Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:5](F)=[C:6]([F:22])[C:7]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2].[N-:24]=[N+]=[N-].[Na+]>CC(C)=O.O>[F:22][C:6]1[C:5]2=[N:24][O:3][C:1]([CH3:2])=[C:4]2[CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(C(C)=O)c(F)c(F)c1Nc1ccccc1F
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1cc2c(C)onc2c(F)c1Nc1ccccc1F
Temperature: 65 °C
Yield: 88.7 %

Procedure:
To a solution of methyl 5-acetyl-3,4-difluoro-2-(2-fluorophenylamino)benzoate (example 3, step D) (1.50 g, 4.64 mmol) in a mixture of acetone (36 ml) and H2O (12 ml) was added NaN3 (452 mg, 6.96 mmol). The reaction was heated at 65° C. for 16 h and cooled to room temperature. Acetone was concentrated and the resulting mixture was extracted with EtOAc (2×50 ml). The combined organic solution was washed with brine (50 ml), dried over MgSO4 and concentrated to give a yellow solid. To the solid was added H2O (24 ml) and the reaction was heated at reflux for 3 h. The reaction was cooled to room temperature, filtered, and washed with H2O. The resulting solid was dried under high vacuum with P2O5 at 65° C. for 24 h to give 1.31 g (89%) of methyl 7-fluoro-6-(2-fluorophenylamino)-3-methylbenzo[c]isoxazole-5-carboxylate as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C1C=CN=CC=1)C.ClCCl.C(Cl)(Cl)Cl>[C:17]([O:9][CH2:8][C:5]1[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1ccc(CO)cn1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(COC(=O)c2ccccc2)cn1
Temperature: 25 °C

Procedure:
To a solution of 958 mg of (6-methylpyridin-3-yl)methanol, 1.3 ml of triethylamine, and 95 mg of DMAP in 40 ml of dichloromethane was added dropwise 1.08 ml of benzoyl chloride, followed by stirring at room temperature. To the reaction solution was added water, followed by carrying out an extraction operation with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 1767 mg of (6-methylpyridin-3-yl)methyl benzoate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.Br[CH2:40][CH2:41][CH2:42][O:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[Cl:50]>>[Cl:50][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=1[O:43][CH2:42][CH2:41][CH2:40][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccccc1OCCCBr
Reactant: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(O)cc3)cc21
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOc4ccccc4Cl)cc3)cc21

Procedure:
Analogously to Method I, 0.100 g of tert-butyl 4-(4-hydroxyphenyl)-3-[1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethoxy]piperidine-1-carboxylate (Example 44d) and 0.062 g of 1-(3-bromopropoxy)-2-chlorobenzene are used to prepare the title compound. Rf=0.27 (2:1 EtOAc-heptane); Rt=6.07.
Reaction SMILES: C[O:2][C:3]1[C:9]2[S:10][CH:11]=[CH:12][C:8]=2[C:7](=[CH:13][C:14]([OH:16])=[O:15])[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[CH:4]=1.Cl>O1CCCC1>[OH:2][C:3]1[C:9]2[S:10][CH:11]=[CH:12][C:8]=2[C:7](=[CH:13][C:14]([OH:16])=[O:15])[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[CH:4]=1
Reactant: COC1=Cc2ccccc2C(=CC(=O)O)c2ccsc21
Agent: Cl
Solvent: C1CCOC1
Product: O=C(O)C=C1c2ccccc2C=C(O)c2sccc21

Procedure:
1 g of the cis isomer product of example 5 is dissolved in tetrahydrofuran and 1N HCl is then added until the solution becomes turbid. The reaction mixture is refluxed for 2.5 hours and the organic solvent then evaporated off under reduced pressure. The remaining aqueous phase is extracted with ethyl acetate and the organic phase separated, washed with brine, dried over MgSO4 and evaporated under reduced pressure. The residue is recrystallised from dichloromethane/hexane to yield the title compound in the form of the pure (Z) isomer: M.P.=203°-208° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[N+:7]=1[O-].C(O)(C(F)(F)F)=[O:15]>C(Cl)Cl>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[N:7]=[C:8]([CH2:12][OH:15])[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1cccc(C2OCCO2)[n+]1[O-]
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OCc1cccc(C2OCCO2)n1
Reaction time: 2 h
Yield: 97.9 %

Procedure:
To a stirred solution of 2-(1,3-dioxolan-2-yl)-6-methylpyridine 1-oxide (2.3 g, 12.69 mmol, 1 eq.) in 200 ml dry DCM was added TFA (6.66 g, 31.73 mmol, 2.5 eq.) via syringe, The reaction was stirred 2 hrs and was evaporated on RFE. The residue was redissolved in 200 ml DCM and 200 ml of 2M aqueous K2CO3 solution was added. Vigorously stirring was allowed for 2 hrs. The aqueous layer was separated and extracted with fresh DCM (2×100 ml). The organics were combined, washed with water (50 ml), brine (50 ml), dried over MgSO4 and concentrated to give [6-(1,3-dioxolan-2-yl)pyridin-2-yl]methanol (2.25 g, 84% yield) as a yellow oil.
Reaction SMILES: [SH:1][CH2:2][C@H:3]1[CH2:8][C@@H:7]([CH2:9][SH:10])[O:6][C:4]1=[O:5].Cl>C1COCC1.[OH-].[Na+]>[C:4]([C@@H:3]1[CH2:2][S:1][C@@H:7]([CH2:9][SH:10])[CH2:8]1)([OH:6])=[O:5]
Reactant: O=C1O[C@H](CS)C[C@@H]1CS
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CS[C@@H](CS)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of cis-2,4-bis(mercaptomethyl)-4-butanolide (600 mg) in THF (20 ml), 1N sodium hydroxide solution (3.4 ml) was added and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo to give crude trans-4-carboxy-2-mercaptomethyltetrahydrothiophene.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]2[N:7]([C:18](=[O:21])[NH:19][N:20]=2)[C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15](O)=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2].Cl.[CH3:23][NH:24][O:25][CH3:26].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[CH3:26][O:25][N:24]([CH3:23])[C:15]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]1[C:18](=[O:21])[NH:19][N:20]=[C:6]1[C:5]([NH:4][CH:1]([CH3:2])[CH3:3])=[N:14]2)=[O:16]
Reactant: CNOC
Reactant: CC(C)Nc1nc2cc(C(=O)O)ccc2n2c(=O)[nH]nc12
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CON(C)C(=O)c1ccc2c(c1)nc(NC(C)C)c1n[nH]c(=O)n12
Temperature: 23 °C
Reaction time: 20 h

Procedure:
A mixture of 4-isopropylamino-1-oxo-1,2-dihydro-[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylic acid (130 mg), N,O-dimethylhydroxylamine hydrochloride (39 mg), HOBT (54 mg), and EDC (77 mg) in DMF (4.0 mL) was stirred at 23° C. for 20 hrs. The solution was then diluted with EtOAc and washed sequentially with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride solutions. The organic layer was dried over sodium sulfate, filtered, and the filtrate concentrated to afford the title compound as a light yellow solid. MS (M+H)+=331.6.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[F:22])[C:5]([N:7]1[CH2:12][CH2:11][CH2:10][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:8]1)=[O:6].[Br:23]Br>>[Br:23][CH:10]1[CH2:11][CH2:12][N:7]([C:5](=[O:6])[C:4]2[CH:19]=[CH:20][C:21]([F:22])=[C:2]([Br:1])[CH:3]=2)[N:8]=[C:9]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrBr
Reactant: O=C(c1ccc(F)c(Br)c1)N1CCCC(c2ccccc2)=N1
Product: O=C(c1ccc(F)c(Br)c1)N1CCC(Br)C(c2ccccc2)=N1

Procedure:
The title compound was prepared as described in Example 22 starting with 1- (3-bromo-4-fluorobenzoyl)-3-phenyl-1,4,5,6-tetrahydropyridazine and bromine to give a solid: mp 147°-148° C.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH3:23])[CH:17]=1.[O:24]1[CH2:29][CH2:28][CH:27]([C:30]2([NH2:33])[CH2:32][CH2:31]2)[CH2:26][CH2:25]1>>[OH:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:33][C:30]3([CH:27]4[CH2:28][CH2:29][O:24][CH2:25][CH2:26]4)[CH2:32][CH2:31]3)=[O:12])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH3:23])[CH:17]=1
Reactant: NC1(C2CCOCC2)CC1
Reactant: COc1cc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccn1
Product: COc1cc(-c2cnn(-c3ccc(C(=O)NC4(C5CCOCC5)CC4)cn3)c2O)ccn1

Procedure:
The title compound was prepared in a manner similar to Example 227 using 6-(5-hydroxy-4-(2-methoxypyridin-4-yl)-1H-pyrazol-1-yl)nicotinic acid and 1-(tetrahydro-2H-pyran-4-yl)cyclopropanamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.82-1.03 (m, 5H) 1.25 (s, 1H) 1.45-1.67 (m, 3H) 1.74 (d, J=12.4 Hz, 2H) 3.37 (t, J=11.6 Hz, 2H) 4.03 (dd, J=11.4, 3.5 Hz, 2H) 4.09 (s, 3H) 7.22 (s, 1H) 7.31 (d, J=6.1 Hz, 1H) 7.41 (s, 1H) 7.83 (d, J 8.6 Hz, 1H) 7.90 (s, 1H) 8.13 (d, J=6.1 Hz, 1H) 8.37 (dd, J=8.7, 2.1 Hz, 1H) 8.83 (d, J=1.8 Hz, 1H). MS m/z [M+H]+ 436.4.
Reaction SMILES: C[C:2]([CH3:15])([CH3:14])[C:3]#[C:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.[C:16](C1CCCC1)#[CH:17]>>[CH:2]1([C:3]#[C:4][C:5]2[CH:6]=[CH:7][C:8]([C:9]([OH:11])=[O:10])=[CH:12][CH:13]=2)[CH2:14][CH2:17][CH2:16][CH2:15]1
Reactant: C#CC1CCCC1
Reactant: CC(C)(C)C#Cc1ccc(C(=O)O)cc1
Product: O=C(O)c1ccc(C#CC2CCCC2)cc1

Procedure:
The same procedure was followed as for 4-(3,3-dimethylbut-1-ynyl)benzoic acid, with the exception that ethynylcylopentane was used in place of 3,3-dimethylbut-1-yne.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([O-:9])=[O:8])[CH:4]=[CH:3][C:2]=1[C:10]([O:12]C)=O.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[N:14]1([C:10]([C:2]2[CH:3]=[CH:4][C:5]([C:7]([O:9][C:5]([CH3:7])([CH3:6])[CH3:4])=[O:8])=[CH:6][N:1]=2)=[O:12])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: COC(=O)c1ccc(C(=O)[O-])cn1
Reactant: C1COCCN1
Product: CC(C)(C)OC(=O)c1ccc(C(=O)N2CCOCC2)nc1

Procedure:
In step B, the 2,5-pyridinedicarboxylic acid, 2-methyl ester, 5-t-butyl ester (5) is amidated with morpholine to give the corresponding 6-(morpholine-4-carbonyl)nicotinic acid, t-butyl ester (6).
Reaction SMILES: Br[C:2]1[C:3]([O:21][CH3:22])=[CH:4][C:5]([Cl:20])=[C:6]([CH:19]=1)[CH2:7][O:8][Si](C(C)C)(C(C)C)C(C)C.[CH2:23]([O:30][C@@H:31]1[C@@H:37]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@H:36]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@@H:35]([CH2:54][O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[O:34][CH:32]1O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Cl:20][C:5]1[CH:4]=[C:3]([O:21][CH3:22])[C:2]([CH:32]2[C@H:31]([O:30][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@@H:37]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@H:36]([O:46][CH2:47][C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)[C@@H:35]([CH2:54][O:55][CH2:56][C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=3)[O:34]2)=[CH:19][C:6]=1[CH2:7][OH:8]
Reactant: COc1cc(Cl)c(CO[Si](C(C)C)(C(C)C)C(C)C)cc1Br
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Product: COc1cc(Cl)c(CO)cc1C1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1

Procedure:
With similar method described in Step 3 of Example 92, (5-bromo-2-chloro-4-methoxybenzyloxy)triisopropylsilane (compound 89, 27.2 g, 66.7 mmol) and 2,3,4,6-tetra-O-benzyl-D-glucopyranose (compound 2, 30.0 g, 55.6 mmol) were converted to title compound (22.6 g, 59%, ca. 8:1 mixture of anomers (13:0) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[N:17]=[CH:16][C:15]([C:18](O)=[O:19])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.[CH3:48][N:49]([CH3:51])[NH2:50]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:48][N:49]([CH3:51])[NH:50][C:18](=[O:19])[C:15]1[CH:14]=[CH:13][C:12]([CH:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:9])=[O:10])[C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])=[N:17][CH:16]=1
Reactant: O=C(O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Reactant: CN(C)N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)NC(=O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 68.4 %

Procedure:
To a dichloromethane (5 ml) solution of the [6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylic acid (80 mg, 0.19 mmol) obtained in Example 50 were added triethylamine (32 μl, 0.23 mmol), 4-dimethylaminopyridine (12 mg, 0.095 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (44 mg, 0.23 mmol) and 1,1-dimethylhydrazine (21 μl, 0.23 mmol). The resulting mixture was stirred at room temperature for 7 hours. The reaction mixture was diluted with dichloromethane. The diluted mixture was washed sequentially with water, a saturated aqueous solution of sodium bicarbonate and brine. The organic layer thus obtained was dried over magnesium sulfate and concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the dichloromethane:methanol=50:1 eluate was concentrated under reduced pressure to give the title compound (60 mg, 0.13 mmol, 68%) as a colorless amorphous substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][C:12]#[C:13][Si](C)(C)C)=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][C:12]#[CH:13])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#CCCC#Cc1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#CCCC#Cc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 37.7 %

Procedure:
To a solution of (6-(4-fluorophenyl)hexa-1,5-diynyl)trimethylsilane (1.90 g, 7.7 mmol) in TH F (24 mL) cooled in a ice bath at 0° C., was added dropwise 7.7 mL of tetrabutylammonium fluoride 1M in THF solution (7.70 mmol). The reaction mixture was stirred 15 min at 0° C., and warmed to room temperature for 2 h 30. The reaction was quenched with water and the aqueous layer was extracted with diethyl ether. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The product was purified by flash chromatography (prepacked 25 g silicagel column, DCM 100% as eluent) to afford 500 mg of 1-fluoro-4-(hexa-1,5-diynyl)benzene (Yield: 45%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[S:17][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:4]=2[CH:3]=1.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1>>[Cl:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[CH2:19][N:14]1[CH2:13][CH2:12][CH:11]([NH:10][C:9]2[C:4]3[CH:3]=[C:2]([Cl:1])[S:17][C:5]=3[N:6]=[CH:7][N:8]=2)[CH2:16][CH2:15]1
Reactant: Clc1cc2c(NC3CCNCC3)ncnc2s1
Reactant: Clc1cccc(CBr)c1
Product: Clc1cccc(CN2CCC(Nc3ncnc4sc(Cl)cc34)CC2)c1

Procedure:
The title compound was prepared (70 mg, 43%) from 6-chloro-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine (110 mg, 0.41 mmol) and 1-(bromomethyl)-3-chlorobenzene (93 mg, 0.45 mmol) by following the general procedure described for Preparation 12. 1H NMR (400 MHz, CDCl3): δ 8.45 (s, 1H), 7.35 (s, 1H), 7.10 (m, 4H), 5.25 (d, 1H), 4.20 (m, 1H), 3.50 (s, 2H), 2.90 (m, 2H), 2.35 (m, 2H), 2.10 (m, 2H), 1.60 (m, 2H). MS (ESI) m/z: Calculated: 392.06; Observed: 393.2 (M++1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][CH3:19])=[N:15][C:16](I)=[C:10]2[CH:9]1[CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([F:28])[C:25]([C:29]([F:32])([F:31])[F:30])=[CH:24][C:23]=1[F:33])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].O>[Pd].CO.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][CH3:19])=[N:15][CH:16]=[C:10]2[CH:9]1[CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([F:28])[C:25]([C:29]([F:31])([F:32])[F:30])=[CH:24][C:23]=1[F:33])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1nc(I)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1cc(F)c(C(F)(F)F)cc1F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CCc1ncc2n1CCN(C(=O)OC(C)(C)C)C2CCc1cc(F)c(C(F)(F)F)cc1F
Temperature: 25 °C

Procedure:
A mixture of 8-[2-(2,5-difluoro-4-trifluoromethyl-phenyl)-ethyl]-3-ethyl-1-iodo-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (1.890 g; 3.229 mmol), 10% palladium on activated charcoal (567 mg), and anhydrous potassium carbonate (1.115 g; 8.072 mmol; 2.5 eq.) in anhydrous MeOH (75 ml) was stirred at rt, under hydrogen (1 atm), for 3 h15. Filtration over a pad of celite, and subsequent concentration to dryness afforded a crude heterogeneous residue which was dissolved in DCM (100 ml), and water (50 ml). The organic layer was then dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure to give 8-[2-(2,5-difluoro-4-trifluoromethyl-phenyl)-ethyl]-3-ethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow oil (1.400 g; 94%). LC-MS: tR=0.94 min.; [M+H]+=460.04 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11](=[O:13])[NH:10][N:9]=2)=[CH:4][CH:3]=1.Cl[CH2:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][C:11](=[O:13])[N:10]([CH2:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C1CC(c2ccc(Cl)cc2)=NN1
Reactant: CC(C)(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)C(=O)CN1N=C(c2ccc(Cl)cc2)CC1=O
Yield: 104.6 %

Procedure:
A mixture of 3.5 g (16 mmol) of 3-(4-chlorophenyl)-4, 5-dihydropyrazol-5-one, 2.9 g (24 mmol) of chloropinacolone, 5.4 g (39 mmol) of anhydrous potassium carbonate and acetonitrile was heated under reflux for 14 hours. Excess potassium carbonate and the formed salts were removed by filtration. The filtrate was concentrated and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1 (v/v)) to give 4.9 g of the object compound as white crystals (yield 97%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][C:15]=1[C:23]([F:26])([F:25])[F:24]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[C:15]([C:23]([F:25])([F:24])[F:26])[CH:16]=2)=[O:22])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1cc(F)cc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: O=C(Nc1cc(F)cc(C(F)(F)F)c1)Nc1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 8 h
Yield: 34.3 %

Procedure:
To a solution of 3-Fluoro-5-trifluoromethyl-aniline (940 mg, 5.25 mmol, 1.05 eq.) in dry THF (20 ml) was added 4-Chloro-3-(trifluoromethyl)-phenylisocyanate (1.11 g, 5.0 mmol) at rt and the mixture was stirred overnight. Then it was diluted with cHexane (100 ml), washed twice with 2 N HCl, once with sat. NaHCO3 and brine (100 ml each) and adsorbed on Celite in vacuo. Flash chromatography on silica with cHexane/TBME (5:1 to 3:1) yielded 687 mg pure product (34%) as a white powder.
Reaction SMILES: CN(C=O)C.[Br-].[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][Zn+].[Cl:16][CH:17]([CH3:21])[C:18](Cl)=[O:19]>C1(C)C=CC=CC=1.CCCCCC.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:7][C:8]1[CH:9]=[C:10]([CH2:11][C:18](=[O:19])[CH:17]([Cl:16])[CH3:21])[CH:13]=[CH:14][CH:15]=1
Reactant: CC(Cl)C(=O)Cl
Reactant: [Zn+]Cc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(Cl)C(=O)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 37.6 %

Procedure:
A mixture of CuCN(LiCl)2 (2.5 mL, 2.500 mmol), DMF (0.194 mL, 2.5 mmol) and (3-bromobenzyl)zinc(II) bromide (5 mL, 2.5 mmol) was stirred at RT for 20 min. A solution of 2-chloropropanoyl chloride (0.244 mL, 2.5 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.087 g, 0.075 mmol) in toluene (5 mL) was added to the reaction mixture. After 45 min the reaction was diluted with hexane and EtOAc and solid silica gel was added. The mixture was stirred for 5 min and the solid was filtered. The organic layer was concentrated, and loaded to silica gel column chromatography for purification (0-30% EtOAc/Hexane) to afford a colorless liquid (246 mg, 38%). MS (ES+) C10H10BrClO requires: 260, 262, found: 261 263 [M+H]+(1:1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:26])=[C:4]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[C:5]2[O:9][CH2:8][C:7](=[O:10])[C:6]=2[CH:11]=1.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([CH:36]=O)=[N:28]1.N1CCCCC1>CO>[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](/[CH:36]=[C:8]2\[O:9][C:5]3[C:4]([CH2:12][N:13]4[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:15][CH2:14]4)=[C:3]([OH:26])[C:2]([Cl:1])=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:28]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)c(Cl)cc3c2OCC3=O)CC1
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)c(Cl)cc3c2O/C(=C\c2n[nH]c4ccccc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 66.7 %

Procedure:
A solution of tert-butyl 4-[(5-chloro-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.100 g, 0.261 mmol) in methanol (1 mL) was added with indazole-3-carbaldehyde (0.0381 g, 0.261 mmol), and piperidine (0.00222 g, 0.0261 mmol) at room temperature, and the mixture was stirred at 60° C. for 3 hours. The reaction mixture was cooled to room temperature, then added with methanol (4 mL), suspended in methanol and thereby washed, and the solid was collected by filtration to obtain tert-butyl (Z)-4-({2-[(1H-indazol-3-yl)methylene]-5-chloro-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0890 g, 66%).
Reaction SMILES: [CH3:1][C:2]1[C:3](=O)[NH:4][CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[N:7]=1.O=P(Cl)(Cl)[Cl:15]>CN(C=O)C>[Cl:15][C:3]1[N:4]=[CH:5][C:6]([C:8]([O:10][CH3:11])=[O:9])=[N:7][C:2]=1[CH3:1]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1c[nH]c(=O)c(C)n1
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(Cl)c(C)n1
Yield: 52 %

Procedure:
To a solution of methyl 4,5-dihydro-6-methyl-5-oxo-2-pyrazine carboxylate (M. Mano, T. Seo, K. Imai, Chem. Pharm. Bull 10:3057-3063, 1980) in DMF (20 mL) was added POCl3 (20 mL). The reaction was refluxed for 0.5 h and then poured into ice. The aqueous layer was extracted with CHCl3 dried (MgSO4) and concentrated. The residue was chromatographed (SiO2, CHCl3) to provide the title compound (2.34 g, 52% yield); m.p. 49°-50° C.