Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Li])CCC.[CH2:12]([Sn:16]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:18][CH2:19][CH2:20][CH3:21])Cl)[CH2:13][CH2:14][CH3:15].C([O-])(O)=O.[Na+]>C1COCC1>[CH3:1][C:2]1[S:3][C:4]([Sn:16]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:5][N:6]=1
Reactant: Cc1nccs1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(C)s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a cold (−78° C.) solution of 2-methylthiazole (2.80 g, 28.2 mmol) in anhydrous THF (100 mL) was added butyllithium (19.41 mL, 31.1 mmol) dropwise. After stirring for 60 min at −78° C., a solution of tributylchlorostannane (9.14 mL, 33.9 mmol) in anhydrous THF was added to the reaction mixture. The reaction mixture was stirred for 30 min at −78° C. and then allowed to warm to RT over a 2 to 3 h period. Saturated aq NaHCO3 was added and the aqueous phase was extracted with ether (3×200 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and evaporated in vacuo. The crude product was purified on a silica gel column eluting with 10-50% EtOAc in Hexane over a 60 min period. The fractions were collected and solvent was removed in vacuo to give the title compound as a yellow oil (72%). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.71-0.92 (m, 9H), 0.96-1.18 (m, 6H), 1.23-1.38 (m, 6H), 1.40-1.64 (m, 6H), 2.69 (s, 3H), 7.56 (d, J=12.69 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH2:17])[C:14]([NH2:18])=[C:13]([NH2:19])[N:12]=3)=[N:9][N:8]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[C:5]2=[N:6][CH:7]=1.Cl[C:29]([O:31][CH3:32])=[O:30]>N1C=CC=CC=1.ClCCl>[NH2:19][C:13]1[C:14]([NH:18][C:29](=[O:30])[O:31][CH3:32])=[C:15]([NH2:17])[N:16]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)[N:8]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:9]=2)[N:12]=1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncc(F)cc23)nc(N)c1N
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Nc1c(N)nc(-c2nn(Cc3ccccc3F)c3ncc(F)cc23)nc1N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
31.75 g (86.20 mmol) of the compound from example 30A were initially charged in pyridine (600 ml) under argon and cooled to 0° C. Then a solution of 6.66 ml (86.20 mmol) of methyl chloroformate in dichloromethane (10 ml) was added dropwise and the mixture was stirred at 0° C. for 1 h. Thereafter, the reaction mixture was brought to RT, concentrated under reduced pressure and co-distilled repeatedly with toluene. The residue was stirred with water/ethanol and then filtered off with suction using a frit, and subsequently washed with ethanol and ethyl acetate. Subsequently, the residue was stirred again with diethyl ether, filtered off with suction and then dried under high vacuum.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Br:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.[C:20](Cl)(=[O:22])[CH3:21]>ClCCl>[C:20]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([Br:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])(=[O:22])[CH3:21]
Reactant: COC(=O)c1cc(N)ccc1Br
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(NC(C)=O)ccc1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
Methyl 5-amino-2-bromobenzoate (Reference Compound No. 1-(1), 21.0 g, 91.2 mmol) and triethylamine (19.0 mL, 137 mmol) were dissolved in anhydrous dichloromethane (450 mL), acetyl chloride (13.0 mL, 182 mmol) was added dropwise over 30 minutes under ice cooling, and then the mixture was stirred at 0° C. for 2 hours. The reaction mixture was washed with water (200 mL, twice), saturated aqueous sodium hydrogen carbonate solution (200 mL, twice), and saturated brine (200 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was filtered with hexane-ethyl acetate (20:1) to give the titled reference compound (24.2 g) as a pale yellow solid. (Yield 98%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][Si](C)(C)C)=[C:4]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[C:4]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:3]=1
Reactant: C[Si](C)(C)C#Cc1ccc(Cl)cc1C1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccc(Cl)cc1C1CCCCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
16.6 g (57.1 mmol) of 8 are dissolved in 154 ml of tetrahydrofuran, cooled to 0° C., and a 1 M solution of tetra-n-butylammonium fluoride (68.48 mmol) is added dropwise. The batch is stirred at room temperature overnight, water is added, the mixture is extracted with methyl t-butyl ether, the organic phase is dried over sodium sulfate and filtered, the solvent is removed in vacuo, and the residue is filtered through silica gel with heptane/toluene, giving the product 9, which is employed in the next step without further purification.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[S:38][CH:39]=[C:40]([C:42]([NH:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[N:41]=1>>[C:45]([NH:44][C:42]([C:40]1[N:41]=[C:37]([C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:18][CH:17]=2)[S:38][CH:39]=1)=[O:43])([CH3:48])([CH3:46])[CH3:47]
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CC(C)(C)NC(=O)c1csc(Br)n1
Product: C[C@@H](c1ccc(-c2nc(C(=O)NC(C)(C)C)cs2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 2-bromo-N-tert-butylthiazole-4-carboxamide following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.315 min, m/z=478.3; 1H NMR (CDCl3) 1.18 (s, 3H), 1.36 (s, 3H), 1.49 (s, 9H), 2.11 (d, 3H), 2.14 (s, 4H), 2.33 (m, 1H), 2.80 (m, 1H), 5.64 (m, 1H), 7.19 (m, 2H), 7.28-7.39 (m, 5H), 7.60 (m, 2H), 7.94 (s, 1H)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.C1(C)C(C#N)=CC=CC=1.[OH-].[K+].Cl>CO>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Oc1cc(Cl)nnc1Cl
Reactant: Cc1cccc(C2CC2)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1C#N
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 55 %

Procedure:
To a mixture of 301 mg (purity: 100%; 1.82 mmol) of 4-hydroxy-3,6-dichloropyridazine and 842 mg (5.59 mmol) of 2-cyclopropyl-6-methylphenol were added orthotolunitrile (2.76 g) and 325 mg (5.51 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 277 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 55%) and 3.2 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.6%) were obtained.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5].[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[CH:18]2.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5])[CH:19]=[CH:18]2
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Reactant: Clc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cc(C(F)(F)F)ccc1-n1ccc2cc(Cl)ccc21
Temperature: 100 °C
Reaction time: 14 h
Yield: 98.1 %

Procedure:
A mixture of 2-fluoro-5-(trifluoromethyl)benzonitrile (1000 mg), 5-chloro-1H-indole (800 mg), potassium carbonate (1.8 g), and DMSO (10 ml) was stirred at 100° C. for 14 hours. The reaction mixture was cooled to room temperature, and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 2-(5-chloro-1H-indol-1-yl)-5-(trifluoromethyl)benzonitrile (1.66 g).
Reaction SMILES: CO[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][N:12]=2)[CH2:7][CH2:6]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[Cl:20][C:16]1[CH:15]=[C:14]2[C:19]([C:11]([CH:8]3[CH2:9][CH2:10][N:5]([CH3:3])[CH2:6][CH2:7]3)=[N:12][NH:13]2)=[CH:18][CH:17]=1
Reactant: COC(=O)N1CCC(c2n[nH]c3cc(Cl)ccc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCC(c2n[nH]c3cc(Cl)ccc23)CC1
Yield: 68.8 %

Procedure:
To a stirred solution, under nitrogen, of 13.0 g of 4-(6-chloro-1H-indazol-3-yl)piperidine-1-carboxylic acid methyl ester in 150 ml of tetrahydrofuran was added, dropwise, 48 ml of a 1M solution of lithium aluminum hydride (0.048 mole) in tetrahydrofuran. The solution was stirred under reflux for 1 hr. The reaction mixture was cooled in an ice-bath and water was added slowly. The reaction mixture was filtered, the filter cake washed with tetrahydrofuran and methanol, and the filtrate was concentrated. Recrystallization of the residue from ethanol-water yielded 7.6 g (69%) of product, mp 211°-213° C.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]1[CH2:19]Br)(=[O:3])[CH3:2].[C:21](=[S:24])([O-:23])[CH3:22].[K+]>CC(C)=O.CCOC(C)=O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]1[CH2:19][S:24][C:21](=[O:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC([O-])=S
Reactant: CCOC(=O)Cc1c(CBr)n(C(C)=O)c2ccccc12
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)Cc1c(CSC(C)=O)n(C(C)=O)c2ccccc12
Yield: 84.2 %

Procedure:
To a solution of ethyl 2-(1-acetyl-2-(bromomethyl)-1H-indol-3-yl)acetate (I-4A, 640 mg, 1.9 mmol) in acetone (10 ml) was added potassium ethanethioate (1.3 g, 11.2 mmol). The solution was heated at reflux for 1 hour. The solution was cooled and then diluted with EtOAc (50 ml) and washed with NaHCO3 (aq) (2×25 ml). The organic layer was dried with Na2SO4, filtered and concentrated. The crude product was introduced to a silica gel loading column and purified by column chromatography (10-30 EtOAc/hexanes) to get 533 mg (1.6 mmol, 84%) product. MS (m/z) 334 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=1.C(O[K])(C)(C)C.[CH:16]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]1)=[O:21])([CH3:18])[CH3:17]>C1COCC1>[CH:16]([O:19][C:20]([N:22]1[CH2:23][CH2:24][CH:25]([O:28][C:2]2[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=2)[CH2:26][CH2:27]1)=[O:21])([CH3:18])[CH3:17]
Reactant: CC(C)OC(=O)N1CCC(O)CC1
Reactant: Cc1nc(Cl)cc(Cl)n1
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Product: Cc1nc(Cl)cc(OC2CCN(C(=O)OC(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.9 %

Procedure:
4,6-Dichloro-2-methyl-pyrimidine (163 mg, 1 mmol) was dissolved in 4 mL of THF. A solution of tBuOK (112 mg, 1 mmol) and 2a (187 mg, 1 mmol) in 2 mL of THF was added slowly at room temperature. The mixture was stirred at room temperature for 8 h and quenched with a saturated solution of NH4Cl. The mixture was diluted with water and extracted with DCM. The organic layer was isolated, dried, filtered and evaporated to give 100 mg of 14a.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.ClC1C=C(O)C=CC=1C=O.C(O)(=O)[CH2:28][C:29]([OH:31])=[O:30].N1CCCCC1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[CH:6][C:3]=1[CH:4]=[CH:28][C:29]([OH:31])=[O:30]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(OC2CCCCO2)cc1Cl
Agent: O=Cc1ccc(O)cc1Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1ccc(OC2CCCCO2)cc1Cl
Yield: 55 %

Procedure:
Using 4.8 g of 2-chloro-4-(2-tetrahydropyranyloxy)benzaldehyde derived from 2-chloro-4-hydroxybenzaldehyde by the introduction of tetrahydropyranyl group thereinto, 4.2 g of malonic acid, 80 ml of pyridine, and 0.5 ml of piperidine, a reaction similar to that performed in Example 99 was carried out. As a result, 3.1 g of 2-chloro-4-(2-tetrahydropyranyloxy)cinnamic acid was obtained as crystal, which had the following physiochemical properties:
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH3:40])=[CH:35][CH:34]=1)=[O:32].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[N:9]([CH2:30][C:31]([C:33]3[CH:38]=[CH:37][C:36]([CH2:39][CH3:40])=[CH:35][CH:34]=3)=[O:32])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C(=O)CBr)cc1
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1ccc(C(=O)Cn2c(=O)c3cc(CC)sc3n(Cc3ccc(-c4ccccc4C#N)cc3)c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.2 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (1 g), 2-bromo-1-(4-ethylphenyl)ethanone (0.88 g) and N,N-dimethylformamide (40 mL) was added 60% sodium hydride (0.15 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.87 g, 63%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:28])[CH2:17][N:18]3[C:22]4=[N:23][CH:24]=[CH:25][CH:26]=[C:21]4[C:20](I)=[N:19]3)[C@@H:12]([CH3:29])[CH2:11]2)=[C:4]([F:30])[CH:3]=1.[C:31]([Cu])#[N:32].CN(C=O)C>C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:28])[CH2:17][N:18]3[C:22]4=[N:23][CH:24]=[CH:25][CH:26]=[C:21]4[C:20]([C:31]#[N:32])=[N:19]3)[C@@H:12]([CH3:29])[CH2:11]2)=[C:4]([F:30])[CH:3]=1
Reactant: COc1cc(N2CCN(C(=O)Cn3nc(I)c4cccnc43)[C@@H](C)C2)c(F)cc1Cl
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(N2CCN(C(=O)Cn3nc(C#N)c4cccnc43)[C@@H](C)C2)c(F)cc1Cl
Temperature: 175 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
A mixture of 1-[(S)-4-(4-Chloro-2-fluoro-5-methoxy-phenyl)-2-methyl-piperazin-1-yl]-2-(3-iodo-pyrazolo[3,4-b]pyridin-1-yl)-ethanone (2.2 g, 4.0 mmol, 1 eq), CuCN (3.6 g, 40 mmol, 10 eq), and DMF (25 ml) was stirred at 175° C. for 1 hrs. The reaction mixture was cooled to rt, diluted with ethyl acetate and filtered. The filtrate was washed with water, dried over Na2SO4, and purified by flash chromatography to provide 1-{2-[4-(4-Chloro-2-fluoro-5-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-2-oxo-ethyl}-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (1.6 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([OH:13])[CH:11]=[CH:12][C:4]=2[O:3]1.[CH2:15](Br)[CH:16]=[CH2:17].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][C:2]1([CH3:14])[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([O:13][CH2:17][CH:16]=[CH2:15])[CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: C=CCBr
Reactant: CC1(C)NC(=O)c2cc(O)ccc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOc1ccc2c(c1)C(=O)NC(C)(C)O2

Procedure:
A solution of 9.65 g of 2,3-dihydro-2,2-dimethyl-6-hydroxy-4H-1,3-benzoxazin-4-one and 9.1 g of allyl bromide in 150 ml of acetonitrile is refluxed for 5 hours, whilst stirring, with the addition of 10.3 g of dry potassium carbonate. The reaction mixture is filtered whilst warm, the filtrate is concentrated by evaporation and the remaining crystals are suction-filtered after trituration with ether. The crude 2,3-dihydro-2,2-dimethyl-6-(1-propen-3-yloxy)-4H-1,3-benzoxazin-4-one obtained in this manner melts at 137°-138°.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1F.[CH:14]1([CH2:20][OH:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[O:21][CH2:20][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: OCC1CCCCC1
Reactant: CNc1ccc(Br)c(F)c1[N+](=O)[O-]
Product: CNc1ccc(Br)c(OCC2CCCCC2)c1[N+](=O)[O-]

Procedure:
This compound was synthesized according to the procedure of Example 11, Step 1, using 4-bromo-3-fluoro-N-methyl-2-nitroaniline and cyclohexanemethanol as the starting materials. LCMS calculated for C14H20BrN2O3 (M+H)+: m/z=343.1, 345.1. found: 343.0, 345.1.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:16][CH3:17])(=[O:15])[CH3:14].[C:18]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:22][C:21]([CH2:24][CH:25]=[O:26])=[CH:20][CH:19]=1>C1COCC1>[C:18]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:19]=[CH:20][C:21]([CH2:24][CH:25]([OH:26])[CH2:14][C:13]([O:16][CH3:17])=[O:15])=[CH:22][CH:23]=1
Reactant: O=CCc1ccc(-c2ccccc2)cc1
Reactant: COC(C)=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)CC(O)Cc1ccc(-c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
A solution of diisopropylamine (0.241 mL, 1.72 mmol) in anhydrous THF (1.5 mL) was treated with n-BuLi (1.6 M in hexane, 0.7 mL, 1.72 mmol) at −78° C. The mixture was kept at this temperature for 1 h, and then a solution of methyl acetate (0.137 mL, 1.72 mmol) in anhydrous THF (1 mL) was added at −78° C. The reaction mixture was stirred for 1 h at −78° C., and a solution of 2-(biphenyl-4-yl)acetaldehyde (S90, 282 mg, 1.43 mmol) in anhydrous THF (2 mL) was added. The reaction mixture was stirred for another hour, then quenched by the addition of saturated aqueous NH4Cl, which was extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was removed under reduced pressure. Flash chromatography (SiO2, 50% Et2O-hexanes) yielded the title compound (226 mg, 58%) as a white solid: 1H NMR (CDCl3, 400 MHz) δ 7.64 (dd, 2H, J=7.2 Hz), 7.58 (dd, 2H, J=8.0 Hz), 7.49 (t, 2H, J=7.6 Hz), 7.38 (t, 1H, J=7.0 Hz), 7.34 (d, 2H, J=8.0 Hz), 4.38-4.34 (m, 1H), 3.71 (s, 3H), 3.35 (s, 1H(—OH)), 2.97-2.82 (m, 2H), 2.61-2.43 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 172.7, 140.5, 139.1, 136.6, 129.6, 128.5, 126.9, 126.7, 68.7, 51.4, 42.3, 40.3.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C@H:3]([CH3:14])[O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:48]1[CH2:53][CH2:52][CH:51]([C:54]2[CH:55]=[C:56]3[C:60](=[CH:61][CH:62]=2)[CH2:59][NH:58][CH2:57]3)[CH2:50][CH2:49]1>CN(C=O)C>[O:48]1[CH2:53][CH2:52][CH:51]([C:54]2[CH:55]=[C:56]3[C:60](=[CH:61][CH:62]=2)[CH2:59][N:58]([C:7]([C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][C@@H:3]([CH3:14])[C:2]([F:1])([F:16])[F:15])=[O:9])[CH2:57]3)[CH2:50][CH2:49]1
Reactant: C[C@H](Oc1ccccc1C(=O)O)C(F)(F)F
Reactant: c1cc2c(cc1C1CCOCC1)CNC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Oc1ccccc1C(=O)N1Cc2ccc(C3CCOCC3)cc2C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.1 %

Procedure:
To a solution of 0.9 g (3.8 mmol) 2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid in 9 ml DMF under argon at room temperature, was added 1.4 g (4.2 mmol) TBTU, 3.3 ml (19.2 mmol) N-ethyldiisopropylamine and finally 0.8 g (3.8 mmol) 5-(tetrahydro-pyran-4-yl)-2,3-dihydro-1H-isoindole (CAS: 905274-50-2). The mixture was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate. The solution was washed twice with water and twice with sat. NaHCO3 solution, dried over Na2SO4, filtered and concentrated in vacuo. The crude oil was purified with flash column chromatography on silica eluting with a gradient formed from heptane and ethylacetate to provide 1.5 g (93%) of the title compound as a yellow oil. MS (m/e): 420.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[N:12]=[C:11]([C:20]([OH:22])=O)[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C([N:44]3[CH2:48][C:47](=[O:49])[NH:46][CH2:45]3)=O)C=2)C=C(F)C=1.Cl.N1C=CNC1=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[N:12]=[C:11]([C:20]([N:44]3[CH2:48][C:47](=[O:49])[NH:46][CH2:45]3)=[O:22])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Reactant: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccncc2)n1
Agent: Cl
Agent: O=c1[nH]cc[nH]1
Product: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccncc3)n2)CN1

Procedure:
9 mg (0.03 mmol) of the compound of Example 27A is reacted analogously to the synthesis of the compound of Example 1 with 4 mg (0.03 mmol) of 4-imidazolinone-hydrochloride. 4 mg (35% of theory) of the title compound is obtained.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][N:11]=2)=[CH:6][CH:5]=1.[OH-].[Na+:21]>O1CCCC1.C(O)C>[Na+:21].[C:16]([C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([O-:19])=[O:2])=[CH:5][CH:6]=2)=[N:11][CH:12]=1)(=[O:18])[CH3:17]
Reactant: COC(=O)c1ccc(-c2ccc(C(C)=O)cn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)c1ccc(-c2ccc(C(=O)[O-])cc2)nc1

Procedure:
Procedure V′: To a stirring solution of 4-(5-acetyl-pyridin-2-yl)-benzoic acid methyl ester (1.0 mmol) in 1:1 tetrahydrofuran/ethanol (0.20M), add 2N sodium hydroxide and heat to reflux for three hours. After this time, concentrate the reaction in vacuo. Rinse the solid with dichloromethane and decant. The title compound, remaining as a solid, requires no further purification. MS (m/e): 242.1 (M+1)
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[C:10]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)#[N:11].N1CCCCC1>CO>[C:10]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[C:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:14][CH:13]=1)#[N:11]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: COC(=O)CC(=O)OC
Solvent: C1CCNCC1
Solvent: CO
Product: COC(=O)C(=Cc1ccc(C#N)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Dimethyl malonate (5.04 g, 38.13 mmol), 4-cyanobenzaldehyde (5.00 g, 38.13 mmol) and piperidine (0.097 g, 1.1 mmol) are dissolved in methanol (150 ml). The reaction mixture is stirred for two days (48 hours) at room temperature. The solvent is removed in vacuo to afford a viscous oil which is recrystallised from methanol.