Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][O:3]1)=O.[C:11]1([CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCCCCC.C(OCC)(=O)C>[C:11]1([CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:1][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:3])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1OCc2ccccc21
Reactant: NCCCCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1c2ccccc2CN1CCCCc1ccccc1
Temperature: 150 °C
Reaction time: 16 h
Yield: 10.4 %

Procedure:
A mixture of phthalide (0.268 g, 2 mmol) and 4-phenyl-butylamine (0.316 mL, 2 mmol) was stirred at 150° C. for 16 h. Workup and silica gel column chromatography (2:1 hexane-ethyl acetate) afforded 2-(4-phenyl-butyl)-2,3-dihydro-isoindol-1-one (0.055 g, 11%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.70 (m, 4H), 2.71 (t, 2H), 3.66 (t, 2H), 4.31 (s, 2H), 7.14-7.56 (m, 8H), 7.82 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9](O)([CH3:11])[CH3:10].S(=O)(=O)(O)O>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]([CH3:11])=[CH2:10]
Reactant: CC(C)(O)c1c(F)cccc1Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: C=C(C)c1c(F)cccc1Cl
Yield: 67.5 %

Procedure:
A mixture of 2-(2-chloro-6-fluorophenyl)propan-2-ol (19.0 g), concentrated sulphuric acid and water was heated at reflux for 2 hours. It was cooled and extracted with ether, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography eluted with hexane to give 2-(2-chloro-6-fluorophenyl)-propene (11.6 g) as a clear oil, NMR (CDCl3) 1.95(s,3H) 4.95(s,1H), 5.85(s,1H), 6.85-7.0(m,1H), 7.05-7.2(m,2H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:16]=[CH:15][C:14]([C:17]4[S:18][C:19]([CH3:25])=[C:20]([C:22]([OH:24])=[O:23])[N:21]=4)=[C:13]([NH:26][CH:27]([CH3:29])[CH3:28])[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.CN.CN(C(ON1N=N[C:42]2C=CC=N[C:41]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:16]=[CH:15][C:14]([C:17]4[S:18][C:19]([CH3:25])=[C:20]([C:22]([O:24][CH2:41][CH3:42])=[O:23])[N:21]=4)=[C:13]([NH:26][CH:27]([CH3:29])[CH3:28])[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Cc1sc(-c2cnc(Nc3ccc4ncsc4c3)cc2NC(C)C)nc1C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(-c2cnc(Nc3ccc4ncsc4c3)cc2NC(C)C)sc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methylthiazole-4-carboxylic acid (25b) was dissolved in DMF (10 mL), to it methanamine (1 equiv.) was added followed by the addition of HATU (1.5 equiv.) and DIPEA (4 equiv.) and stirred for 3 h at room temperature. The reaction mixture was concentrated to remove DMF under reduced pressure. The crude material obtained was purified by flash column chromatography using silica gel and MeOH:CHCl3 as eluent. The material obtained was triturated with diethyl ether and hexane to afford ethyl 2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methylthiazole-4-carboxylate. 1H NMR: 400 MHz, DMSO-d6: δ 1.32 (d, J=6.40 Hz, 6H), 2.73 (s, 3H), 2.81 (d, J=4.40 Hz, 3H), 3.64-3.69 (m, 1H), 6.13 (s, 1H), 7.58 (dd, J=2.00, 8.80 Hz, 1H), 7.95 (d, J=8.80 Hz, 1H), 8.13 (d, J=4.80 Hz, 1H), 8.20 (d, J=7.20 Hz, 1H), 8.37 (s, 1H), 8.71 (d, J=2.00 Hz, 1H), 9.15 (s, 1H), 9.33 (s, 1H). LC/MS: ZORBAX SB C18, 4.6×50 mm, 5 μm; Solvent A=10% MeOH: 90% H2O: 0.1% TFA; Solvent B=90% MeOH: 10% H2O: 0.1% TFA; gradient 0-100% B over 2 min (3 min run time); retention time: 1.606 min; LCMS (ES-API), m/z 439.0 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 6.323 min; Purity: 96.3%.
Reaction SMILES: [I-].[K+].C[N:4]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][N:6]=[C:5]1[S:12]([CH3:15])(=[O:14])=[O:13].O.[CH3:17]N(C)C=O>>[CH3:17][N:6]1[CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[N:4]=[C:5]1[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: CN(C)C=O
Reactant: Cn1c([N+](=O)[O-])cnc1S(C)(=O)=O
Agent: [I-]
Agent: [K+]
Solvent: O
Product: Cn1cc([N+](=O)[O-])nc1S(C)(=O)=O
Temperature: 160 °C

Procedure:
Potassium iodide (4.8 g) and 1-methyl-2-methylsulfonyl-5-nitroimidazole (5.0 g) were combined in N,N-dimethylformamide (30 ml) and the reaction mixture heated to 160° C. for 2 hours. Upon cooling, the reaction mixture was added to 150 ml of a water and ice mixture. The product precipitated and was filtered and dried affording 4.4 g of 1-methyl-2-methylsulfonyl-4-nitroimidazole.
Reaction SMILES: C(Cl)Cl.CCCCCCCCCCCCCCC[C:19]1[C:24](=[O:25])[N:23]([CH3:26])[C:21](=[O:22])[C:20]=1[C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]([CH3:36])[CH:28]=1.[C:37](Cl)(=[O:44])C1C=CC=CC=1.[OH-].[Na+]>O>[CH3:36][N:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27]([C:20]2[C:21](=[O:22])[N:23]([CH3:26])[C:24](=[O:25])[C:19]=2[O:44][CH3:37])=[CH:28]1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCCCCCCCCCCCCC1=C(c2cn(C)c3ccccc23)C(=O)N(C)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COC1=C(c2cn(C)c3ccccc23)C(=O)N(C)C1=O
Reaction time: 4 h
Yield: 15.5 %

Procedure:
Into a methylene chloride (500 ml)/a triethylamine (11 g, 1.1 mol) was dissolved IM-7 (124.6 g, 1 mol). Benzoyl chloride (140.6 g, 1 mol) was added dropwise at room temperature. After the mixture was stirred for four hours, water (100 ml) and an aqueous 5% NaOH solution (50 ml) were added, then, the mixture was separated. After a methylene chloride layer was dried with magnesium sulfate, it was concentrated, then, distillated under a reduced pressure (150 to 160° C., 6 mmHg) to obtain 42 g of IM-8.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][C:9]([CH2:10][NH2:11])=[C:4]2[CH:3]=[CH:2]1.Cl[C:13]1[N:18]=[C:17]([NH:19][C:20]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[NH:22][N:21]=2)[CH:16]=[CH:15][N:14]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][C:9]([CH2:10][NH:11][C:13]3[N:18]=[C:17]([NH:19][C:20]4[CH:24]=[C:23]([CH:25]5[CH2:27][CH2:26]5)[NH:22][N:21]=4)[CH:16]=[CH:15][N:14]=3)=[C:4]2[CH:3]=[CH:2]1
Reactant: NCc1cncc2[nH]ccc12
Reactant: Clc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: c1cc(Nc2cc(C3CC3)[nH]n2)nc(NCc2cncc3[nH]ccc23)n1
Temperature: 120 °C
Reaction time: 18 h
Yield: 11.1 %

Procedure:
A mixture of (1H-pyrrolo[2,3-c]pyridin-4-yl)methanamine (236 mg, 1.61 mmol), 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (344 mg, 1.46 mmol) and DIPEA (565 mg, 4.38 mmol) in IPA (2 mL) was stirred in a sealed tube at 120° C. for 18 h. The reaction mixture was cooled to RT and concentrated in vacuo. The crude residue was purification by preparative HPLC to afford 56 mg (11.1%) of the title compound as white solid: 1H NMR (500 MHz, CD3OD) δ 8.64 (s, 1H), 8.06 (s, 1H), 7.85 (s, 1H), 7.59 (d, J=3.0, 1H), 6.72 (d, J=3.0, 1H), 6.17-5.96 (m, 2H), 4.92 (s, 2H), 1.75 (s, 1H), 0.85 (d, J=4.5, 2H), 0.51 (s, 2H); MS (ESI) m/z: 347.2 [M+1]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[OH:18]O>C(O)(=O)C>[CH3:1][S:2]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)=[O:18]
Reactant: OO
Reactant: CSc1ccc(Oc2ccc(C#N)cc2)cc1
Solvent: CC(=O)O
Product: CS(=O)c1ccc(Oc2ccc(C#N)cc2)cc1
Temperature: 50 °C
Yield: 95.6 %

Procedure:
To a solution of 4.6 g (0.0191 mole) of 4-(4-(methylthio)phenoxy)benzonitrile dissolved in 50 ml of glacial acetic acid was added dropwise 2.38 g (0.0210 mole) of 30% aqueous hydrogen peroxide. The mixture was heated at 50° C. for 1 hr and most of the solvent removed in vacuo. The crude product was dissolved in CH2Cl2 and washed with 2N aqueous NaOH and water. The organic layer was dried (Na2SO4) and solvent removed in vacuo leaving 4.7 g (95.9% yield) of 4-(4-(methylsulfinyl)phenoxy)benzonitrile as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])/[C:7](/[C:10]1[N:11]=[C:12]([NH2:15])[S:13][CH:14]=1)=[N:8]\[OH:9])([CH3:4])([CH3:3])[CH3:2].Br[CH2:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20].C(N(C(C)C)C(C)C)C.[I-].[Na+]>C(#N)C>[C:1]([O:5][C:6](=[O:16])[C:7]([C:10]1[N:11]=[C:12]([NH2:15])[S:13][CH:14]=1)=[N:8][O:9][CH2:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)/C(=N\O)c1csc(N)n1
Reactant: O=C(CBr)OCc1ccc([N+](=O)[O-])cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)C(=NOCC(=O)OCc1ccc([N+](=O)[O-])cc1)c1csc(N)n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 75.2 %

Procedure:
6.1 g (25 mmol) of 2-(2-amino-4-thiazolyl)-2-(Z)-hydroxyimino-acetic acid t-butyl ester are dispersed in 250 ml of dry acetonitrile. There are now added thereto at room temperature while stirring 13.7 g (50 mmol) of 4-nitrobenzyl bromoacetate and 12.9 ml (75 mmol) of N-ethyldiisopropylamine. 5 minutes later 7.5 g (50 mmol) of sodium iodide are added thereto. The mixture is stirred at room temperature for 3.5 hours in an argon atmosphere. The solvent is subsequently removed by evaporation and the residue is diluted with 500 ml of ethyl acetate. The resulting solution is washed four times with a total of 2 l of water. The water is extracted with 300 ml of ethyl acetate and the combined ethyl acetate solutions are dried over sodium sulphate and evaporated to dryness. After crystallization from ethyl acetate/hexane, there are obtained 8.2 g (75%) of 2-(2-amino-4-thiazolyl)-2-[[(p-nitrobenzyloxycarbonyl)methoxy]imino]-acetic acid t-butyl ester of melting point 146.8° (decomposition).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18]C)C.B(Br)(Br)Br.CO>C(Cl)Cl>[OH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][CH2:10][N:9]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=1)[CH2:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH3:1])=[O:31]
Reactant: CCOC(=O)CCCCN(CCc1ccccc1OC)Cc1ccc(C(=O)OC)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CCCCN(CCc1ccccc1O)Cc1ccc(C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 3.00 g (7.02 mmol) of methyl 4-{[(5-ethoxy-5-oxopentyl)(2-methoxy-phenethyl)amino]methyl}benzoate from Example 1.2 in 60 ml of methylene chloride is cooled to 0° C., and 23.16 ml (23.16 mmol) of a 1N boron tribromide solution in methylene chloride are added dropwise. The solution is stirred at 0° C. for one hour. After addition of 30 ml of dry methanol, the batch is heated at 60° C. for one hour. After cooling, the solvent is removed under reduced pressure and the residue is taken up in a mixture of 57 ml of ethyl acetate and 3 ml of methanol and made alkaline using 10% sodium carbonate solution. The aqueous phase is extracted repeatedly with ethyl acetate/methanol 9/1 and the combined organic phases are washed using saturated sodium chloride solution. After drying over magnesium sulphate and distillative removal of the solvent under reduced pressure, the crude product is purified by flash chromatography over silica gel (0.04-0.063 nm) using the mobile phase cyclohexane/ethyl acetate 2/1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10](=O)[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:4][CH:3]=1.[NH3:19]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:19][C:10](=[O:9])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:4][CH:3]=1
Reactant: O=c1oc(-c2ccc(Br)cc2)cc2ccccc12
Reactant: N
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c(-c2ccc(Br)cc2)cc2ccccc12
Temperature: 80 °C
Reaction time: 72 h

Procedure:
To a suspension of 3-(4-bromo-phenyl)-isochromen-1-one (1.05 g, 3.50 mmol) in DMF (7 ml) is added aqueous ammonia (25% by weight, 7 ml) and the mixture is stirred at 80° C. for 3 days. The reaction mixture is diluted with water. The resulting precipitate is filtered off, washed with water and dried under vacuum to afford 3-(4-bromo-phenyl)-2H-isoquinolin-1-one as brown powder; HPLC/MS 1.96 min (A), [M+H] 300/302;
Reaction SMILES: [NH2:1][C:2]([CH3:15])([CH3:14])[CH:3]([OH:13])[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:6]([O:5][CH2:4][CH:3]1[O:13][C:24](=[O:26])[NH:1][C:2]1([CH3:15])[CH3:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(N)C(O)COCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)NC(=O)OC1COCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 77.1 %

Procedure:
To a cold, 0° C., solution of 3-amino-1-(benzyloxy)-3-methylbutan-2-ol (2 g, 9.6 mmol) and triethylamine (3.3 mL, 24 mmol) in 95 mL of anhydrous dichloromethane was added triphosgene (3.1 g, 10.5 mmol). The reaction was stirred at 0° C. for 3.5 hr and at RT for 1.5 hr. A solution of saturated sodium bicarbonate (95 mL) was added and the mixture was stirred for 15 min, then the organic layer was isolated and washed successively with 0.25N HCl, sat. NaHCO3, and brine. The organic layer was dried over sodium sulfate, concentrated to a residue and purified by column chromatography (30 to 75% ethyl acetate in hexanes) to give the title compound (1.8 g, 7.4 mmol, 78%). 1H NMR (CDCl3, 400 MHz) δ 1.27 (s, 3H), 1.40 (s, 2H), 1.90 3.67-3.76 (m, 2H), 4.37-4.41 (t, J=6.4 Hz, 1H), 4.56-4.64 (dd, J=9.6, 12 Hz, 2H), 5.27 (s, H), 7.28-7.40 (m, 5H). LRMS (ESI/APCI) m/z 236 [M+H]+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C@@H:14]1[C@H:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:17][C:16](=[O:25])[N:15]1[C:26](=[O:35])[CH2:27][CH2:28][C@H:29]([CH3:34])[CH2:30][CH2:31][CH2:32][CH3:33].Br[CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>C1COCC1>[C:41]([O:40][C:38](=[O:39])[CH2:37][C@@H:27]([C:26]([N:15]1[C@H:14]([CH3:13])[C@H:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:17][C:16]1=[O:25])=[O:35])[CH2:28][C@H:29]([CH3:34])[CH2:30][CH2:31][CH2:32][CH3:33])([CH3:44])([CH3:43])[CH3:42]
Reactant: CCCC[C@@H](C)CCC(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCC[C@@H](C)C[C@@H](CC(=O)OC(C)(C)C)C(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
To a solution of diisopropylamine (1.8 mL, 12.6 mmol) in 30 mL THF at −78° C. was added n-butyllithium (1.6 M soln in hexanes, 7.6 mL, 12.1 mmol), and the mixture stirred 10 minutes at which time oxazolidinone 137 (3.2 g, 10.1 mmol) in 10 mL THF was added dropwise. The solution was stirred for 30 minutes, t-butyl bromoacetate (1.8 mL, 12.1 mmol) was added quickly dropwise at −50° C., and the mixture was allowed to warm slowly to 10° C. over 3 hours. The mixture was partitioned between Et2O and sat. NH4Cl (aq), the phases were separated, and the organic phase dried (MgSO4), and concentrated. The residue was purified by flash chromatography (16:1 to 8:1 hexanes:EtOAc) to provide 2.65 g (61%) of ester 138 as a colorless crystalline solid, mp=84–86° C. [α]D23+17.1 (c=1.00, CHCl3); 1H NMR (CDCl3): δ 7.34 (m, 5H), 5.62 (d, J=7.3 Hz, 1H), 4.73 (quint, J=6.8 Hz, 1H), 4.29 (m, 1H), 2.67 (dd, J=9.8, 16.4 Hz, 1H), 2.40 (dd, J=5.1, 16.4 Hz, 1H), 1.69 (m, 1H), 1.38 (s, 9H), 1.28 (m, 7H), 1.08 (m, 1H), 0.88 (m, 9H); 13C NMR (CDCl3) δ 176.45, 171.22, 152.71, 133.64, 128.86, 125.86, 80.83, 78.87, 55.33, 40.02, 38.21, 37.59, 36.31, 30.86, 29.29, 28.22, 23.14, 20.41, 14.36, 14.26. Anal. Calcd for C25H37NO5: C, 69.58; H, 8.64; N, 3.25. Found: C, 69.37; H, 8.68; N, 3.05.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[C:15]([CH3:17])[CH:16]=1>>[CH3:9][C:4]1[CH:5]=[C:6]([C:13]2[CH:14]=[C:15]([CH3:17])[CH:16]=[C:11]([CH3:10])[CH:12]=2)[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: Cc1cc(C)cc(B(O)O)c1
Reactant: Cc1cc(Cl)nc(N)n1
Product: Cc1cc(C)cc(-c2cc(C)nc(N)n2)c1

Procedure:
The title compound is synthesized according to general procedure GP4 starting from 2.0 g (14 mmol) 2-amino-4-chloro-6-methylpyrimidine and 2.7 g (18 mmol) 3,5-dimethyl-phenyl boronic acid. Yield after extraction and crystallization from diethylether: 3.2 g (75%, approximately 70% pure).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH:9]=[CH:10][C:11](=[O:24])[C:12]2[S:13][C:14]([CH3:23])=[C:15]3[CH2:20][C:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][C:16]=23)[CH:6]=[C:5]([CH3:25])[C:4]=1[CH:26]=[CH:27][C:28]([OH:30])=[O:29])[CH3:2].CCN(C(C)C)C(C)C>C(O)C.[Pd]>[CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11](=[O:24])[C:12]2[S:13][C:14]([CH3:23])=[C:15]3[CH2:20][C:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][C:16]=23)[CH:6]=[C:5]([CH3:25])[C:4]=1[CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH3:2]
Reactant: CCc1cc(C=CC(=O)c2sc(C)c3c2CCC(C)(C)C3)cc(C)c1C=CC(=O)O
Agent: [Pd]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(CCC(=O)c2sc(C)c3c2CCC(C)(C)C3)cc(C)c1CCC(=O)O
Temperature: 50 °C
Reaction time: 72 h
Yield: 44.8 %

Procedure:
To a solution of 3-{2-ethyl-6-methyl-4-[3-oxo-3-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propenyl]-phenyl}-acrylic acid (Intermediate 3; 340 mg, 0.805 mmol) and DIPEA (182 mg, 1.41 mmol) in ethanol, Pd/C (340 mg, 10% Pd, moistened with 50% water) is added and the resulting slurry is stirred at 50° C. for 72 h under 10 bar of H2. Another portion of Pd/C is added and stirring is continued for 16 h at 50° C. under 10 bar of H2. The reaction mixture is filtered and the filtrate is evaporated. The crude product is purified by prep. HPLC (Grom-Sil 120 ODS-4-HE, 30×75 mm, 10 μm, acetonitrile/water (0.5% HCOOH), 20% to 95% acetonitrile) to give 3-{2-ethyl-6-methyl-4-[3-oxo-3-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propyl]-phenyl}-propionic acid (154 mg) as a colourless foam; LC-MS: tR=1.15 min, [M+1]=427.30.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20](O)=[O:21])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][NH:24][C@H:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[O:21])[N:24]([CH3:23])[CH:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:28][CH2:27][CH2:26]3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(C(=O)O)n2)CC1
Reactant: CN[C@@H]1CCCc2ccccc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1cccc(C2CCN(C(=O)OC(C)(C)C)CC2)n1)C1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
To a solution of 3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-6,1′-dicarboxylic acid 1′-tert-butyl ester (150 mg, 0.49 mmol), methyl-(R)-1,2,3,4-tetrahydro-naphthalen-1-yl-amine (0.079 g, 0.49 mmol), and diisopropylethylamine (0.50 mL, 0.49 mmol) in DMF (10 mL) was added dropwise BOP (238 mg, 0.49 mmol) at RT. After stirring overnight at RT, the reaction mixture was poured on water (10 mL) and extracted with ethylacetate (20 mL). The aqueous phase was re-extracted with ethylacetate (20 mL). The combined organic layers were washed with aq. sat. sodium bicarbonate solution (30 mL), 1M HCl solution (30 mL) and brine (30 mL), dried over sodium sulfate, filtered, and evaporated under reduce pressure. The crude mixture was purified by column chromatography on silica gel (ethylacetate/hexane 4:1) to give 6-[methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-carbamoyl]-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (215 mg, 97%). 1H-NMR (400 MHz, CDCl3): δ=1.47 (s, 9H), 1.64-2.05 (m, 8H), 2.18-2.22 (m, 1H), 2.72-2.81 (m, 4H), 2.82 (s, 3H), 4.15-4.25 (m, 2H), 5.15-5.20 (m, 1H), 7.18-7.25 (m, 5H), 7.53-7.71 (m, 1H), 7.73-7.74 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:14][CH3:15])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[C:16]([OH:20])(=O)[CH2:17]O>>[OH:20][CH2:16][C:17]1[N:14]([CH3:15])[C:3]2[C:2]([N:1]=1)=[CH:7][CH:6]=[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[N:4]=2
Reactant: CNc1nc(-c2ccccc2)ccc1N
Reactant: O=C(O)CO
Product: Cn1c(CO)nc2ccc(-c3ccccc3)nc21
Yield: 15.3 %

Procedure:
A procedure similar to that described in Preparation 43 was repeated, except that 4.9 g of 3-amino-2-methylamino-6-phenylpyridine (prepared as described in Preparation 109) and 5.6 g of glycolic acid were used, and that the product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and ethanol in ratios ranging from 1:0 to 10:1 by volume as the eluent, to give 0.9 g of the title compound, melting at 174°-177° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][CH2:29][O:30][C:23]=3[CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][CH2:29][O:30][C:23]=4[CH:22]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: O=[N+]([O-])c1cc2c(NCc3ccc4c(c3)OCCO4)nc(Cl)nc2s1
Product: O=[N+]([O-])c1cc2c(NCc3ccc4c(c3)OCCO4)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-nitro-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidin e gives 2-(pyrazol-1-yl)-6-nitro-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:27]([O:29]C)=O)=[N:11][NH:12][C:13]=1[C:14]([N:16]([CH2:18][CH:19](O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[F:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[C:35]([C:41]([NH:43][CH3:44])=[O:42])[CH:34]=1>>[CH2:1]([O:8][C:9]1[C:10]([C:27]([NH:38][CH2:37][C:36]2[CH:39]=[CH:40][C:33]([F:32])=[CH:34][C:35]=2[C:41]([NH:43][CH3:44])=[O:42])=[O:29])=[N:11][N:12]2[CH:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:18][N:16]([CH3:17])[C:14](=[O:15])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1n[nH]c(C(=O)N(C)CC(O)c2ccccn2)c1OCc1ccccc1
Reactant: CNC(=O)c1cc(F)ccc1CN
Agent: Cl
Product: CNC(=O)c1cc(F)ccc1CNC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2c1ccccn1

Procedure:
The title compound was prepared from methyl 4-(benzyloxy)-5-{[(2-hydroxy-2-pyridin-2-ylethyl)(methyl)amino]carbonyl}-1H-pyrazole-3-carboxylate using a procedure similar to that described in Example 43, Steps 2-4, except that 4-fluoro-2-[(methylamino)carbonyl]benzylamine hydrochloride was used in place of 4-fluorobenzylamine. Purification was achieved by removing the solvent in vacuo, and purifying the resulting residue by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA). Collection and concentration of the appropriate fractions afforded the product. ES MS (M+1)=543.