Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][CH:19]([C:34]2[N:39]=[CH:38][C:37]([NH2:40])=[CH:36][N:35]=2)[C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2].[C:43](Cl)(=[O:45])[CH3:44].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][CH:19]([C:34]2[N:35]=[CH:36][C:37]([NH:40][C:43](=[O:45])[CH3:44])=[CH:38][N:39]=2)[C:20]2[CH:21]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](NC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(N)cn2)C[C@H]1CC
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](NC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(NC(C)=O)cn2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(2R*,4S*)-4-{(5-Aminopyrimidin-2-yl)-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (150 mg) is dissolved in N,N-dimethylformamide (4 ml), then thereto are added acetyl chloride (0.03 ml) and triethylamine (0.1 ml), and the mixture is stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution is added to the reaction solution and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane: ethyl acetate=4:1→1:1) to give (2R*,4S*)-4-{(5-acetylaminopyrimidin-2-yl)-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (132 mg). MS (m/z): 641 [M+H]+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:16][CH:15]=2)[C@@H:10]([O:30][CH2:31][C:32]2[CH:41]=[C:40]3[C:35]([CH2:36][CH2:37][CH2:38][N:39]3[CH2:42][CH2:43][CH2:44][OH:45])=[CH:34][CH:33]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:46][S:47](Cl)(=[O:49])=[O:48]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]([F:27])([F:29])[F:28])=[CH:18][CH:19]=2)[C@@H:10]([O:30][CH2:31][C:32]2[CH:41]=[C:40]3[C:35]([CH2:36][CH2:37][CH2:38][N:39]3[CH2:42][CH2:43][CH2:44][O:45][S:47]([CH3:46])(=[O:49])=[O:48])=[CH:34][CH:33]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCCCOCC(F)(F)F)cc2)[C@@H](OCc2ccc3c(c2)N(CCCO)CCC3)C1
Reactant: CS(=O)(=O)Cl
Product: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCCCOCC(F)(F)F)cc2)[C@@H](OCc2ccc3c(c2)N(CCCOS(C)(=O)=O)CCC3)C1

Procedure:
In analogy to the procedure described in example 8(b), the (3R,4R)-3-[1-(3-hydroxy-propyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2,2,2-trifluoro-ethoxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester was reacted with methanesulfonyl chloride to yield the (3R,4R)-3-[1-(3-methanesulfonyloxy-propyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2,2,2-trifluoro-ethoxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester which was used without further purification or characterization.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[Br:12][C:13]1[CH:14]=[C:15]([C:18](O)=[O:19])[S:16][CH:17]=1>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:18]([C:15]1[S:16][CH:17]=[C:13]([Br:12])[CH:14]=1)=[O:19])[CH2:4]2
Reactant: O=C(O)c1cc(Br)cs1
Reactant: N[C@H]1CN2CCC1CC2
Agent: Cl
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc(Br)cs1

Procedure:
Prepared by a method analogous to that described for the preparation of Intermediate 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and 4-bromothiophene-2-carboxylic acid. The residue from evaporation of the reaction mixture was partitioned between aqueous hydrochloric acid and chloroform. The aqueous layer was then basified with aqueous sodium hydroxide and extracted with chloroform. The organic extracts were dried (MgSO4), filtered, and evaporated and resulting solid was recrystallised from ethyl acetate/hexane to give the title compound as a colourless solid; MS (ES+) 315, 317 (MH+).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.[Cl:22][C:23]1[C:24]([CH2:33][NH2:34])=[N:25][CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1>ClCCl>[Cl:22][C:23]1[C:24]([CH2:33][NH:34][C:7]([C:5]2[O:6][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:9])=[N:25][CH:26]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:28]=1
Reactant: NCc1ncc(C(F)(F)F)cc1Cl
Reactant: O=C(O)c1ccc(Br)o1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Product: O=C(NCc1ncc(C(F)(F)F)cc1Cl)c1ccc(Br)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-bromofuroic acid (0.19 g) and carbonyl diimidazole (CDI) in dichloromethane was added (3-chloro-5-trifluoromethyl-2-pyridyl)methylamine and the mixture was stirred at room temperature overnight. The mixture was washed with 2M hydrochloric acid, then saturated sodium bicarbonate, dried (MgSO4) and evaporated to give the title product, m.p. 77.8° C.
Reaction SMILES: [C:1]1([C:9]([CH:11]([C:13]2[CH:20]=[CH:19][C:16]([O:17][CH3:18])=[CH:15][CH:14]=2)O)=[O:10])[CH:8]=[CH:7][C:4]([O:5][CH3:6])=[CH:3][CH:2]=1.N1C=CC=CC=1.S(Cl)([Cl:29])=O.O>CCOCC>[CH3:6][O:5][C:4]1[CH:7]=[CH:8][C:1]([C:9]([CH:11]([Cl:29])[C:13]2[CH:20]=[CH:19][C:16]([O:17][CH3:18])=[CH:15][CH:14]=2)=[O:10])=[CH:2][CH:3]=1
Reactant: COc1ccc(C(=O)C(O)c2ccc(OC)cc2)cc1
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(C(=O)C(Cl)c2ccc(OC)cc2)cc1
Reaction time: 1 h
Yield: 35.2 %

Procedure:
One hundred grams (0.37 mole) of anisoin and 45 ml (0.55 mole) of pyridine were placed in a beaker and heated until the anisoin was completely in solution. After cooling the beaker in an ice bath, a solid was formed. This solid was broken up and then 36 ml (0.50 mole) of thionyl chloride was added with stirring, forming a liquid mixture. After 1 hr, 250 ml water was added and the organic materials extracted with ether, washed with water, dried over Na2SO4 and evaporated to afford a crude oil. Most of the oil was taken up in ether and a residual solid was filtered away. Cooling resulted in a yellow-brown solid which was filtered and collected. Recrystallization again from ether yielded 37.9 g (36%) of a solid. The product had a melting point of about 80°-81° C.
Reaction SMILES: [CH2:1]([NH:8][NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11]([CH3:18])([CH3:17])[C:12](=O)[CH2:13][C:14]#[N:15]>>[CH2:1]([N:8]1[C:14]([NH2:15])=[CH:13][C:12]([C:11]([CH3:18])([CH3:17])[CH3:10])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNCc1ccccc1
Product: CC(C)(C)c1cc(N)n(Cc2ccccc2)n1
Yield: 36.3 %

Procedure:
Following the procedure in Example 161A Step 3, benzylhydrazine (977 mg, 8.0 mmol) and 4,4-dimethyl-3-oxopentanenitrile (1.0 g, 8.0 mmol) to give 1-benzyl-3-tert-butyl-1H-pyrazol-5-amine (666 mg, 2.90 mmol, 36%). 1H NMR (300 MHz, DMSO-d6) δ 7.32-7.21 (m, 3H), 7.09 (d, 2H), 5.17 (s, 1H), 5.05 (d, 4H), 1.15 (s, 9H); LC-MS (ESI) m/z 230 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([S:16][CH3:17])[C:4]=1[C:5]([OH:7])=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:51][CH:52]1[CH2:57][CH2:56][CH2:55][CH2:54][C:53]1=[O:58]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([S:16][CH3:17])[C:4]=1[C:5]([NH:51][CH:52]1[CH2:57][CH2:56][CH2:55][CH2:54][C:53]1=[O:58])=[O:7]
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)O
Reactant: NC1CCCCC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoic acid (intermediate A, 400 mg, 1.5 mmol) was dissolved in 10 mL dimethylformamide. N,N-Diisopropyl ethyl amine (505 mg, 3.9 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (571 mg, 1.5 mmol) were added. After 5 minutes of stirring at room temperature 2-amino-cyclohexanone (CAS 6946-05-0) (247 mg, 1.6 mmol) was added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated off. The residue was taken up in 2N sodium carbonate solution and ethyl acetate and was extracted three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (heptane/ethyl acetate 1:0→0:1) yielded 2-methoxy-6-methylsulfanyl-N-(2-oxo-cyclohexyl)-4-trifluoromethyl-benzamide as a white foam (370 mg, 68%), MS: m/e=362.2 [(M+H)+].
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][C:14]([O-:16])=[O:15])=[C:5]1[CH2:17][S:18][C:19](=O)[CH3:20])(=O)C.[OH-].[K+].Cl[CH2:25][C:26]1[CH:27]=[C:28]([CH2:32][C@H:33]([NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])[C:34]([N:36]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[CH3:37])=[O:35])[CH:29]=CC=1.Cl.[CH2:55](O)[CH3:56]>>[C:49]([O:48][C:47]([NH:46][C@H:33]([C:34]([N:36]([C:38]1[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=1)[CH3:37])=[O:35])[CH2:32][C:28]1[CH:29]=[C:20]([CH:25]=[CH:26][CH:27]=1)[CH2:19][S:18][CH2:17][C:5]1[NH:4][C:12]2[C:7]([C:6]=1[CH2:13][C:14]([O:16][CH2:55][CH3:56])=[O:15])=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:53])([CH3:50])([CH3:51])[CH3:52]
Reactant: COc1ccc(N(C)C(=O)[C@H](Cc2cccc(CCl)c2)NC(=O)OC(C)(C)C)cc1
Reactant: CCO
Reactant: CC(=O)SCc1c(CC(=O)[O-])c2ccccc2n1C(C)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CCOC(=O)Cc1c(CSCc2cccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)c3ccc(OC)cc3)c2)[nH]c2ccccc12
Reaction time: 0.17 h

Procedure:
To a solution 2-(1-acetyl-2-(acetylthiomethyl)-1H-indol-3-yl)acetate (392 mg, 1.17 mmol) in ethanol (10 ml), was added potassium hydroxide (0.13 g, 2.32 mmol). After 10 minutes, (S)-tert-butyl 3-(3-(chloromethyl)phenyl)-1-((4-methoxyphenyl)(methyl)amino)-1-oxopropan-2-ylcarbamate (507 mg, 1.17 mmol) was added to the solution. The reaction was stirred for 2 hours and then neutralized with 1N (aq) HCl. The mixture was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was introduced to a silica gel loading column and purified by column chromatography (3-6% MeOH/DCM) to provide the desired product (650 mg, 1.0 mmol), 85%. MS (m/z) 646 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH3:11])[CH3:10].Cl[Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])=[CH:4][C:3]=1[CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)c1cc(O)ccc1Br
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1cc(O[Si](C)(C)C(C)(C)C)ccc1Br
Yield: 86.8 %

Procedure:
A solution of 4-bromo-3-isopropyl-phenol (Intermediate 144, 1.13 g, 5.25 mmols), chloro-tert-butyl-dimethylsilane (0.95 g, 6.30 mmols), and imidazole (428.0 mg, 6.3 mmols) in 10 mL DMF was stirred at 25° C. for 3 hours. The solution was diluted with H2O and extracted with Et2O and the combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (MgSO4) before being concentrated under reduced pressure. Column chromatography (1-2% EtOAc-hexanes) afforded 1.50 g (87%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].[Br:8][C:9]([CH3:14])([CH3:13])[C:10](Br)=[O:11]>C1COCC1>[Br:8][C:9]([CH3:14])([CH3:13])[C:10]([NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])=[O:11]
Reactant: CN(C)CCCN
Reactant: CC(C)(Br)C(=O)Br
Solvent: C1CCOC1
Product: CN(C)CCCNC(=O)C(C)(C)Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-dimethylaminopropylamine (25 ml, 0.1 mol) in THF (50 ml) was added dropwise over 50 minutes and while keeping the temperature between 0-10° C. bromoisobutyroyl bromide (23.0 g, 0.1 mol). The mixture is stirred for another 3 h at room temperature and the THF is then evaporated in vacuo. Water (20 ml) is added to the residue and the mixture is extracted with t-butyl-methyl ether (2×30 ml) and ethylacetate (30 ml).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1.[C:9](=[O:12])(O)[O-].[Na+].[CH2:14]([O:21][CH2:22][C:23](Cl)=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(OCC)(=O)C>[CH2:14]([O:21][CH2:22][C:23]([NH:7][C:4]1[CH:5]=[CH:6][C:1]([NH:8][C:9](=[O:12])[CH2:22][O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:2][CH:3]=1)=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccc(N)cc1
Reactant: O=C([O-])O
Reactant: O=C(Cl)COCc1ccccc1
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(COCc1ccccc1)Nc1ccc(NC(=O)COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a mixture of 1,4-phenylenediamine (10 grams, 92.47 mmol), sodium bicarbonate (15.46 grams, 184.07 mmol) in ethyl acetate (100 mL) at 0° C. is added benzyloxy acetyl chloride (23.19 grams, 125.71 mmol) drop wise. The reaction mixture is stirred at room temperature for 10 hours. The solids are filtered, and the ethyl acetate layer is washed with 5% sodium bicarbonate solution (2×25 mL), water (2×25 mL), dried over sodium sulfate, and distilled to get crude 3, which can be purified by suitable solvent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:14]([O:16]C)=O)[C:10]([O:12]C)=O.[CH3:18][C:19]1[O:23][C:22]([C:24]2[CH:28]=[N:27][NH:26][C:25]=2[NH2:29])=[N:21][N:20]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([OH:12])=[N:29][C:25]2[N:26]([N:27]=[CH:28][C:24]=2[C:22]2[O:23][C:19]([CH3:18])=[N:20][N:21]=2)[C:14]=1[OH:16]
Reactant: COC(=O)C(C(=O)OC)c1ccc(F)cc1Cl
Reactant: Cc1nnc(-c2cn[nH]c2N)o1
Product: Cc1nnc(-c2cnn3c(O)c(-c4ccc(F)cc4Cl)c(O)nc23)o1
Temperature: 185 °C
Reaction time: 3 h

Procedure:
0.789 g of dimethyl 2-chloro-4-fluorophenylmalonate and 0.79 ml of tributyalmine were added to 0.5 g of the 4-(5-methyl-[1,3,4]oxadiazol-2-yl)-2H-pyrazol-3-ylamine obtained under Ac), and the mixture was stirred at 185° C. for 3 h. Concentration gave a glass-like substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=3)[C:15](=[O:24])[N:14]2[CH3:25])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:26]=[C:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=3)[C:15](=[O:24])[N:14]2[CH3:25])[CH2:10][CH2:11][N:36]2[CH2:37][CH2:38][CH:33]([N:28]3[CH2:29][CH2:30][CH2:31][CH2:32][C:27]3=[O:26])[CH2:34][CH2:35]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc2c(c1)C(=O)N(C)C2C(CC=O)c1ccc(Cl)c(Cl)c1
Reactant: O=C1CCCCN1C1CCNCC1
Product: COc1ccc2c(c1)C(=O)N(C)C2C(CCN1CCC(N2CCCCC2=O)CC1)c1ccc(Cl)c(Cl)c1
Product: Cl
Yield: 56.2 %

Procedure:
3-(3,4-Dichlorophenyl)-3-(5-methoxy-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.366 g) was coupled to 4-(2-oxopiperidino)piperidine (0.176 g) by a method similar to that described in Example 8. The reaction product was purified by chromatography and converted to the corresponding hydrochloride salt as described in the Example 8 to afford the title compound (0.158 g); mp 154°-156° C.; MS: m/z=544(M+1); NMR(CD3OD): 2.3 (m,13), 3.4 (s,3), 4.5 (m,1), 4.8 (d,1, J=3.8), 6.71 (dd,1, J=2, 8.4), 6.9 (d,1, J=2), 7.13 (d,1, J=2.4), 7.24 (m,2), 7.77 (d,1, J=8.4), Analysis for C29H35Cl2N3O3.1.0 HCl.1.1H2O: Calculated: C, 59.95; H, 6.24, N, 7.23; Found: C, 57.97; H, 6.24; N, 6.73.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[I-:16].[Na+].CC1C=CC(S([N-]Cl)(=O)=O)=CC=1.O.O.O.[Na+].Cl>CN(C=O)C.O>[CH2:6]([O:5][P:4]([C:9]1[CH:14]=[C:13]([I:16])[CH:12]=[CH:11][C:10]=1[OH:15])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: [I-]
Reactant: CCOP(=O)(OCC)c1ccccc1O
Agent: Cc1ccc(S(=O)(=O)[N-]Cl)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)c1cc(I)ccc1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.5 %

Procedure:
To a cooled (0° C.) mixture of (2-hydroxy-phenyl)-phosphonic acid diethyl ester (13.1 g, 56.9 mmol) and sodium iodide (10.2 g, 68.3 mmol) in DMF (200 mL) was added chloramine-T trihydrate (19.2 g, 68.3 mmol) over 5 min. After 10 min, the reaction was allowed to warm to rt and the mixture was allowed to stir at rt for 2 h. The mixture was diluted with H2O (50 mL), acidified using 0.5 N HCl and extracted twice with EtOAc. The organic extracts were pooled and washed sequentially with satd. Na2S2O3/brine (1/1) and then brine. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was chromatographed over silica gel (elution with a stepwise gradient 5-15% EtOAc-hexanes) to give 14.9 g (73%) of a colorless solid after recrystallization (EtOAc-hexanes). Rf 0.30 (20% EtOAc-hexanes). Electrospray Mass Spectrum (50/50 acetonitrile/water) m/z 357 (M+H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:19]=[C:9]2[N:10]=[C:11](S(C)(=O)=O)[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=1.[NH:20]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CC#N>[N:20]1([C:11]2[N:12]=[C:13]([NH2:14])[N:8]3[N:7]=[C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)[CH:19]=[C:9]3[N:10]=2)[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1
Reactant: CS(=O)(=O)c1nc(N)n2nc(-c3ccco3)cc2n1
Reactant: C1CNCCNC1
Solvent: CC#N
Product: Nc1nc(N2CCCNCC2)nc2cc(-c3ccco3)nn12
Temperature: 25 °C

Procedure:
7-Furan-2-yl-2-methanesulfonyl-pyrazolo[1,5-a][1,3,5]triazin-4-ylamine (18 mmol; see Example 12(a) above) was suspended in 50 mL of CH3CN along with 5 eq. of homopiperazine. The reaction mixture was stirred under reflux for 2 hours. It was then cooled to room temperature and concentrated under reduced pressure. The residue was taken up in CH2Cl2 and washed with H2O, brine, dried with Na2SO4, and concentrated under reduced pressure. The resulting crude product was purified by chromatography (95% CH2Cl2, 4% MeOH, 1% Et3N) to afford 2-[1,4]Diazepan-1-yl-7-furan-2-yl-pyrazolo[1,5-a][1,3,5]triazin-4-ylamine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=2[C:7]=1[C:19]#[N:20].[N:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1)=[C:25]=[O:26]>CN(C)C=O.C(OCC)(=O)C>[C:19]([C:7]1[C:8]2[S:12][C:11]([NH:13][C:14](=[O:16])[CH3:15])=[N:10][C:9]=2[CH:17]=[CH:18][C:6]=1[O:5][C:4]1[CH:21]=[CH:22][CH:23]=[C:2]([NH:1][C:25](=[O:26])[NH:24][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:36])[F:35])[CH:28]=2)[CH:3]=1)#[N:20]
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)c(C#N)c2s1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)Nc4cccc(C(F)(F)F)c4)c3)c(C#N)c2s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.2 %

Procedure:
N-[6-(3-Aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]acetamide (120 mg, 0.369 mmol) produced in Example 12(ii) was dissolved in N,N-dimethylformamide (2 mL), 1-isocyanato-3-(trifluoromethyl)benzene (66 μL, 0.48 mmol) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (10 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (5 mL) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (methanol/ethyl acetate=0/100→5/95), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from methanol to give the title compound (106 mg, 56%) as a white powder.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1.C(N(CC)C(C)C)(C)C.[F:19][C:20]([F:32])([F:31])[C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C(Cl)Cl>[OH:9][C@H:6]1[CH2:7][CH2:8][C@H:3]([N:2]([CH3:1])[S:27]([C:24]2[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:31])[F:32])=[CH:26][CH:25]=2)(=[O:29])=[O:28])[CH2:4][CH2:5]1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CN[C@H]1CC[C@H](O)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN([C@H]1CC[C@H](O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
To 3 g (23.2 mmol) trans-4-Methylamino-cyclohexanol in 120 ml CH2Cl2 were added 4.2 ml (24.4 mmol, 1.05 eq) N,N-diisopropylethylamine followed by 5.96 g (24.4 mmol, 1.05 eq) 4-(trifluoromethyl)-benzenesulfonyl chloride in 50 ml CH2Cl2. The mixture was stirred at RT over night and the organic phase extracted with 1M KHSO4, followed by 5% NaHCO3 and brine. The combined organic phases were washed with brine, dried over Na2SO4 and evaporated. Column chromatography on silica gel with hexane:EtOAc 1:1 yielded 6.0 g (77%) trans-N-(4-Hydroxy-cyclohexyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide as off-white solid, MS: 338 (MH+).
Reaction SMILES: C(Br)Br.[C:4](Cl)(=O)C.[C:8]1([O:17][CH3:18])[CH:16]=[CH:15][C:11]([CH2:12][CH:13]=[CH2:14])=[CH:10][CH:9]=1.CC(OC)(C)C>C(OCC)C.[Zn].Cl[Cu]>[CH:13]1([CH2:12][C:11]2[CH:15]=[CH:16][C:8]([O:17][CH3:18])=[CH:9][CH:10]=2)[CH2:4][CH2:14]1
Reactant: C=CCc1ccc(OC)cc1
Reactant: CC(=O)Cl
Agent: Cl[Cu]
Agent: [Zn]
Solvent: BrCBr
Solvent: CCOCC
Solvent: COC(C)(C)C
Product: COc1ccc(CC2CC2)cc1
Temperature: 45 °C
Reaction time: 12 h
Yield: 589.7 %

Procedure:
CH2Br2 (220 g) was added to a slurry of zinc powder (340 g) and CuCl (54 g) in diethyl ether (450 ml). The reaction was started by the addition of acetyl chloride (8 g). The reaction mixture was heated to 45° C. and a solution of estragol (192 g) in ether (150 ml) was added during 25 minutes. Additional CH2Br2 (456 g) dissolved in ether (150 ml) was dropped into the grey-red suspension during 45 minutes. Afterwards, the mixture was stirred at 50° C. for 12 hours. The suspension was cooled to room temperature and MTBE (900 ml) was added. The mixture was filtered through celite, and the filtrate was washed with saturated NH4Cl, water, saturated NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo. The residue was distilled (b.p. 90-95° C./0.1 Torr) to yield 97.5 g (46%) of a colorless oil, which was found to have the following characteristics, NMR and MS spectra.