Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([CH:7]=[N:8][OH:9])=[CH:5][CH:4]=1)#[N:2].[CH:12]([CH2:14][C:15]([OH:17])=[O:16])=[CH2:13].Cl[O-].[Na+]>O1CCCC1>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]2[CH2:13][CH:12]([CH2:14][C:15]([OH:17])=[O:16])[O:9][N:8]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C=NO)cc1
Reactant: C=CCC(=O)O
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1CCOC1
Product: N#Cc1ccc(C2=NOC(CC(=O)O)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.9 %

Procedure:
To a solution of 4-cyanobenzaldoxime (see Ex 2) (312 g, 2.13 mol) in tetrahydrofuran (3 L) at room temperature was added vinylacetic acid (552 g, 6.41 mol). The yellow solution was cooled in an ice bath and sodium hypochlorite solution (5200 mL)was added in a dropwise fashion over 2 h. After stirring overnight at room temperature the reaction was quenched with a 5% citric acid solution and diluted with 200 mL ether. The layers were separated and the aqueous acidified to pH 4 using citric acid. The acid layer was washed twice with 200 mL ether, the ether layers combined and extracted with saturated sodium bicarbonate solution. After acidifying the basic layer with citric acid, the product was extracted into 400 mL ether. The organic phase was washed three times with 150 mL water, once with brine, dried (MgSO4) and concentrated to give 220 g of 3-(4-cyanophenyl)isoxazolin-5-ylacetic acid as a white solid. Recrystallization from 25% water/ethanol yielded 165 g of analytically pure material; 1H NMR (300 MHz, CDCl3) δ 7.77-7.76 (d, J=1.8 Hz, 2H), 7.72-7.71 (d, J=1.8 Hz, 2H), 5.22-5.14 (m, 1H), 3.63-3.54 (dd, J=10.6 Hz, 16.8 Hz, 1H), 3.19-3.11 (dd, J=7.3 Hz, 16.8 Hz, 1H), 3.00-2.93 (dd, J=6.2 Hz, 16.5 Hz, 1H), 2.79-2.72 (dd, J=7.3 Hz, 16.5 Hz, 1H); IR (KBr): 3202, 2244, 1736, 1610, 1432, 1416, 1194, 1152, 928, 840, 562 cm-1. Anal. Calcd for C12H10N2O3 : C, 62.61; H, 4.38; N, 12.17. Found: C, 62.37; H, 4.47; N, 11.71.
Reaction SMILES: N[NH-].[C:3](Cl)(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[NH2:19][C:20]1[CH:38]=[CH:37][C:23]2[N:24]=[C:25]([NH:28][C:29]3[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:36])[N:26]([CH3:27])[C:22]=2[C:21]=1[C:39]([NH2:41])=[O:40]>C1COCC1>[Cl:36][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([Cl:35])[C:29]=1[NH:28][C:25]1[N:26]([CH3:27])[C:22]2=[C:21]3[C:20](=[CH:38][CH:37]=[C:23]2[N:24]=1)[N:19]=[C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH:41][C:39]3=[O:40]
Reactant: O=C(Cl)c1ccccc1
Reactant: Cn1c(Nc2c(Cl)cccc2Cl)nc2ccc(N)c(C(N)=O)c21
Agent: [NH-]N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(Nc2c(Cl)cccc2Cl)nc2ccc3nc(-c4ccccc4)[nH]c(=O)c3c21
Reaction time: 1 h

Procedure:
The above amino amide (50 mg, 0.15 mmol) was added to a solution of benzoyl chloride (32 mg, 0.23 mmol) in THF (1 mL). Triethylamine (0.03 mL, 0.23 mmol) was added and the mixture stirred for 1 h. TLC showed conversion to the benzamide. The solvent was evaporated and the residue dissolved in MeOH (1 mL). Sodium methoxide in MeOH (25%, 0.2 mL) was added and the solution heated to reflux for 45 min. The cooled mixture was partitioned between 1M NH4C1 and CH2Cl2. The residue from the organic layer was stirred and refluxed with MeOH (2 mL) for 1 h, cooled, filtered and washed with MeOH to yield the title compound, 7 (52 mg, 79%) Mp>300° C. MS (ES+) 436, 438 (MH+).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][CH:7]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:9][C:8]1=[O:17])[CH3:5])[CH3:2].C(N(CC)CC)C.[N:25]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:25]1([C:31]([N:9]2[C@@H:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@@H:7]([O:6][CH:4]([O:3][CH2:1][CH3:2])[CH3:5])[C:8]2=[O:17])=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCOC(C)OC1C(=O)NC1c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(C)O[C@H]1C(=O)N(C(=O)N2CCOCC2)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 30 mg (0.13 mmol) of 3-(1-ethoxyethoxy)-4-phenyl-2-azetidinone 6 in 2 mL of CH2Cl2, 2 mg of DMAP and 0.05 mL of triethylamine was added at room temperature. After 5 min, 22.9 mg (0.15 mmol) of morpholinecarbonyl chloride was added. The reaction mixture was stirred for 2 h at room temperature. The reaction mixture was diluted with 20 mL of CH2Cl2 and the organic layer was washed two times with brine, dried over Na2CO3 and concentrated. The crude solid product was purified by chromatography on silica gel to yield pure 7f: 87%; pale yellow oil; 1H NMR (250 MHz, CDCl3) δ [0.90 (d, J=5.3 Hz), 1.01 (d, J=5.3 Hz) (3H)], [1.04 (t, J=7.1 Hz), 1.18 (t, J=7.1 Hz)] (3H), 3.20 (m, 4H), [3.28 (m), 3.53 (m), 3.67 (m) (2H)], 3.60 (m, 4H), [4.41 (g, J=5.3 Hz), 4.63 (q, J=5.3 Hz) (1H)], [5.07 (d, J=5.8 Hz), 5.08 (d, J=5.8 Hz) (1H)], [5.29 (d, J=5.8 Hz), 5.32 (d, J=5.8 Hz) (1H)], 7.23-7.27 (m, 5H).
Reaction SMILES: CC(C)([O-])C.[K+].C1COCC1.[CH3:12][C:13]1([CH3:25])[C:17]([CH3:19])([CH3:18])[O:16][B:15]([C:20]2[CH:21]=[N:22][NH:23][CH:24]=2)[O:14]1.Br[CH2:27][CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>CN(C)C=O.C(OCC)(=O)C>[Si:30]([O:29][CH2:28][CH2:27][N:23]1[CH:24]=[C:20]([B:15]2[O:16][C:17]([CH3:18])([CH3:19])[C:13]([CH3:25])([CH3:12])[O:14]2)[CH:21]=[N:22]1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC1(C)OB(c2cnn(CCO[Si](C)(C)C(C)(C)C)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Potassium tert-butoxide (1.0 M) in THF (0.60 mL, 0.60 mmol) was added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.1 g, 0.5 mmol) in N,N-dimethylformamide (1.5 mL) at 0° C. The reaction mixture was stirred at room temperature for 5 minutes, then cooled to 0° C. and treated with (2-bromoethoxy)(tert-butyl)dimethylsilane (0.2 mL, 0.8 mmol). The reaction was stirred at room temperature overnight, then diluted with ethyl acetate, washed with sat. NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated to provide the crude product which was purified by silica gel chromatography eluting with 0 to 30% EtOAc in hexanes. Calculated for C17H34BN2O3Si (M+H)+: m/z=353.2; Found: 353.1.
Reaction SMILES: Br[CH:2]([C:4]#[C:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:7]=1)[CH3:3].[NH2:20][OH:21]>CN1CCCC1=O.O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:8]2[CH:7]=[C:6]([C:5]#[C:4][CH:2]([NH:20][OH:21])[CH3:3])[CH:11]=[CH:10][CH:9]=2)=[CH:14][CH:15]=1
Reactant: NO
Reactant: CC(Br)C#Cc1cccc(Oc2ccc(F)cc2)c1
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C#Cc1cccc(Oc2ccc(F)cc2)c1)NO
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The 2-bromo-4-[3-(4-fluorophenoxy)phenyl]-3-butyne prepared in step 2 was taken up in N-methyl-2-pyrollidinone (27 kg) and 50% aqueous hydroxylamine (21 kg) was added. The reaction mixture was agitated for 2.5 hours at ambient temperature and then was diluted with distilled water (18 kg). The layers were separated and the organic phase was concentrated in vacuo to give N-[4-(3-(4-fluorophenoxy)phenyl)-3-butyn-2-yl]hydroxylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][C:4]=1[CH3:16].COC1C=CC(C=O)=CC=1C.[Br:28]Br>C(Cl)(Cl)Cl>[Br:28][C:8]1[CH:7]=[C:6]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:4]([CH3:16])[C:3]=1[O:2][CH3:1]
Reactant: CCOC(=O)CCc1ccc(OC)c(C)c1
Reactant: BrBr
Agent: COc1ccc(C=O)cc1C
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCc1cc(C)c(OC)c(Br)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85 %

Procedure:
To a solution of ethyl 3-(4-methoxy-3-methylphenyl)propionate (derived from 10.0 g (66.6 mmol) of 4-methoxy-3-methylbenzaldehyde) in chloroform (200 ml) was added dropwise bromine (10.6 g, 66.6 mmol). The mixture was stirred for 12 hours at room temperature. The reaction mixture was washed with water, an aqueous solution of sodium thiosulfate, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of a silica gel column chromatography (hexane→hexane/ethyl acetate, 9:1) to give 17.0 g (yield 85%; 3 steps) of the above-titled compound as an oily product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[CH2:9]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)[CH2:10][C:11]#[CH:12]>>[CH3:8][C:4]1[N:3]=[C:2]([C:12]#[C:11][CH2:10][CH2:9][C:13]2[S:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cccc(Br)n1
Reactant: C#CCCc1nc2ccccc2s1
Product: Cc1cccc(C#CCCc2nc3ccccc3s2)n1
Yield: 68.8 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-methyl-pyridine (110 mg, 0.64 mmol) and 2-but-3-ynyl-benzo[d]thiazole (120 mg, 0.64 mmol, Example 35(A)). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 7:3) to yield 122 mg (0.44 mmol, 68%) of 2-(4-(6-methylpyridin-2-yl)but-3-ynyl)benzo[d]thiazole as a beige solid.
Reaction SMILES: CCN=C=NCCCN(C)C.[O:12]1[C:20]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[CH:14]=[C:13]1[C:21]([OH:23])=O.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([SH:37])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([S:37][C:21]([C:13]2[O:12][C:20]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[CH:14]=2)=[O:23])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: O=C(O)c1cc2cnccc2o1
Reactant: CC(C)(C)OC(=O)N1CCC(S)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(SC(=O)c2cc3cnccc3o2)CC1
Reaction time: 1 h

Procedure:
A solution of EDCI (66 mg, 0.35 mmol) in anhydrous DMF (2 mL) was added to a stirred solution of furo[3,2-c]pyridine-2-carboxylic acid (45 mg, 0.28 mmol) in anhydrous DMF (1 mL). After 1 h, the mixture was treated with a solution of DMAP (6 mg, 0.05 mmol) and 4-mercaptopiperidine-1-carboxylic acid tert-butyl ester (50 mg, 0.23 mmol), before being stirred for an additional 16 h. The DMF was removed under reduced pressure, then the residue was purified by flash chromatography (IH-EtOAc, 1:1 to 3:7) to furnish the title compound: RT=3.34 min; m/z (ES+)=363.1 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:38])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:30]=[CH:29][CH:28]=[C:27]4[C:23]=3/[C:24](=[CH:32]/[C:33]3[NH:34][CH:35]=[CH:36][CH:37]=3)/[C:25](=[O:31])[NH:26]4)[CH:17]=2)[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C(OCC)(=O)C>[NH2:7][CH:8]1[CH2:9][CH2:10][CH:11]([C:14]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:30]=[CH:29][CH:28]=[C:27]4[C:23]=3/[C:24](=[CH:32]/[C:33]3[NH:34][CH:35]=[CH:36][CH:37]=3)/[C:25](=[O:31])[NH:26]4)[CH:17]=2)=[O:38])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCC(C(=O)Nc2cccc(-c3cccc4c3/C(=C/c3ccc[nH]3)C(=O)N4)c2)CC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: NC1CCC(C(=O)Nc2cccc(-c3cccc4c3/C(=C/c3ccc[nH]3)C(=O)N4)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.7 %

Procedure:
A solution of the (Z)-[4-[3-[2,3-dihydro-2-oxo-3-[(1H-pyrrol-2-yl)methylene]-1H-indol-4-yl]-phenylcarbamoyl]-cyclohexyl]-carbamic acid tert-butyl ester (51.4 mg, 0.098 mmol) in 3 mL of methylene chloride was then treated with 2 mL of trifluoroacetic acid. The reaction mixture was stirred at room temperature for 1 h, and the reaction mixture was diluted with 50 mL of ethyl acetate. The organic phase was carefully washed with a saturated aqueous sodium bicarbonate solution (3×20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to provide a yellow-brown solid. This crude solid was washed with 70% chloroform-hexanes, and the insoluble solid was collected by suction filtration to provide pure (Z)-4-amino-N-[3-[2,3-dihydro-2-oxo-3-[(1H-pyrrol-2-yl)methylene]-1H-indol-4-yl]phenyl]cyclohexanecarboxamide (yield: 17 mg, 40%) as a yellow solid (mp 210-212° C.).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:7][N:6]1[C:19](=S)[CH2:20][C:21](=O)[CH3:22])=[O:4].[F:25][C:26]([F:36])([F:35])[C:27]1[CH:32]=[CH:31][C:30]([NH:33][NH2:34])=[CH:29][CH:28]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:7][N:6]1[C:19]1[N:33]([C:30]2[CH:29]=[CH:28][C:27]([C:26]([F:25])([F:35])[F:36])=[CH:32][CH:31]=2)[N:34]=[C:21]([CH3:22])[CH:20]=1)=[O:4]
Reactant: NNc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2)CN1C(=S)CC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2)CN1c1cc(C)nn1-c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-benzenesulfonyl-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with 4-(trifluoromethyl)phenylhydrazine (CAS Reg. No. 368-90-1) to give the title compound as yellow solid. MS (ESI): m/z=394.1 [M+H]+.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([CH:24]=O)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=CC1CCN(Cc2ccccc2)CC1
Reactant: c1ccc2c(c1)CCNC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(CN2CCC(CN3CCc4ccccc4C3)CC2)cc1

Procedure:
The title compound was prepared from 1,2,3,4-tetrahydroisoquinoline, 1-benzyl-piperidine-4-carbaldehyde (from Example 162, step A), diisopropylethylamine and sodium triacetoxyborohydride using a procedure analogous to that described in Example 1,, Step J.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.S(=O)(=O)(O)O.[Br:18]N1C(=O)CCC1=O>O.ClCCl.CC(O)=O>[Br:18][C:4]1[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[F:12]
Reactant: CC(=O)c1cc(Cl)c(F)cc1O
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c(F)c(Br)c1O
Temperature: 60 °C
Yield: 80.7 %

Procedure:
1-(5-Chloro-4-fluoro-2-hydroxyphenyl)ethanone (e.g., from Example 13, step 1) (20.0 g, 101 mmol, 1.00 eq) and a 50% aqueous sulfuric acid (120 mL) were added to the flask. The resulting mixture was heated to 60° C. in a water bath with stirring. N-Bromosuccinimide (21.52 g, 120.9 mmol, 1.20 eq) was added in three portions [7.0 g+7.0 g+7.52 g] in 8 minute intervals. After the reaction mixture was heated at 60° C. for 3 hours, the reaction was complete. The reaction mixture was diluted with water (160 ml) and dichloromethane (DCM) (300 ml), and the mixture was stirred for 0.5 hour. The organic layer was separated and the aqueous layer was extracted with dichloromethane (100 ml). The combined organic layers were washed with 1 N HCl (100 ml×2), water (100 ml), brine (60 ml), and concentrated under reduced pressure to afford the crude product (29.1 g) as a yellowish solid. The crude product was dissolved in HOAc (100 ml) and then diluted with water (200 ml) under stirring. The resulting mixture was stirred for 20 min at room temperature and the product was collected by filtration and dried to give 1-(3-bromo-5-chloro-4-fluoro-2-hydroxyphenyl)ethanone (21.8 g, 80.9%) as a yellowish solid. 1H-NMR (300 MHz, CDCl3) δ 13.18 (s, 1H, —OH), 7.78 (d, J=7.78 Hz, 1 H), 2.63 (s, 3 H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH2:10]>>[C:9]([C:4]1[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=1)([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])[CH3:8]
Reactant: C=C(C)CC(C)(C)C
Reactant: Oc1ccccc1
Product: CC(C)(C)CC(C)(C)c1ccc(O)cc1
Reaction time: 20 h
Yield: 0.9 %

Procedure:
A suspension of 1,000 parts of phenol, 700 parts of diisobutylene and 40 parts of ion exchange resin is prepared in a stirred reactor at 100° C. and 1 bar pressure, the mixture being stirred at 500 rpm. The ion exchange resin is a sulfonated styrene/divinylbenzene copolymer resin, which has been dehydrated under reduced pressure for 20 hours at 100° C. before being used; it has a gel structure and its particle size is from 20 to 150 micrometers. The suspension is then stirred constantly in the reactor at 500 rpm. After 30 minutes, 1,000 parts of phenol and 700 parts of diisobutylene are introduced per hour at 100° C. and 1 bar pressure and correspondingly 1,700 parts per hour of suspension are filtered through a suction line equipped with a metal filter (pore diameter 10 micrometers) and are subjected to fractional distillation. After 100 hours' operation, 116,100 parts (86% of theory, based on starting material II) of 4-tert.-octylphenol of boiling point 160°-162° C./27 millibars are obtained, in addition to 3,400 parts (2.5% of theory, based on starting material II) of 2-tert.-octylphenol and 1,750 parts (0.9% of theory, based on starting material II) of tert.-butylphenol. The conversion is 54%, based on phenol employed, or 91%, based on starting material II.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13]C)=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:15]([O:17]C)=[O:16].[CH2:19]([CH2:34][O:35][C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[CH:42]=[C:41]([C:46]([OH:48])=[O:47])[CH:40]=[CH:39]2)[O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[C:26]([C:31]([OH:33])=[O:32])[CH:25]=[CH:24]2>[O-]CCCC.[O-]CCCC.[O-]CCCC.[O-]CCCC.[Ti+4].C(O)CO>[CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:15]([OH:17])=[O:16].[CH2:34]([CH2:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[C:26]([C:31]([OH:33])=[O:32])[CH:25]=[CH:24]2)[O:35][C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[CH:42]=[C:41]([C:46]([OH:48])=[O:47])[CH:40]=[CH:39]2
Reactant: COC(=O)c1ccc2cc(C(=O)OC)ccc2c1
Agent: [Ti+4]
Agent: CCCC[O-]
Agent: O=C(O)c1ccc2cc(OCCOc3ccc4cc(C(=O)O)ccc4c3)ccc2c1
Solvent: OCCO
Product: O=C(O)c1ccc2cc(C(=O)O)ccc2c1

Procedure:
Further, an esterification reaction and a transesterification reaction were carried out among dimethyl 2,6-naphthalenedicarboxylate, 6,6′-(ethylenedioxy)di-2-naphthoic acid and ethylene glycol in the presence of titanium tetrabutoxide and then a polycondensation reaction was carried out to obtain an aromatic polyester (B-1) for the film layer (B) which comprised 73 mol % of a 2,6-naphthalenedicarboxylic acid component and 27 mol % of a 6,6′-(ethylenedioxy)di-2-naphthoic acid component based on the total of all the acid components and 98 mol % of an ethylene glycol component and 2 mol % of a diethylene glycol component based on the total of all the glycol components. 0.15 wt % of silica particles having an average particle diameter of 0.3 μm and 0.10 wt % of silica particles having an average particle diameter of 0.15 μm were contained in the aromatic polyester (B-1) based on the weight of the resin composition obtained before the polycondensation reaction. This aromatic polyester (B-1) had a melting point of 240° C. and a glass transition temperature of 117° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH2:11][CH2:12][OH:13].[N+:14]([O-])([OH:16])=[O:15].CCO>C(O)(=O)C>[OH:1][C:2]1[C:9]([N+:14]([O-:16])=[O:15])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH2:11][CH2:12][OH:13]
Reactant: O=Cc1ccc(O)c(OCCO)c1
Reactant: O=[N+]([O-])O
Solvent: CCO
Solvent: CC(=O)O
Product: O=Cc1cc(OCCO)c(O)c([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 88.7 %

Procedure:
To the solution of 4-hydroxy-3-(2-hydroxyethoxy)benzaldehyde in acetic acid (5 mL) was added 65% nitric acid (34.6 mg, 0.55 mmol) at 0° C., and the mixture was stirred at 0° C. 4 hours. The reaction mixture was poured into ice water followed by a standard aqueous/EtOH workup. Isolated 110 mg, yield 88.7% of Intermediate 10.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][N:4]([C@@H:8]2[CH2:13][CH2:12][CH2:11][NH:10][C@@H:9]2[CH3:14])[C:3]1=[O:15].[Cl:16][C:17]1[C:18]([C:24]#[N:25])=[N:19][CH:20]=[C:21](Cl)[N:22]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Cl:16][C:17]1[C:18]([C:24]#[N:25])=[N:19][CH:20]=[C:21]([N:10]2[CH2:11][CH2:12][CH2:13][C@@H:8]([N:4]3[CH2:5][CH2:6][CH2:7][N:2]([CH3:1])[C:3]3=[O:15])[C@H:9]2[CH3:14])[N:22]=1
Reactant: C[C@H]1NCCC[C@H]1N1CCCN(C)C1=O
Reactant: N#Cc1ncc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H]1[C@H](N2CCCN(C)C2=O)CCCN1c1cnc(C#N)c(Cl)n1
Temperature: 25 °C
Yield: 31.3 %

Procedure:
1-Methyl-3-((2R,3R)-2-methylpiperidin-3-yl)tetrahydropyrimidin-2(1H)-one (404, 120 mg, 0.55 mmol) was dissolved in 10 mL DMF. To it were added 3,5-dichloropyrazine-2-carbonitrile (175 mg, 1.0 mmol) and DIEA (350 μL, 2.0 mmol). The mixture was stirred at RT for 30 mM, diluted with 150 mL EtOAc, washed with water ×3, dried, concentrated in vacuo, and subjected to silica flash column using 0 to 3.5% MeOH in DCM to isolate 3-chloro-5-((2R,3R)-2-methyl-3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)piperidin-1-yl)pyrazine-2-carbonitrile (405, 60 mg, 31% yield).
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:15][C:14]=2[F:30])[CH:12]=1)=O>CN(C=O)C>[F:30][C:14]1[CH:15]=[C:16]([NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=[CH:18][C:13]=1[N:11]1[CH:12]=[C:8]([C:6]#[N:5])[CH:9]=[N:10]1
Reactant: NC(=O)c1cnn(-c2ccc(NC(=O)OCc3ccccc3)cc2F)c1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: N#Cc1cnn(-c2ccc(NC(=O)OCc3ccccc3)cc2F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
Thionyl chloride (0.23 ml) was added to a stirred solution of benzyl 4-[4-(aminocarbonyl)-1H-pyrazol-1-yl]-3-fluorophenylcarbamate (Intermediate 40) (0.76 g, 2.14 mmol) in DMF (20 ml) at 0° C. The resulting mixture was warmed to room temperature and stirred for 1 hour. It was quenched with aqueous saturated sodium bicarbonate solution, extracted with ethyl acetate, dried over sodium sulfate and solvent was removed under vacuum to give the title product (0.71 g).
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][C:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:10][CH:9]=2)=[CH:5][CH:4]=1.[Cl:26]Cl.CO.C(Cl)(Cl)Cl>C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[ClH:2].[Cl:1][CH:9]1[C:8]([Cl:26])([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([Cl:2])=[CH:25][CH:24]=2)[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[CH2:10]1
Reactant: Fc1ccc(OCCN2CC=C(Cc3ccc(Cl)cc3)CC2)cc1
Reactant: ClCl
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(OCCN2CCC(Cl)(Cc3ccc(Cl)cc3)C(Cl)C2)cc1
Yield: 49 %

Procedure:
To a stirred solution of 4-(4-chlorobenzyl)-1-(2-(4-fluorophenoxy)ethyl)-1,2,5,6-tetrahydropyridine hydrochloride (70 mg, 136 μmol) in CHCl3 (10 mL) a dilute solution of Cl2 in CCl4 was added in portions. After each addition the reaction was checked by TLC (1% MeOH/CHCl3). Cl2 addition was continued until all the starting material was converted to the much higher Rf product spot. The reaction mixture was washed with dilute NH4OH and the organic portion was filtered (cotton). Solvent removal gave a yellow oil. The oil was purified on silica gel with CHCl3 elution to give the free base of the title compound as a pale yellow oil (37 mg, 49%). The free base was converted to hydrochloride as a pale beige powder (40 mg): mp 78-83° C. (foams), 1H NMR (CDCl3) 1.98 (d, J=15 Hz, 1H), 2.95-4.00 (m, 9H), 4.10-4.20 (m, 1H), 4.38-4.75 (m, 2H), 6.79-7.02 (m, 2H), 7.27-7.37 (m, 2H), 12.48 (bs, 1H); HRMS calcd for C20H21Cl3FNO 415.0673, found 415.0664.