15 equiv.) of pivaloyl chloride (Aldrich). The mixture was warmed to 0° C. for 60 min, and then recooled to −78° C. A solution of 13.4 g (75.6 mmol, 1.00 equiv) of (S)-(−)-(phenylmethyl)-2-oxazolidone (Aldrich) and 22 mg of triphenylmethane (indicator) in 150 mL of dry THF, stirred at −30° C. to 45° C. under N2, was treated dropwise with n-butyllithium (˜2.5 M in hexanes) (Aldrich) until an orange color persisted (˜30 mL required). The resulting solution was cooled to −78° C. and then added, via rapid cannulation, to the above stirred mixture containing the mixed anhydride. The residual lithiated oxazolidone was rinsed in with two 10-mL portions of dry THF and the resulting mixture was stirred at −78° C. for 1.5 h, and then at 0° C. for 1 h. The mixture was partitioned between CH2Cl2 and pH 7 phosphate buffer. The CH2Cl2 phase was washed with saturated aqueous NaHCO3 followed by half-saturated aqueous NaCl, dried (MgSO4), and evaporated in vacuo. The residual cream-colored solid (22.4 g) was chromatographed (Waters Prep 2000, 5.0 cm×25 cm 10μ Kromasil KR60-10SIL-5025 column) in two batches eluting with 85:15 hexanes/EtOAc. The chromatographed product was recrystallized from hexane to yield 14.34 g (first crop, 69%) of the title compound as fine white needles. 1H NMR (300 MHz, CDCl3) a 7.37-7.20 (m, 5H, —C6H5), 5.60-5.43(m, 2H, CH═CHCH3), 4.71-4.63(m, 1H, NCH(Ph) CH20), 4.23-4.14(m, 2H, NCH(Ph)CH2O), 3.295(dd, J=13.3, 3.3 Hz, 1H, CHHC6H5), 3.11-2.90 (m, 2H, CH2C═O), 2.758 (dd, J=13.3, 9.6 Hz, 1H, CHHC6H5), 2.42-2.34 (m, 2H, CH═CHCH2), 1.67-1.65 (m, 2H, CH═CHCH3).
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]=[C:4]([OH:7])[CH:3]=1.[CH:8]#[C:9][C:10](=[O:12])[CH3:11].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:12]=[C:10]([CH:9]=[CH:8][N:5]1[C:4](=[O:7])[CH:3]=[C:2]([Cl:1])[S:6]1)[CH3:11]
Reactant: C#CC(C)=O
Reactant: Oc1cc(Cl)sn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)C=Cn1sc(Cl)cc1=O

Procedure:
A stirred solution of 5-chloro-3-hydroxyisothiazole (1.5 g, 0.011 mole), 1-butyn-3-one (3.5 g, 0.05 mole) and p-toluenesulfonic acid (0.02 g) in 25 ml of toluene was heated at 80° C. for 24 hours. Upon cooling, the dark brown reaction mixture was concentrated and the residual oil was column chromatographed on silica gel, using diethyl ether/hexane as eluant. Compound 11 was obtained as a yellowish solid; 1.8 g; mp 137°-139° C.; IR (KBr) 1675, 1620 cm-1 ; NMR (CDCl3) δ8.2 (d, 1H, J=13.9 Hz); 6.35 (s, 1H); 5.85 (d, 1H, J=13.9 Hz); 2.35 (s, 3H).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH:13]([O:16][C:17]1[CH:18]=[C:19]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[C:24]2[CH3:48])[CH:20]=[CH:21][CH:22]=1)([CH3:15])[CH3:14]>O.C(OCC)(=O)C>[CH:13]([O:16][C:17]1[CH:18]=[C:19]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:3][C:4](=[O:7])[O:5][N:44]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[C:24]2[CH3:48])[CH:20]=[CH:21][CH:22]=1)([CH3:15])[CH3:14]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1nc(C)n(-c2cccc(OC(C)C)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2cccc(OC(C)C)c2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
A mixture of hydroxylammonium chloride (1.81 g), sodium hydrogen carbonate (2.62 g) and dimethyl sulfoxide (13 mL) was stirred at 40° C. for 30 min, 4′-{[1-(3-isopropoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.24 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (13 mL). N,N′-carbonyldiimidazole (0.51 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.47 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.96 g, 68%).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:32])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=[C:16]4[C:28]([O:30]C)=[O:29])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[OH-].[Na+].C(O)(=O)C.O>CO>[CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:32])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=[C:16]4[C:28]([OH:30])=[O:29])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: COC(=O)c1cn(CC2CC2)c(=O)c2ccc(-c3cc(C(=O)NC4CC4)ccc3C)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C(=O)O)c2c1
Reaction time: 0.5 h

Procedure:
To a solution of the product of step iv) (1.5 g) in methanol (20 mL) at reflux was added sodium hydroxide (1N, 5.23 mL) and the solution stirred at this temperature for 30 min. The reaction mixture was treated with acetic acid (0.34 mL) and water and stirred overnight at room temperature. The solid was filtered and washed with methanol:water (1:1) then water. The solid was dried under vacuum at 60° C. to yield the sub-title compound (1.25 g).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][NH:10][C:9]=2[C:8](=[O:14])[N:7]2[CH:15]=[N:16][N:17]=[C:6]12)[CH2:2][CH2:3][CH3:4].[Br:18]N1C(=O)CCC1=O>C1COCC1>[Br:18][C:11]1[NH:10][C:9]2[C:8](=[O:14])[N:7]3[CH:15]=[N:16][N:17]=[C:6]3[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:13]=2[N:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCn1c2nc[nH]c2c(=O)n2cnnc12
Solvent: C1CCOC1
Product: CCCCn1c2nc(Br)[nH]c2c(=O)n2cnnc12
Temperature: 70 °C
Yield: 5.5 %

Procedure:
To a mixture of 9-butyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (65 mg, 0.28 mmol) in THF (2 mL) was added N-bromosuccinimide (49.8 mg, 0.280 mmol). The mixture was heated in a microwave reactor at 70° C. for 10 minutes. The mixture was purified with prep LCMS to give the desired product (4.8 mg, 6%). LCMS calculated for C10H12BrN6O (M+H): 311.0. Found: 311.0, 313.0.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([CH3:10])=[CH2:9])=[CH:6][C:5]([C:11]#[N:12])=[CH:4][C:3]=1[NH:13][C:14]1[N:19]=[C:18]([N:20]([CH:30]2[CH2:32][CH2:31]2)CC2C=CC(OC)=CC=2)[C:17]2=[N:33][CH:34]=[C:35]([C:36]#[N:37])[N:16]2[N:15]=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]([CH3:10])=[CH2:9])=[CH:6][C:5]([C:11]#[N:12])=[CH:4][C:3]=1[NH:13][C:14]1[N:19]=[C:18]([NH:20][CH:30]2[CH2:32][CH2:31]2)[C:17]2=[N:33][CH:34]=[C:35]([C:36]#[N:37])[N:16]2[N:15]=1
Reactant: C=C(C)c1cc(C#N)cc(Nc2nc(N(Cc3ccc(OC)cc3)C3CC3)c3ncc(C#N)n3n2)c1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: C=C(C)c1cc(C#N)cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
A solution of 2-((2-chloro-5-cyano-3-(prop-1-en-2-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (748 mg, 1.46 mmol) and anisole (4.00 mL, 36.6 mmol) in DCM (23 mL) and TFA (23 mL, 290 mmol) was left stirring at room temperature overnight. The solvents were removed and the yellow solid was suspended in DCM. This was washed with saturated aq. NaHCO3 solution and dried with sodium sulfate. The solvent was removed and the residue was suspended in a mixture of EtOAc: hexane=1:1. This was filtered to give 2-((2-chloro-5-cyano-3-(prop-1-en-2-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (365 mg) as a light yellow solid.
Reaction SMILES: [CH2:1]([C@H:8]([NH:13][C:14](=[O:17])[O:15][CH3:16])[C:9](=[O:12])[CH2:10][Cl:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-]>C(O)(C)C>[CH2:1]([C@H:8]([NH:13][C:14](=[O:17])[O:15][CH3:16])[C@H:9]([OH:12])[CH2:10][Cl:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)N[C@@H](Cc1ccccc1)C(=O)CCl
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CC(C)O
Product: COC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CCl
Temperature: 50 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
25.57 g of methyl (S)-(1-benzyl-3-chloro-2-oxo-propyl)carbamate were added portionwise at 22° C. to a suspension of 21.44 g of aluminum isopropoxide in 260 ml of isopropanol. The suspension was stirred at 50° C./400 mbar for 2 hours, hydrolyzed at 0° C. with 100 ml of 3N hydrochloric acid, subsequently concentrated to a volume of 125 ml, diluted with 125 ml of water, cooled to 0° C. and filtered. The residue was washed with water/isopropanol (4:1) and dried, yielding 23.01 g (89%) of isomerically-pure methyl (1S,2S)-(1-benzyl-3-chloro-2-hydroxypropyl)-carbamate, m.p. 162°-163.5° C. IR (KBr): 3323s, br. (NH, OH), 1689 (C=O), 1546s (amide II).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N-:15]=[N+]=[N-].[Na+].OS(O)(=O)=O.N#N>CC(O)=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][CH2:9][CH2:10][C:11](=[O:14])[NH:15][C:12]=2[CH:13]=1)([O-:3])=[O:2]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Agent: N#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1CCCc2ccc([N+](=O)[O-])cc2N1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 30.4 %

Procedure:
7.87 g of 7-nitro-1-tetralone from step A were placed in 55 ml of AcOH. Next, 7.0 g of NaN3 were added and the resulting mixture was heated to 60° C. Then, 10.3 ml of conc. H2SO4 were slowly added dropwise. N2 evolution took place and the temperature rose to 90° C. The reaction mixture was held at this temperature for 1/2 hour, then cooled and poured cautiously into an ice/28% NaOH solution. The mixture was extracted thoroughly with AcOEt, washed with a small amount of water, dried and evaporated. Flash chromatography on SiO2 (hexane/ethyl acetate (1/1→pure ethyl acetate)) yielded 2.58 g of 2,3,4,5-tetrahydro-8-nitro-2-oxo-1H-1-benzazepine as brown crystals of m.p. 224°-226° C. besides regioisomeric lactam and unreacted starting material.
Reaction SMILES: Cl[CH2:2][CH2:3][C@@H:4]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[I:18])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:19][NH2:20]>C(O)C>[CH3:19][NH:20][CH2:2][CH2:3][C@@H:4]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[I:18])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CN
Reactant: ClCC[C@@H](Oc1ccccc1I)c1ccccc1
Solvent: CCO
Product: CNCC[C@@H](Oc1ccccc1I)c1ccccc1
Yield: 97.4 %

Procedure:
Compound 1-A (2.68 g, 7.2 mmole) was dissolved in an aqueous solution of ethanol (80 ml) and methylamine (160 ml), and heated to reflux for 30 h. After cooling, the solution was extracted with chloroform (100 ml, twice), and an organic layer was decanted. The organic layer was dried over anhydrous sodium sulfate, and dried by evaporation under vacuum, to obtain the product as oil (2.75 g, 97.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([NH:12][C:13]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=4)[N:16]=[CH:15][N:14]=3)=[CH:7][CH:8]=2)[N:3]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[ClH:1].[N:29]1([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][C:6]([NH:12][C:13]4[CH:18]=[C:17]([C:19]5[CH:20]=[CH:21][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:24]=5)[N:16]=[CH:15][N:14]=4)=[CH:7][CH:8]=3)[N:3]=2)[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1
Reactant: C1COCCN1
Reactant: FC(F)(F)c1ccc(-c2cc(Nc3ccc4ccc(Cl)nc4c3)ncn2)cc1
Product: Cl
Product: FC(F)(F)c1ccc(-c2cc(Nc3ccc4ccc(N5CCOCC5)nc4c3)ncn2)cc1
Temperature: 200 °C

Procedure:
A solution of (2-chloroquinolin-7-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine, Example 13(b), (150 mg, 0.37 mmol) in morpholine (0.65 mL, 7.4 mmol, Aldrich) was stirred and heated in a microwave at 200° C. for 10 min. The resulting bright yellow solid was precipitated from EtOAc and CH2Cl2, then dissolved in EtOAc (100 mL) and treated with 1 N HCl (50 mL). The resulting bright yellow precipitate was collected by filtration, washed with water (20 mL), EtOAc (20 mL) and air-dried to provide the title product as a yellow amorphous solid. MS (ESI, pos. ion) m/z: 452 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[N+:28]([C:31]1[C:32]([NH2:46])=[N:33][CH:34]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:36]=1)([O-:30])=[O:29]>>[CH3:21][S:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:8][C:6]3[N:7]=[C:2]([C:35]4[CH:36]=[C:31]([N+:28]([O-:30])=[O:29])[C:32]([NH2:46])=[N:33][CH:34]=4)[N:3]=[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:5]=3[CH:10]=2)[CH2:13][CH2:14]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reactant: CC1(C)OB(c2cnc(N)c([N+](=O)[O-])c2)OC1(C)C
Product: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(-c4cnc(N)c([N+](=O)[O-])c4)nc3s2)CC1
Yield: 16.8 %

Procedure:
4-(2-Chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[2,3-d]pyrimidin-4-yl)morpholine (100 mg, 0.2 mmol) was reacted with 3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (0.24 g, 0.9 mmol) according to General Procedure Suzuki to afford 360 (18 mg) following reverse phase HPLC purification. MS (Q1) 535 (M)+
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[NH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=1[Cl:20].O>C1COCC1>[Cl:20][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:10]=1[NH:9][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[C:14]([O:16][CH3:17])=[O:15]
Reactant: O=C(Cl)CCCCCl
Reactant: COC(=O)c1ccc(N)c(Cl)c1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)CCCCCl)c(Cl)c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A solution of 696 μl (0.84 g, 5.39 mmol) 5-chloro-pentanoylchloride in 10 ml THF is slowly added dropwise to 1.00 g (5.39 mmol) methyl 4-amino-3-chloro-benzoate in 20 ml THF with 1 ml TEA with stirring in the ice bath. After stirring for 16 hours at ambient temperature, for 3 hours at 50° C. and for 3 hours at reflux temperature the mixture is poured into water and extracted with ethyl acetate. After the organic phases have been dried over sodium sulphate the mixture is evaporated down i. vac. and the residue remaining is purified by chromatography on silica gel (eluant: petroleum ether/ethyl acetate 85:15).
Reaction SMILES: C(CC#N)(=O)C1C=CC=CC=1.[NH2:12][C:13]1[S:21][C:16]2[CH2:17][NH:18][CH2:19][CH2:20][C:15]=2[C:14]=1[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1.[CH2:31]([O:38][C:39](Cl)=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[NH2:12][C:13]1[S:21][C:16]2[CH2:17][N:18]([C:39]([O:38][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:40])[CH2:19][CH2:20][C:15]=2[C:14]=1[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1
Reactant: Nc1sc2c(c1C(=O)c1ccc(F)cc1)CCNC2
Reactant: O=C(Cl)OCc1ccccc1
Agent: N#CCC(=O)c1ccccc1
Product: Nc1sc2c(c1C(=O)c1ccc(F)cc1)CCN(C(=O)OCc1ccccc1)C2

Procedure:
Using the procedures in Examples 7 and 8, substituting p-fluorobenzoyl acetonitrile for benzoyl acetonitrile, 2-amino-3-(4-fluorobenzoyl)-4,5,6,7-tetrahydrothieno(2,3 -c)pyridine was prepared. This compound was reacted with benzyloxycarbonyl chloride to yield the title compound as a solid (mp 90-92° C). 1H NMR (CDCl3) 1.96 (m, 2H); 3.45 (m, 2H); 4.45 (s, 2H); 5.15 (s, 2H); 6.71 (bs, 2H); 7.05-7.52 (m, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:13]2[CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:35]=[CH:34][C:33](OS(C(F)(F)F)(=O)=O)=[C:32]2[C:27]=1[CH:28]1[CH2:44][CH:31]2[CH2:30][CH2:29]1.[H][H]>O1CCCC1.CO.[OH-].[Pd+2].[OH-]>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:13]2[CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH:28]1[CH2:44][CH:31]2[CH2:30][CH2:29]1
Reactant: [H][H]
Reactant: CCOC(=O)c1[nH]c2c(-c3ccccc3C)cccc2c1CCCOc1ccc(OS(=O)(=O)C(F)(F)F)c2c1C1CCC2C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]c2c(-c3ccccc3C)cccc2c1CCCOc1cccc2c1C1CCC2C1

Procedure:
To a solution of EXAMPLE 546D (80 mg) in tetrahydrofuran and methanol (40 ml, 1:1) was added 10% palladium hydroxide (40 mg). The mixture was shaken under 30 psi of hydrogen for 4 hours. The catalyst was filtered off, the filtrate was concentrated and the residue was hydrolyzed with LiOH/tetrahydrofuran/methanol/H2O. The product was purified by reverse phase HPLC.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:19]=[CH:18][NH:17][N:16]=3)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1.C(OCC)(=O)C>[N+:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:19]=[CH:18][N:17]([C:22](=[O:24])[CH3:23])[N:16]=3)=[CH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(-c3cc[nH]n3)cc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)n1ccc(-c2ccc(Oc3ccc([N+](=O)[O-])cc3)cc2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.9 %

Procedure:
A solution of 3-[4-(4-nitrophenoxy)phenyl]-1H-pyrazole (0.16 g, 0.57 mmol) in pyridine (12 mL) was treated with neat acetic anhydride (1.0 mL, 1.0 mmol) and allowed to stir at room temperature for 16 hours. The reaction was then diluted with ethyl acetate, washed several times with an aqueous 2N HCl solution, dried over sodium sulfate, and evaporated under reduced pressure. The crude product was purified by column chromatography, affording 116 mg (63%) of the title compound. TLC Rf 0.78 (70:30 hexane/ethyl acetate). 1H NMR (CDCl3): δ8.31 (d, J=3.0 Hz, 1H), 8.22 (d, J=9.3 Hz, 2H), 7.94 (d, J=8.7 Hz, 2H), 7.17 (d, J=9.0 Hz, 2H), 7.07 (d, J=9.3 Hz, 2H), 6.77 (d, J=3.0 Hz, 1H), 2.78 (s, 3H).
Reaction SMILES: C([N:3]([CH2:6][CH3:7])[CH2:4]C)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[C:20]([O:23][CH2:24][CH3:25])(=[O:22])[CH3:21].[CH3:26][CH2:27][CH2:28][CH2:29]CC>C(Cl)Cl>[CH2:24]([O:23][C:20](=[O:22])[CH2:21][C@H:27]1[CH2:26][CH2:7][C@H:6]([N+:3]#[C-:4])[CH2:29][CH2:28]1)[CH3:25]
Reactant: CCOC(C)=O
Reactant: CCCCCC
Reactant: CCN(CC)CC
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: [C-]#[N+][C@H]1CC[C@H](CC(=O)OCC)CC1
Temperature: 2.5 °C

Procedure:
5 g (22.8 mmol) of trans-(4-Amino-cyclohexyl)-acetic acid ethyl ester hydrochloride were suspended in a mixture of 40 ml (731 mmol) ethylformiate and 10 ml DMF. 5.6 ml (25 mmol) of DIPEA were added and the mixture was heated to 80° C. for 72 h. The solvent mixture was evaporated to dryness and the crude product extracted from ethyl acetate/water. 4.2 g of a yellow solid were obtained which were dissolved in 40 ml DCM. 6.6 ml (47 mmol) triethylamine were added and the mixture was cooled to 0-5° C. 2.3 ml (7.9 mmol) of triphosgene were dissolved in 10 ml DCM and added dropwise. The reaction mixture was warmed to room temperature and the product was isolated directly via silica gel chromatography using ethyl acetate/hexane as an eluant. The intermediate was used without further characterization.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][C:22]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:26][CH2:25][CH2:24][O:23]1>>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][N:17]([CH2:21][C:22]3([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[O:23][CH2:24][CH2:25][O:26]3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Reactant: BrCC1(c2ccccc2)OCCO1
Product: c1ccc(Oc2ccc(C3CCN(CC4(c5ccccc5)OCCO4)CC3)cc2)cc1

Procedure:
The same procedure was followed as in Example 11 using the compound (9) synthesized in Example 2 and 2-bromomethyl-2-phenyl-1,3-dioxolane to produce the above.