Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C(N=C=NCCCN(C)C)C.Cl.C(N(CC)C(C)C)(C)C.[CH3:34][N:35]([CH3:40])[S:36]([NH2:39])(=[O:38])=[O:37]>ClCCCl.CN(C)C1C=CN=CC=1>[CH3:34][N:35]([CH3:40])[S:36]([NH:39][C:4](=[O:5])[C:3]1[CH:7]=[C:8]([F:12])[C:9]([CH3:11])=[CH:10][C:2]=1[F:1])(=[O:38])=[O:37]
Reactant: CN(C)S(N)(=O)=O
Reactant: Cc1cc(F)c(C(=O)O)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(F)c(C(=O)NS(=O)(=O)N(C)C)cc1F
Temperature: 60 °C
Yield: 862.5 %

Procedure:
To a suspension of 2,5-difluoro-4-methylbenzoic acid (6.0 g, 3.5 mmol) in 1,2-dichloroethane (100 mL) was added 4-dimethylaminopyridine (10.65 g, 8.7 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide:hydrochloride (16.65 g, 8.7 mmol) in 1,2-dichloroethane (60 mL) and N,N-diisopropylethylamine (15 mL, 8.60 mmol) and the mixture stirred at room temperature for 20 minutes. N,N-Dimethylsulfamide (8.64 g, 6.9 mmol) was added to the solution and the mixture heated at 60° C. under nitrogen. After 3 hours the mixture was cooled to room temperature and extracted with dichloromethane (100 mL). The extract was washed successively with 2M hydrochloric acid (2×300 mL), brine (100 mL), dried over magnesium sulfate, filtered and evaporated to afford an oil (8.40 g) which solidified at room temperature. The crude product was purified by silica gel column chromatography eluting with ethyl acetate/heptane 1:4 as eluent to afford the title compound (7.17 g, 79%) as a white solid.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH:4][CH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.C(=O)([O-])O.[Na+]>CO>[OH:3][N:2]=[C:10]([C:9]1[CH:12]=[CH:13][C:6]([CH2:5][OH:4])=[CH:7][CH:8]=1)[NH2:11]
Reactant: N#Cc1ccc(CO)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: NC(=NO)c1ccc(CO)cc1

Procedure:
A solution of hydroxylamine hydrochloride (5.2 g), 4-(hydroxymethyl)benzonitrile (5.0 g), and sodium hydrogen carbonate (12.6 g) in methanol (50 mL) was heated to reflux for 20 hours. The reaction mixture was filtered through Celite (trade name). Thus, the filtrate was concentrated to thereby give the title compound having the following physical properties. The product was used for next reaction without further purification.
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]=1O.C(Cl)Cl.[OH2:13]>FC(F)(F)C(O)=O>[OH:13][C@@H:7]1[C@@H:2]([OH:1])[CH2:3][C:4](=[O:8])[CH:5]=[CH:6]1
Reactant: O
Reactant: O=C1CCCC(O)=C1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1C=C[C@H](O)[C@@H](O)C1
Yield: 75 %

Procedure:
The α,β-unsaturated ketone 9 (FIG. 6) (0.344 g, 1.42 mmol) was stirred in a mixture of trifluroacetic acid (18 mL), CH2Cl2 (2 mL) and water (2 mL) for 30 minutes at 0° C. Solvents were removed in vacuo. The residue was azotroped with toluene (20 ml) and purified by flash chromatography to give compound 2 (FIG. 4) as a white solid (0.137 g, 75%). 1H NMR (D2O) δ 7.04 (dd, J=10.2, 2.4 Hz, 1H), 6.08 (dm, J=10.2 Hz, 1H), 4.45 (dm, J=8.4 Hz, 1H), 3.99-4.07 (m, 1H), 2.82 (ddd, J=16.4, 4.8, 1.2 Hz, 1H), 2.58 (dd, J=16.4, 11.9 Hz, 1H); 13C NMR (D2O) δ 204.8, 156.1, 131.4, 74.4, 74.3, 46.5.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:5]=1[O:12][CH3:13])=[O:3].[C:14]([O:19][CH2:20]C)(=[O:18])[C:15]([O-])=[O:16].C[O-].[Na+:24].[Na].C(OC(C)C)(C)C>CO>[Na+:24].[CH3:13][O:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([O:10][CH3:11])[C:4]=1[C:2]([O-:3])=[CH:1][C:15](=[O:16])[C:14]([O:19][CH3:20])=[O:18]
Reactant: CCOC(=O)C(=O)[O-]
Reactant: COc1cccc(OC)c1C(C)=O
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(C)OC(C)C
Solvent: CO
Product: COC(=O)C(=O)C=C([O-])c1c(OC)cccc1OC
Reaction time: 8 h

Procedure:
A solution of 100 g of 2,6-dimethoxyacetophenone and 7.5 ml of ethyl oxalate in 520 ml of anhydrous MeOH is added slowly to a solution of sodium methylate prepared from 12.7 g of sodium and 285 ml of anhydrous MeOH. The reaction mixture is heated to reflux for 7 hours and left overnight at RT. It is poured into 2 liters of isopropyl ether and left stirring for 15 minutes. The expected product is obtained by filtration, washing with isopropyl ether and drying under vacuum, m=120 g, m.p.=178° C.
Reaction SMILES: [C:1]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1>N1C=CC=CC=1>[C:18]([O:16][C:13]1[CH:14]=[CH:15][C:10]([C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)([CH3:3])[CH3:2])=[CH:11][CH:12]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1
Reactant: CC(C)(c1ccccc1)c1ccc(O)cc1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(c1ccccc1)c1ccc(OC(=O)c2cccnc2)cc1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
42.4 g (200 mmol) of p-cumylphenol and 40 g (220 mmol) nicotinic acid chloride hydrochloride was mixed with 600 ml dry pyridine and stirred for 24 hours at 40° C. After cooling precipitated pyridine hydrochloride was sucked off and the filtrate mixed with 150 ml of water. The precipitated raw product was washed with two 100 ml portions of water and recrystallized from methanol.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].Br[CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:18]1([O:1][C:2]2[C:3]([N+:14]([O-:16])=[O:15])=[C:4]([CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COC(=O)c1ccc(OC)c(O)c1[N+](=O)[O-]
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(OC)c(OC2CCCC2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture of methyl 3-hydroxy-4-methoxy-2-nitrobenzoate (1.14 g, 5.0 mmol), bromocyclopentane (0.7 mL, 6.5 mmol), potassium carbonate (2.0 g, 14 mmol), and anhydrous acetonitrile (15 mL) was refluxed under N2. After 19 h, the reaction was allowed to cool to rt, concentrated, and purified by silica gel chromatography (4:1→3:2; hexanes:ethyl acetate) to give methyl 3-(cyclopentyloxy)-4-methoxy-2-nitrobenzoate: MS (ESI): 296.5.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].[CH3:20][S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1>[CH3:20][S:21]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])(=[O:23])=[O:22]
Reactant: O=C(O)CCCCCCCCCCCCCCCO
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCCCCCCCCCCCCCCC(=O)O
Reaction time: 8 h

Procedure:
16-Hydroxyhexadecanoic acid (1 g) dissolved in a 10% hydrochloric acid-methanol solution was stirred at room temperature for 1 hour. The mixture was then concentrated and distributed into chloroform and water, and the chloroform layer was washed with a 1% aqueous sodium hydrogen carbonate solution and water, dried with anhydrous sodium sulfate and concentrated to give the methyl ester of 16-hydroxyhexadecanoic acid (1.02 g). To the methyl ester of 16-hydroxyhexadecanoic acid dissolved in pyridine (20 ml) was added methanesulfonyl chloride (0.50 g), and the mixture was stirred for 8 hours. Then, the pyridine was removed by distillation, and the residue was distributed into chloroform and water. The chloroform layer was dried with anhydrous sodium sulfate, concentrated and subjected to chromatography on a silica gel column with an eluent system of n-hexane-ethyl acetate (50:1) to give the methyl ester of 16-methanesulfonyloxy hexadecanoic acid (1.02 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([NH:7][C:8]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH2:12][NH:13]2)=[O:6])[CH3:2].[Br:22]N1C(=O)CCC1=O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:21])[C:5]([NH:7][C:8]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:15]([Br:22])=[C:14]2[C:9]=1[CH2:10][CH2:11][CH2:12][NH:13]2)=[O:6])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C(=O)Nc1c([N+](=O)[O-])ccc2c1CCCN2
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)Nc1c([N+](=O)[O-])cc(Br)c2c1CCCN2
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.6 %

Procedure:
A mixture of the product from Example 87 (0.15 g, 0.5 mmol) and N-bromosuccinimide (0.23 g, 1 mmol) in 2 mL dimethylformamide was stirred at room temperature for 18 hours. The solution was poured onto methylene chloride/water and separated and the water layer back extracted with methylene chloride. The combined organic layers were washed with water, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (4:1 to 1:1 heptane:ethyl acetate as eluant) to give the title compound (0.15 g, 81% yield).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([OH:19])[CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[N:15]1.Cl[CH2:21][C:22]1[C:23]([CH3:35])=[N:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)=[CH:26][CH:27]=1.O>CN(C)C=O>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([C:25]2[N:24]=[C:23]([CH3:35])[C:22]([CH2:21][O:19][C:6]3[CH:7]=[CH:8][C:9]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]4[CH:18]=[CH:17][N:16]=[N:15]4)=[C:4]([CH3:3])[CH:5]=3)=[CH:27][CH:26]=2)=[CH:29][CH:30]=1
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Reactant: Cc1nc(-c2ccc(Cl)cc2)ccc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2ccc(-c3ccc(Cl)cc3)nc2C)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
33 mg (0.83 mmol) of 60% sodium hydride were added to at 0° C. to a solution of 172 mg (0.79 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 8.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 200 mg (0.79 mmol) 3-chloromethyl-6-(4-chloro-phenyl)-2-methyl-pyridine were given to the reaction mixture and stirring continued at room temperature (r.t.) overnight. After addition of 16 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed with water, water/methanol 1:1, ethyl acetate, and ether. 324 mg (91%) of the title compound were obtained as slightly beige powder.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[C:8]([O:11][C@@H:12]1[C@@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:25]([O:31][C:32](=[O:34])[CH3:33])[CH2:24][S:23][C@H:13]1[O:14][C:15]1[C:16]([F:22])=[N:17][CH:18]=[C:19](Br)[CH:20]=1)(=[O:10])[CH3:9]>>[C:8]([O:11][C@@H:12]1[C@@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:25]([O:31][C:32](=[O:34])[CH3:33])[CH2:24][S:23][C@H:13]1[O:14][C:15]1[C:16]([F:22])=[N:17][CH:18]=[C:19]([C:2]2[CH:3]=[N:4][CH:5]=[N:6][CH:7]=2)[CH:20]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cc(Br)cnc1F
Reactant: Brc1cncnc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cc(-c2cncnc2)cnc1F

Procedure:
By carrying out the operation analogously to the first part of example 137, 5-(pinacolatoboryl)pyrimidine is prepared from 5-bromopyrimidine and is reacted immediately in the same reactor with 5-bromo-2-fluoro-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation VIII, under conditions analogous to those applied in the preparation of example 177. The expected product is thus obtained in the form of a yellow solid (yield=40%).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:20][CH3:21])=[C:9]([O:12][CH2:13][CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:5]=[CH:4][N:3]=1.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:20][CH3:21])=[C:9]([O:12][CH2:13][CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2ncnc(O)c2cc1OCCCS(C)(=O)=O
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc2ncnc(Cl)c2cc1OCCCS(C)(=O)=O
Yield: 65 %

Procedure:
The intermediate 4-hydroxy-7-methoxy-6-(3-(methylsulfonyl)propoxy)quinazoline (700 mg, 2.24 mmol) from the previous step was reacted with POCl3 in the manner described in Example 4A Step 2 to give 4-chloro-7-methoxy-6-(3-(methylsulfonyl)propoxy)quinazoline (480 mg, 1.45 mmol, 65%). LC-MS (ESI) m/z 331 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][C:5](=O)/[C:6](/[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:12]=2)=[CH:7]\N(C)C)[CH2:3][CH2:2]1.[OH:25][C@@H:26]([CH3:32])[CH2:27][NH:28][C:29]([NH2:31])=[NH:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:1]1([CH2:4][C:5]2[C:6]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[N:12]=3)=[CH:7][N:31]=[C:29]([NH:28][CH2:27][C@@H:26]([OH:25])[CH3:32])[N:30]=2)[CH2:3][CH2:2]1
Reactant: CN(C)/C=C(\C(=O)CC1CC1)c1ccnc(Nc2ccncc2)n1
Reactant: C[C@H](O)CNC(=N)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@H](O)CNc1ncc(-c2ccnc(Nc3ccncc3)n2)c(CC2CC2)n1
Temperature: 90 °C
Reaction time: 3 h
Yield: 45.5 %

Procedure:
To a solution of (Z)-1-cyclopropyl-4-(dimethylamino)-3-(2-(pyridin-4-ylamino)pyrimidin-4-yl)but-3-en-2-one (9) (50 mg, 0.155 mmol) in DMF (1288 μl), (S)-1-(2-hydroxypropyl)guanidine (18.11 mg, 0.115 mmol), and potassium carbonate (64.1 mg, 0.464 mmol) were added, and the reaction mixture was stirred at 90° C. for 3 hours. The crude product was purified by reverse-phase HPLC [30-90% organic phase over 15 minutes] followed by Biotage™ silica gel chromatography [10 g SNAP column, 100% DCM to 12% MeOH/DCM] to obtain the desired product (19.76 mg, 33%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[I:12]I.[OH-].[K+]>CN(C=O)C>[I:12][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[CH:5]=2)[NH:1][N:2]=1
Reactant: O=Cc1ccc2[nH]ncc2c1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=Cc1ccc2[nH]nc(I)c2c1
Reaction time: 4 h

Procedure:
To a solution of 1H-indazole-5-carboxaldehyde (670.2 mg, 4.59 mmol) in DMF (5 mL) were added iodine (2.33 g, 9.17 mmol) and potassium hydroxide pellets (1.03 g, 18.36 mmol) at room temperature under stirring. After 4 h, the mixture was quenched with aqueous Na2S2O3 solution and extracted with EtOAc. The combined extracts were washed with brine, dried, and evaporated to afford the title product.
Reaction SMILES: [CH:1]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[C:19]1[CH:33]=[CH:32][C:22]([CH2:23]P(=O)(OCC)OCC)=[CH:21][CH:20]=1.[C:34]1([N:40]([C:47]2[CH:54]=[CH:53][C:50]([CH:51]=O)=[CH:49][CH:48]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CC(C)([O-])C.[K+]>C1COCC1>[C:34]1([N:40]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:47]2[CH:54]=[CH:53][C:50](/[CH:51]=[CH:23]/[C:22]3[CH:32]=[CH:33][C:19]([C:2]4[CH:3]=[CH:4][C:5]5[C:6]6[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=6)[C:12]6[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=6)[C:18]=5[CH:1]=4)=[CH:20][CH:21]=3)=[CH:49][CH:48]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: CCOP(=O)(Cc1ccc(-c2ccc3c4ccccc4c4ccccc4c3c2)cc1)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C(=C/c1ccc(N(c2ccccc2)c2ccccc2)cc1)\c1ccc(-c2ccc3c4ccccc4c4ccccc4c3c2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
Compound E (1.0 g, 2.20 mmol) or E1 and 4-(N,N-diphenylamino)benzaldehyde (0.72 g, 2.64 mmol) and dry THF (20 ml) were charged in two necked-bottle in an ice bath, potassium-tert-butoxide (0.49 g, 4.4 mmol) in dry THF (20 ml) was added under nitrogen. The reaction mixture was stirred for 15 min at 0° C., followed by 1 h at room temperature. The solution mixture was extracted with ethyl acetate and washed with water. The combined organic layers were dried over MgSO4 and the solvent removed under reduced pressure to afford a crude product that was purified by sublimating at a temperature of 260° C. to obtain TSTA (1.04 g, yield=82%) as yellow solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:14][CH2:15][OH:16])=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:16][CH2:15][CH2:14][CH:13]([NH:17][C:18]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:24])[C:10]1[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC(CCO)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CCOS(C)(=O)=O)c1ccc(Cl)cc1
Temperature: 22 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
Methanesulfonyl chloride (0.097 mL, 1.25 mmol) was added dropwise to tert-butyl 1-(4-chlorophenyl)-3-hydroxypropylcarbamate (Intermediate 30) (0.326 g, 1.14 mmol) and triethylamine (0.191 mL, 1.37 mmol) in DCM (15 mL) at 22° C. The resulting solution was stirred at 22° C. for 2 hours. The mixture was concentrated and the residue was purified by flash silica chromatography, elution gradient 20 to 40% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 3-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propyl methanesulfonate (0.366 g, 88%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([NH:18][CH3:19])=[O:17])=S)=[O:5].N.OO>CO>[CH3:19][N:18]1[C:16](=[O:17])[C:11]2[C:10](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:9]=[C:7]1[NH:6][C:4](=[O:5])[C:3]1[CH:20]=[CH:21][CH:22]=[CH:23][C:2]=1[CH3:1]
Reactant: CNC(=O)c1ccccc1NC(=S)NC(=O)c1ccccc1C
Agent: N
Agent: OO
Solvent: CO
Product: Cc1ccccc1C(=O)Nc1nc2ccccc2c(=O)n1C
Reaction time: 8 h
Yield: 25.4 %

Procedure:
To a stirred mixture of 6.6 g of the above benzamide, 100 ml of methanolic ammonia and 100 ml methanol was added, in increments, 20 ml of 30% hydrogen peroxide. After stirring overnight, the solid was collected, partially dissolved in 500 ml of hot acetonitrile and filtered. The filtrate was chilled, giving 1.5 g of the desired product as white crystals, mp 185°-186° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][N:3]=1.Cl.[F:13][CH2:14][CH:15]([NH2:18])[CH2:16][F:17]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([S:8]([NH:18][CH:15]([CH2:16][F:17])[CH2:14][F:13])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: NC(CF)CF
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=S(=O)(NC(CF)CF)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
2-Chloropyridine-5-sulfonyl chloride (18 g, 85 mmol) was added to a solution of 1,3-difluoro-2-propylamine hydrochloride (11.2 g, 58.1 mmol) in pyridine (25 mL) at 0° C. The reaction mixture was stirred at room temperature for 30 minutes, diluted with ethyl acetate (200 mL) and washed with 3N aq. HCl (3×100 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was triturated with hexane (2×50 mL) and filtered to provide the title compound as an off-white solid (15.7 g, 70%). 1H NMR (500 MHz, CDCl3): δ 8.79 (1H, d, J=2.4 Hz), 8.17 (1H, dd, J=2.6 Hz, 2.5 Hz), 7.49 (1H, d, J=8.2 Hz), 5.25 (1H br s), 4.58 (2H, m), 4.47 (2H, m), 3.77 (1H, m).
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([Cl:13])[CH:7]=1.CCOCC>C(O)C>[Cl:13][C:8]1[CH:7]=[C:6]([CH2:5][C:1]#[N:2])[CH:11]=[C:10]([CH3:12])[CH:9]=1
Reactant: [C-]#N
Reactant: Cc1cc(Cl)cc(CBr)c1
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Product: Cc1cc(Cl)cc(CC#N)c1
Temperature: 70 °C
Yield: 75.5 %

Procedure:
To a flask equipped with additional funnel, was placed potassium cyanide (29.6 g, 0.45 mol) and distilled water (55 ml). The mixture was heated up to 70° C. in an oil bath. With stirring, 1-Bromomethyl-3-chloro-5-methyl-benzene (46) (35 g, 0.16 mol) in ethanol (180 ml) was then dropwise added over 1 hr through the addition funnel. After completion of addition, the mixture was refluxed for 8 hr. After cooling to room temperature, ether was added to the mixture. The mixture was washed with water, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ether:hexane (1:9)) to afford 20 g (77%) of a pale brown oil. 1H NMR (200 MHz, CDCl3) δ: 2.31 (3H, s), 3.66 (2H, s), 7.02 (1H, s), 7.09 (2H, s).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:19]=[C:20]1[CH:27]2[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:29][CH:21]1[CH2:22]3)[CH2:26]2.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:1]([O:6][C:20]1([CH3:19])[CH:21]2[CH2:29][CH:25]3[CH2:24][CH:23]([CH2:28][CH:27]1[CH2:26]3)[CH2:22]2)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)O
Reactant: C=C1C2CC3CC(C2)CC1C3
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OC1(C)C2CC3CC(C2)CC1C3
Temperature: 5 °C
Reaction time: 5 h
Yield: 90.8 %

Procedure:
A 500 ml flask was flushed with nitrogen to displace the air with nitrogen, and was charged with 43.0 g (0.50 mol) of methacrylic acid, 0.95 g (5 mmol) of p-toluenesulfonic acid monohydrate (supplied by Wako Pure Chem. Ind. Ltd.) and 100 g of toluene. Separately 74.0 g (0.50 mol) of 2-methyleneadamantane, prepared by the same procedures as described in Reference Example 1, was dissolved in 100 g of toluene. The obtained solution of 2-methyleneadamantane in toluene was dropwise added to the content in the flask over a period of about 3 hours, while the content was maintained at a reaction temperature of about 5° C. Then the content was stirred for 5 hours at the same temperature. After completion of the reaction, the residual catalyst was neutralized by adding 40.0 g (50 mmol) of a 5% aqueous sodium hydroxide solution, and the neutralized liquid was washed with an aqueous saturated sodium chloride solution. The thus-obtained organic phase was subjected to column chromatography, and further, analyzed by NMR and mass spectrometry. Thus, 106.2 g (yield: 90.8%) of the object 2-methyl-2-adamantyl methacrylate was obtained.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[OH:16])[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[C:30]([CH:38]=[CH:39][CH:40]=1)[CH:31]([OH:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33]>CN(C=O)C>[CH2:1]([C:4]1[CH:9]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[O:16][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[C:30]([CH:38]=[CH:39][CH:40]=1)[CH:31]([OH:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:2][CH3:3]
Reactant: CCOC(=O)C(O)c1cccc(OCCCBr)c1
Reactant: CCCc1cc(C2CCCCC2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1cc(C2CCCCC2)ccc1OCCCOc1cccc(C(O)C(=O)OCC)c1

Procedure:
A solution of 2-propyl-4-cyclohexylphenol (0.9 g) (as prepared in Step A), potassium carbonate (0.69 g) and ethyl 3-(3-bromopropoxy)mandelate (1.18 g) in DMF (30 mL) was stirred at 40° C. for 30 h. The reaction mixture was partitioned between ethyl acetate and 1.0 N HCl. The organic layer was washed twice with water, once with brine and then dried over sodium sulfate. The organic layer was then filtered and the solvent remove in vacuo. The resulting oil was chromatographed on silica gel, using ethyl acetate/hexane to yield the titled compound.