Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCOCC1.C(Cl)Cl>[C:28]1([NH:27][C:2]2[C:7]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCC(=O)c1cccnc1Cl
Reactant: Nc1ccccc1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCC(=O)c1cccnc1Nc1ccccc1
Temperature: 70 °C
Yield: 70.4 %

Procedure:
A solution of 1-(2-chloro-pyridin-3-yl)-propan-1-one (6.0 g, 35.4 mmol) in 1,4-dioxane (59.0 mL) in a high pressure reaction tube was treated with (1S)-(+)-10-camphorsulfonic acid (20.5 g, 88.4 mmol). The resulting mixture was heated to 70° C. until all of the solids went into solution. The reaction was raised out of the heating bath, opened and treated with aniline (4.94 g, 4.84 mL, 53.1 mmol). The vessel was then re-sealed and heated at 95° C. overnight. After cooling to room temperature, the reaction was diluted with methylene chloride (75 mL) and was washed with a saturated aqueous sodium bicarbonate solution (2×100 mL). The organics were then dried over sodium sulfate, filtered, concentrated in vacuo and dried under high vacuum. The residue was then recrystallized from methanol. Collection by filtration (washing with 10 mL of methanol and 30 mL of hexanes) afforded 1-(2-phenylamino-pyridin-3-yl)-propan-1-one (5.64 g) of the desired product as a yellow, crystalline solid. The mother liquor was dry loaded onto silica gel. Flash chromatography (40 g, 10-25% ethyl acetate-hexanes) afforded an additional amount (1.28 g, 86% total yield) of the desired product as a yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH:10]([NH2:14])[CH2:9][CH2:8]2)([CH3:4])([CH3:3])[CH3:2].[N:15]([C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][N:22]=[CH:23]2)=[C:16]=[O:17]>C(OCC)C>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH:10]([NH:14][C:16]([NH:15][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]3[C:19]=1[CH:20]=[CH:21][N:22]=[CH:23]3)=[O:17])[CH2:9][CH2:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=Nc1cccc2cnccc12
Reactant: CC(C)(C)c1ccc2c(c1)CCC2N
Solvent: CCOCC
Product: CC(C)(C)c1ccc2c(c1)CCC2NC(=O)Nc1cccc2cnccc12
Reaction time: 2 h

Procedure:
5-tert-Butyl-2,3-dihydro-1H-inden-1-ylamine (150 mg, 1.13 mmol) in diethyl ether (10 mL) was treated with 5-isocyanatoisoquinoline in diethyl ether. The mixture was stirred for 2 hours, filtered, and the filter cake was washed with diethyl ether to provide the title compound. NMR (DMSO-d6) 1.29 (s, 9H), 1.78-1.90 (m, 1H), 2.43-2.54 (m, 1H, buried under DMSO), 2.76-3.05 (m, 2H), 5.19 (m, 1H), 7.27 (m, 2H), 7.31 (m, 1H), 7.43 (d, 1H), 7.89 (t, 1H), 8.05 (d, 1H), 8.63 (d, 1H), 8.69 (d, 1H), 9.33 (s, 1H), 9.73 (s, 1H); MS (ESI+) 360 (M+H)+; Elemental: Calculated for C23H25N3O.HCl.0.5H2O: C, 68.22; H, 6.72; N, 10.38. Found: C, 68.31; H, 6.81; N, 10.16.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1C[O:14]CC1.[Cl:16][C:17]1[N:22]2[N:23]=[C:24]([C:26]3[CH:35]=[CH:34][C:33]4[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=4[CH:27]=3)[CH:25]=[C:21]2[N:20]=[C:19]([CH3:36])[C:18]=1[CH2:37][C:38]([O:40][CH3:41])=[O:39].C1(C2ON2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>C1COCC1>[Cl:16][C:17]1[N:22]2[N:23]=[C:24]([C:26]3[CH:35]=[CH:34][C:33]4[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=4[CH:27]=3)[CH:25]=[C:21]2[N:20]=[C:19]([CH3:36])[C:18]=1[CH:37]([OH:14])[C:38]([O:40][CH3:41])=[O:39]
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc2cc(-c3ccc4c(c3)CCCC4)nn2c1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Agent: [K+]
Product: COC(=O)C(O)c1c(C)nc2cc(-c3ccc4c(c3)CCCC4)nn2c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To a stirred solution of 0.9M KHMDS/THF (9.76 mL, 8.79 mmol) in THF (25 mL) at −78° C. was added dropwise a THF (25 mL) solution of methyl 2-(7-chloro-5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)acetate (2.5 g, 6.76 mmol) over 5 min. After 30 min, a THF (20 mL) solution of 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (2.296 g, 8.79 mmol) was added to the resulting red reaction mixture and stirred for additional 30 min at −78° C. Then, the resulting orange reaction mixture was quenched with sat. NH4Cl (50 mL), diluted with EtOAc (200 mL), washed with water (100 mL), brine (100 mL), dried (Na2SO4), filtered and concentrated to give yellow solid. This was purified by flash column chromatography on silica gel column (5-40% EtOAc/hexane) to afford the 2.2 g desired methyl 2-(7-chloro-5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate as off-white solid. Impurities were present by NMR and LCMS. Used in the next step without further purification. 1H NMR (500 MHz, CDCl3) δ 7.77-7.71 (m, 2H), 7.19 (d, J=7.6 Hz, 1H), 6.93 (s, 1H), 5.78 (d, J=2.7 Hz, 1H), 3.86 (s, 3H), 3.56 (d, J=2.7 Hz, 1H), 2.89-1.81 (m, 4H), 2.64 (s, 3H), 1.86 (dt, J=6.5, 3.3 Hz, 4H). LCMS (M+H)=386.3.
Reaction SMILES: [CH2:1]([S:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4].Cl.[CH3:27]O>>[CH2:1]([S:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:22](=[O:24])(=[O:25])[NH2:23])[C:14]=1[O:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:9]([O:11][CH3:27])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCSc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Reactant: CO
Agent: Cl
Product: CCCCSc1cc(C(=O)OC)cc(S(N)(=O)=O)c1Oc1ccccc1
Reaction time: 5 h

Procedure:
A mixture of 3-n-butylthio-4-phenoxy-5-sulfamylbenzoic acid (2.5 g) and methanol (75 ml) is saturated with gaseous hydrogen chloride. The reaction mixture is allowed to warm during saturation. After cooling and standing for 5 hours, the reaction mixture is evaporated in vacuo. The residue is triturated with water and sufficient sodium hydrogen carbonate to neutralize traces of hydrochloric acid. The precipitated methyl 3-n-butylthio-4-phenoxy-5-sulfamylbenzoate is collected and recrystallized from methanol/water to yield the ester with a melting point of 122°-123° C.
Reaction SMILES: Cl.[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][CH3:15])[CH2:10][CH2:9]1.[F:16][C:17]1[CH:18]=[C:19]([S:24](Cl)(=[O:26])=[O:25])[CH:20]=[CH:21][C:22]=1[F:23]>>[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([N:14]([CH3:15])[S:24]([C:19]2[CH:20]=[CH:21][C:22]([F:23])=[C:17]([F:16])[CH:18]=2)(=[O:26])=[O:25])[CH2:12][CH2:13]1
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Reactant: CN[C@H]1CC[C@H](OCCCCBr)CC1
Agent: Cl
Product: CN([C@H]1CC[C@H](OCCCCBr)CC1)S(=O)(=O)c1ccc(F)c(F)c1

Procedure:
In analogy to example 11.9, trans-[4-(4-Bromo-butoxy)-cyclohexyl]-methyl-amine hydrochloride and 3,4-difluoro-benzenesulfonyl chloride (with 2.1 eq N,N-diisopropylethylamine) were reacted to yield trans-N-[4-(4-Bromo-butoxy)-cyclohexyl]-3,4-difluoro-N-methyl-benzenesulfonamide which was used directly in the next steps see Example 12.55-12.56 and 12.65 and 12.66.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.C(N(CC)CC)C.[Br:19][CH2:20][C:21](Br)=[O:22].CCOCC>C(Cl)Cl>[Br:19][CH2:20][C:21]([N:1]1[C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:22]
Reactant: O=C(Br)CBr
Reactant: c1ccc2c(c1)CCCCN2
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CBr)N1CCCCc2ccccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
To a 0° C. solution of 2,3,4,5-Tetrahydro-1H-benzo[b]azepine (5.5 g, 37.4 mmol) and triethylamine (5.21 mL, 37.4 mmol) in anhydrous methylene chloride (180 mL) under N2 was added dropwise bromoacetyl bromide (3.25 mL, 37.4 mmol). The mixture was stirred at 0° C. for 2 h, then allowed to warm to ambient temperature and stirred for 1 h. The mixture was worked up by washing with 0.5 M aq. HCl (100 mL) and brine (100 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated to give the crude product as a brown semi-solid. Trituration with ether gave the product (5.69 g) as a tan solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:54]([C:57]1[C:65]2[O:64][C:63]([CH3:67])([CH3:66])[CH2:62][C:61]=2[CH:60]=[CH:59][CH:58]=1)=[C:55]=[O:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:48][CH2:49][N:50]([C:55]([NH:54][C:57]2[C:65]3[O:64][C:63]([CH3:67])([CH3:66])[CH2:62][C:61]=3[CH:60]=[CH:59][CH:58]=2)=[O:56])[CH2:51][CH2:52]1
Reactant: Clc1cnc2nc1Nc1ccc(OCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Reactant: CC1(C)Cc2cccc(N=C=O)c2O1
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)Cc2cccc(NC(=O)N3CCC(CCOc4ccc5cc4CCc4cncc(c4)Nc4ncc(Cl)c(n4)N5)CC3)c2O1
Yield: 60 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using 6-chloro-12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 7-isocyanato-2,2-dimethyl-2,3-dihydro-1-benzofuran as the starting materials in 60% yield. LCMS for C35H39ClN7O3 (M+H)+: m/z=640.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][CH2:18]C)=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH2:15])[N:9]=2)[CH:7]=1.NC1N=C(C2C=C(Br)C=CC=2O)C=C(Cl)N=1.[N:36]1(CCO)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][CH2:18][N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH2:15])[N:9]=2)[CH:7]=1
Reactant: CCCOc1ccc(Br)cc1-c1cc(Cl)nc(N)n1
Reactant: OCCN1CCOCC1
Agent: Nc1nc(Cl)cc(-c2cc(Br)ccc2O)n1
Product: Nc1nc(Cl)cc(-c2cc(Br)ccc2OCCN2CCOCC2)n1
Yield: 41 %

Procedure:
Following the method described in Example 135 for the synthesis of 4-(5-bromo-2-propoxy-phenyl)-6-chloro-pyrimidin-2-ylamine, 2-(2-amino-6-chloro-pyrimidin-4-yl)-4-bromo-phenol and 2-morpholin-4-yl-ethanol provided 4-[5-bromo-2-(2-morpholin-4-yl-ethoxy)-phenyl)-6-chloro-pyrimidin-2-ylamine (41% yield).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[S:7](Cl)(=[O:9])=[O:8].[NH:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1>>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[S:7]([N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1)(=[O:9])=[O:8]
Reactant: c1cc[nH]c1
Reactant: O=S(=O)(Cl)c1sccc1Br
Product: O=S(=O)(c1sccc1Br)n1cccc1

Procedure:
N-(3-Bromothiophene-2-sulfonyl)pyrrole was prepared in the same manner as described in Example 14A by reacting 3-bromothiophene-2-sulfonyl chloride with pyrrole (for 16 hr). N-(3-Bromothiophene-2-sulfonyl)pyrrole was obtained in 54% yield.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[C-:10]#[N:11].[Na+].[CH3:13][NH2:14].Cl>CO.O>[CH3:10][NH:11][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:2])[C:13]#[N:14]
Reactant: [C-]#N
Reactant: CC(=O)c1ccccc1
Reactant: CN
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNC(C)(C#N)c1ccccc1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
To a solution of acetophenone (10 g) in 50 mL methanol, a solution of sodium cyanide (12.23 g) and methylamine.HCl (16.71 g) in 50 mL water was added slowly at room temp. The reaction mixture was heated at 40° C. for 2 h and then at room temperature for 18 h and was monitored by TLC. After completion, the reaction mixture was extracted with 3×100 mL dichloromethane. The organic layer was then dried over Na2SO4 and concentrated to afford the desired 2-methylamino-2-phenyl-propionitrile (12.5 g) which was used in the next step without further purification.
Reaction SMILES: ClCCC[N:5]1[C:9]2[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:8]=2[N:7]=[N:6]1.[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:17]1.[CH:31](N(C(C)C)CC)([CH3:33])[CH3:32].[I-].[K+]>C(#N)C>[O:14]([C:11]1[CH:12]=[C:13]([CH2:32][CH2:31][CH2:33][N:28]2[CH2:29][CH2:30][CH:25]([C:18]3[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:16][CH:17]=3)[CH2:26][CH2:27]2)[C:8]2[N:7]=[N:6][NH:5][C:9]=2[CH:10]=1)[CH3:15]
Reactant: CCN(C(C)C)C(C)C
Reactant: c1ccc2c(C3CCNCC3)coc2c1
Reactant: COc1ccc2nnn(CCCCl)c2c1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(CCCN2CCC(c3coc4ccccc34)CC2)c2nn[nH]c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.5 %

Procedure:
N-(3-chloropropyl)-6-methoxyl benzotriazole (0.06 mol) was dissolved into 150 ml of acetonitrile, 4-(3-benzofuranyl) piperidine (0.05 mol), diisopropylethylamine (0.2 mol) and potassium iodide (0.05 mol) were respectively added. The mixture was stirred for 10 min at ambient temperature, and then heated and refluxed to react for 15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3, purified, eluted with dichloromethane/methanol mixture to produce 12.40 g N-(3-(6-methoxyl benzotriazolyl)propyl)-4-(3-benzofuranyl)piperidine (I-102) with a yield of 68.1%. ESI-MS [M+H]+: m/z 409.2.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[CH2:21][N:22]2[C@@H:26]([CH3:27])[C@@H:25]([C:28]3[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=3)[CH:31]=O)[O:24][C:23]2=[O:36])=[C:4]([O:37][CH3:38])[CH:3]=1.[CH3:39][NH2:40].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl.C1COCC1>[F:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][C:12]=2[CH2:21][N:22]2[C@@H:26]([CH3:27])[C@@H:25]([C:28]3[CH:35]=[CH:34][CH:33]=[C:30]([CH2:31][NH:40][CH3:39])[CH:29]=3)[O:24][C:23]2=[O:36])=[C:4]([O:37][CH3:38])[CH:3]=1
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cccc(C=O)c2)[C@@H]1C
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNCc1cccc([C@H]2OC(=O)N(Cc3cc(C(F)(F)F)ccc3-c3cc(C(C)C)c(F)cc3OC)[C@H]2C)c1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a solution of 3-((4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-2-oxo-1,3-oxazolidin-5-yl)benzaldehyde (15 mg, 0.028 mmol) in 1,2-dichloroethane (1 mL) was added methylamine (1 mL of a 2.0 M solution in THF). The resulting mixture was treated with sodium triacetoxyborohydride (34.8 mg, 0.16 mmol) and AcOH (0.05 mL). The mixture was stirred under N2 at room temperature for 5 days. The reaction mixture was quenched with 1N NaOH and the aqueous layer was extracted with ether (3×15 mL). The ether extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (Si) to afford (4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-5-{3-[(methylamino)methyl]phenyl}-1,3-oxazolidin-2-one. LCMS calc.=545.23; found=545.4 (M+1)+. 1H NMR (500 MHz, CDCl3, 1:1 mixture of atropisomers) δ 7.74 (s, 0.5H); 7.67 (s, 0.5H); 7.64 (s, 0.5H); 7.62 (s, 0.5H); 7.33 (m, 3H); 7.20 (s, 1H); 7.13 (s, 0.5H); 7.12 (s, 0.5H); 7.01 (d, J=8.4 Hz, 0.5H); 6.98 (d, J=8.5 Hz, 0.5H); 6.71 (d, J=2.9 Hz, 0.5H); 6.68 (d, J=2.8 Hz, 0.5H); 5.51 (d, J=8.1 Hz, 0.5H); 5.37 (d, J=8.0 Hz, 0.5H); 4.82 (d, J=15.9 Hz, 0.5H); 4.75 (d, J=15.9 Hz, 0.5H); 4.16 (d, J=15.9 Hz, 0.5H); 3.92 (d, J=15.9 Hz, 0.5H); 3.77 (m, 5.5H); 3.70 (t, J=6.6 Hz, 0.5H); 3.25-3.18 (m, 1H); 2.45 (s, 3H); 1.93 (br, s, 1H); 1.27 (m, 4.5H); 1.19 (d, J=6.9 Hz, 1.5H); 0.53 (d, J=6.5 Hz, 1.5H); 0.40 (d, J=6.5 Hz, 1.5H).
Reaction SMILES: Cl.[C:2]([NH2:6])([CH3:5])([CH3:4])[CH3:3].C(N)(C)(C)C.Cl.[Br:13][CH2:14][CH2:15][C:16](Cl)=[O:17].C(N(CC)C(C)C)(C)C>C(Cl)Cl.CCOCC>[C:2]([NH:6][C:16](=[O:17])[CH2:15][CH2:14][Br:13])([CH3:5])([CH3:4])[CH3:3]
Reactant: O=C(Cl)CCBr
Reactant: CC(C)(C)N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)CCBr
Temperature: 25 °C
Reaction time: 2.75 h

Procedure:
To a suspension of t-butylamine hydrochloride (prepared by treatment of an Et2O solution of t-butylamine (2.7 mL, 1.9 g, 0.026 mol) with HCl) in a solution of 3-bromopropionic acid chloride (4.47 g, 0.0261 mol) with CH2Cl2 (145 mL) was added N,N-diisopropylethylamine (9.1 mL, 6.8 g, 0.052 mol) over 10-15 minutes at room temperature. The solution was stirred at room temperature for 2.5-3 hours. A few mL's of N,N-diisopropylethylamine were added until the solution became homogeneous. The solution was washed twice with dilute HCl and once with H2O, dried with MgSO4 and evaporated to provide 3.34 g of N-tert-butyl 3-bromopropanamide and N-tert-butyl acrylamide (approximately 36%/64% by weight). The reaction mixture was taken up in EtOH (200 mL), and to the solution of amides was added 1-(2-pyrimidinyl)piperazine dihydrochloride (6.82 g, 0.0288 mol) and sodium acetate (4.72 g, 0.0575 mol). The mixture was refluxed for 8 days. The solvent was evaporated. The residue was partitioned between CH2Cl2 and aqueous Na2CO3. The CH2Cl2 phase was washed with aqueous NaCl and dried with MgSO4. Evaporation of the CH2Cl2 gave 5.61 of crude compound which was purified by HPLC to give 4.13 g of free base. Treatment in EtOH with HCl gave the title compound, 4.48 g (46%), mp 220°-222° C.
Reaction SMILES: [CH3:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:10]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1)([OH:12])=[O:11]>>[C:10]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[N:4][C:3]2[CH:5]=[CH:6][CH:7]=[C:8]([Cl:9])[C:2]=2[CH3:1])=[CH:15][CH:14]=1)([OH:12])=[O:11]
Reactant: Cc1c(N)cccc1Cl
Reactant: O=Cc1ccc(C(=O)O)cc1
Product: Cc1c(Cl)cccc1N=Cc1ccc(C(=O)O)cc1
Reaction time: 1.5 h

Procedure:
2-methyl-3-chloroaniline (0.25 moles) and p-carboxybenzaldehyde (0.25 moles) were ground in a mortar. The mixture was heated, with stirring in a water bath for 1.5 hours. Distillation at reduced pressure gave N-(p-carboxybenzylidene)-2-methyl-3-chloroaniline as a second fraction.
Reaction SMILES: [Br:1]([O-])(=O)=O.[Na+].[CH3:6][C:7]1[O:8][C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:10][C:11]=1[C:12]([O:14][CH3:15])=[O:13].S([O-])(O)=O.[Na+].C(OCC)C>O.C1CCCCC1>[Br:1][CH2:6][C:7]1[O:8][C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:18][CH:17]=2)=[CH:10][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)oc1C
Reactant: [O-][Br+2]([O-])[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: O
Solvent: CCOCC
Product: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)oc1CBr
Temperature: 10 °C

Procedure:
A solution of sodium bromate (8.14 g) in water (27 ml) was treated with a suspension of methyl 2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furoate (intermediate 23, 5.12 g) in cyclohexane (36 ml). The system was cooled to <10° C. in ice/water bath and treated with a solution of sodium hydrogen sulfite (9.4 g) in water (54 ml) in a drop-wise manner over 30 minutes. The reaction was allowed to warm up to 10° C. for 2 hours and then poured into diethylether (400 ml) and washed with fresh water. The organic layer was washed with 10% sodium thiosulfite solution and dried over magnesium sulfate. The crude product isolated by evaporation, was pre-adsorbed onto silica and purified by flash column chromatography using 39:1 cyclohexane:ethyl acetate as eluent to give the title compound as a white powder.
Reaction SMILES: P(=O)(O)(O)O.[ClH:6].N[C:8]1[C:9]([CH3:19])=[N:10][S:11][C:12]=1[O:13][CH2:14][C:15]([F:18])([F:17])[F:16].N([O-])=O.[Na+].[S:24](=[O:26])=[O:25]>C(O)(=O)C>[CH3:19][C:9]1[C:8]([S:24]([Cl:6])(=[O:26])=[O:25])=[C:12]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[S:11][N:10]=1
Reactant: Cc1nsc(OCC(F)(F)F)c1N
Reactant: O=S=O
Reactant: Cl
Agent: O=N[O-]
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1nsc(OCC(F)(F)F)c1S(=O)(=O)Cl
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
5 ml of acetic acid, 6 ml of 85% phosphoric acid, and 3 ml of concentrated hydrochloric acid was added to 2.1 g of 4-amino-3-methyl-5-(2,2,2-trifluoroethoxy)isothiazole prepared in the above step (2). 2 ml of aqueous solution containing 0.77 g of sodium nitrite was added dropwise to the above mixture at -20° to -10° C. The resulted solution was stirred at -5° C. for 30 minutes and was gradually added dropwise at -10° to -5° C. into 30 ml of an acetic acid solution, which had been saturated with sulfur dioxide and had contained 0.3 g of cuprous chloride. After the completion of dropping, the resulted solution was stirred and reacted at 0° to 5° C. for an hour. After the completion of the reaction, the reaction mixture was poured into ice-cold water, and was extracted with dichloromethane, and the extracted layer was sufficiently washed with water and dried. The solvent was subjected to distillation under reduced pressure to give 1.2 g of oily 3-methyl-5-(2,2,2-trifluoroethoxy)-4-isothiazolesulfonyl chloride.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][O:20][C:21]1[CH:34]=[CH:33][C:24]([C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:26])=[C:23]([OH:35])[CH:22]=1>>[S:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:18][CH2:19][O:20][C:21]2[CH:34]=[CH:33][C:24]([C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:26])=[C:23]([OH:35])[CH:22]=2)=[CH:7][CH:6]=1
Reactant: Oc1ccc(-c2nc3ccccc3s2)cc1
Reactant: O=C(c1ccccc1)c1ccc(OCCBr)cc1O
Product: O=C(c1ccccc1)c1ccc(OCCOc2ccc(-c3nc4ccccc4s3)cc2)cc1O

Procedure:
A hot solution of 16 g. of zinc, o-aminophenylmercaptide and 12.5 g. of p-hydroxybenzaldehyde in 1 l. of acetic acid was treated with hydrogen sulfide for two hours, filtered hot, diluted with an equal volume of water and cooled. 2-(p-Hydroxyphenyl)benzothiazole (47% yield, m.p. 227°-229° F.) was obtained. The 2-(p-hydroxyphenyl)benzothiazole was reacted with 4-(2-bromoethoxy)-2-hydroxybenzophenone as in Example 1 to produce 4-(2-[4-(2-benzothiazolyl)phenoxy]ethoxy)-2-hydroxybenzophenone.
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7](O)[CH:8]=[CH:9][C:3]=2[O:2]1.[H-].[Na+].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].CN(C=[O:26])C>>[CH2:14]([O:26][C:6]1[C:4]2[O:5][CH2:1][O:2][C:3]=2[CH:9]=[CH:8][CH:7]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCBr
Reactant: Oc1ccc2c(c1)OCO2
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CCCCCCCCOc1cccc2c1OCO2
Reaction time: 120 h

Procedure:
A solution of sesamol (6.9 g; 50 mmol) in DMF (100 mL) under N2 was cooled to 0° C. and sodium hydride (60% w/w dispersion; 2.3 g; 60 mmol) carefully added. The slurry was allowed to warm to room temperature over 1 hour after which time 1-bromooctane (13 mL; 75 mmol) was added. The mixture was stirred for 5 days, poured onto H2O and extracted with diethylether (2×). The combined organic fractions were dried (MgSO4), filtered and evaporated in vacuo to yield 12.8 g (quantitative yield) of a white solid. Mp. 120° C.