Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[H-].[Na+].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1.Cl>C1COCC1.CCOCC.C(OCC)(=O)C>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:1][C:21](=[O:22])[NH:20][C:17]2[CH:18]=[CH:19][C:14]([C:13]([F:12])([F:24])[F:23])=[CH:15][CH:16]=2)[N:3]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)Nc1nc(Cl)cc(Cl)n1
Reaction time: 0.33 h
Yield: 29.6 %

Procedure:
To a solution of 2-amino-4,6-dichloropyrimidine (4.10 g, 25 mmol) in anhydrous THF (125 mL), under an atmosphere of N2, at 0° C. was added NaH (25 mmol, 1.02 g, 60% in mineral oil) and the mixture was stirred for 20 min. To this mixture was added 4-trifluoromethylphenyl isocyanate (4.678 g, 25 mmol) and stirred at 0° C. for 2 h. The mixture was poured into a mixture of ethyl acetate and 2N aq. HCl and the organic phase separated. The organic phase was washed with sodium bicarbonate and brine, dried (MgSO4), filtered and concentrated in vacuo to give a solid. This solid was mixed with ether and filtered to give N′-[4,6-dichloropyrimidin-2-yl]-N-[4-(trifluoromethyl)phenyl]urea (2.6 g, 30% yield): m.p. 99-101° C.; 1H NMR (DMSO-d6) δ 10.78 (bs, 1H), 10.55 (bs, 1H), 7.69 (m, 4H), 7.58 (s, 1H); ESI/MS 348.88 (M−H) 350.97 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:11]2[C:20]3[N:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:14][CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.CCN(C(C)C)C(C)C.[NH:36]1[CH:40]=[CH:39][N:38]=[C:37]1[NH:41][C:42](N1C=CN=C1)=[O:43]>CN(C=O)C.[Cl-].[Na+].O>[NH:36]1[CH:40]=[CH:39][N:38]=[C:37]1[NH:41][C:42]([N:24]1[CH2:23][CH2:22][CH:21]([N:10]([CH2:9][C:3]2[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=2)[CH:11]2[C:20]3[N:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:14][CH2:13][CH2:12]2)[CH2:26][CH2:25]1)=[O:43]
Reactant: O=C(Nc1ncc[nH]1)n1ccnc1
Reactant: Cc1cnc(CN(C2CCNCC2)C2CCCc3cccnc32)c(C)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cnc(CN(C2CCN(C(=O)Nc3ncc[nH]3)CC2)C2CCCc3cccnc32)c(C)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
To a warm (70° C.), stirred, solution of (3,5-dimethyl-pyridin-2-ylmethyl)-piperidin-4-yl-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (0.43 g, 0.41 mmol) and DIPEA (0.43 mL, 2.47 mmol) in DMF (4 mL) was added imidazole-1-carboxylic acid (1H-imidazol-2-yl)-amide (2 equivs). After 1 hour, the mixture was cooled to room temperature, diluted with brine (5 mL) and extracted with CH2Cl2 (4×10 mL). The combined organic extracts were washed with water (5×10 mL), dried (Na2SO4) and concentrated. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 25:1:1 CH2Cl2-MeOH—NH4OH) provided 70 mg (31%) of COMPOUND 368 as a white solid. 1H NMR (CDCl3) δ 1.52-2.06 (m, 8H), 2.21 (s, 3H), 2.38 (s, 3H), 2.56-2.79 (m, 5H), 3.91-4.21 (m, 5H), 6.68 (s, 2H), 6.96 (dd, 1H, J=7.5, 4.5 Hz), 7.12 (s, 1H), 7.23-7.27 (m, 1H), 8.09 (s, 1H), 8.41 (d, 1H, J=3.6 Hz); 13C NMR (CDCl3) δ 18.27, 19.02, 22.26, 29.28, 29.81, 30.93, 31.98, 44.84, 44.98, 53.77, 58.48, 60.37, 112.13, 121.44, 123.44, 131.64, 133.40, 132.32, 136.38, 139.06, 145.49, 146.39, 147.30, 155.71, 155.77, 159.01; ES-MS m/z 460 (M+H). Anal. Calcd. For C26H33N7O.1.1CH2Cl2: C, 58.86; H, 6.42; N, 17.73. Found: C, 59.01; H, 6.32; N, 17.68.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:30]=[CH:29][C:12]([O:13][CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)=[C:11]([C:31]([F:34])([F:33])[F:32])[CH:10]=2)O1.C([O-])([O-])=O.[Na+].[Na+].[Cl:42][C:43]1[N:44]=[C:45](Cl)[C:46]2[CH:51]=[CH:50][NH:49][C:47]=2[N:48]=1.O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O.O>[Cl:42][C:43]1[N:44]=[C:45]([C:9]2[CH:30]=[CH:29][C:12]([O:13][CH2:14][CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:20][CH2:21]3)=[C:11]([C:31]([F:32])([F:34])[F:33])[CH:10]=2)[C:46]2[CH:51]=[CH:50][NH:49][C:47]=2[N:48]=1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C(F)(F)F)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(-c3nc(Cl)nc4[nH]ccc34)cc2C(F)(F)F)CC1
Temperature: 150 °C
Reaction time: 2 h
Yield: 43.3 %

Procedure:
After tert-butyl 4-{2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenoxy]ethyl}piperidine-1-carboxylate (266 mg), Na2CO3 (169 mg), and tetrakis(triphenylphosphine)palladium (0) (31 mg) were added to a mixture of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (100 mg), dioxane (1.6 mL), and water (0.6 mL), the mixture was stirred at 150° C. for 2 hours under microwave irradiation, and cooled to room temperature. After water and EtOAc were added to the reaction mixture, the mixture was stirred, filtered, and washed with EtOAc, whereby tert-butyl 4-{2-[4-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-(trifluoromethyl)phenoxy]ethyl}piperidine-1-carboxylate (121 mg) was obtained as a brown solid.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:21][CH2:20][C:15]4[CH:16]=[N:17][N:18]=[CH:19][C:14]=4[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][CH:3]=1.Br[C:23]1[CH:31]=[C:30]2[C:26]([CH2:27][C:28]3([CH2:42][CH2:41][CH2:40][C:35]4[CH:36]=[N:37][N:38]=[CH:39][C:34]=4[CH2:33]3)[C:29]2=[O:32])=[CH:25][CH:24]=1.[C:43]([C:45]1[CH:46]=[C:47](B(O)O)[CH:48]=[CH:49][CH:50]=1)#[N:44].C([O-])([O-])=O.[Cs+].[Cs+]>C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.O1CCOCC1>[O:11]=[C:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:49]3[CH:50]=[C:45]([CH:46]=[CH:47][CH:48]=3)[C:43]#[N:44])[CH:10]=2)[CH2:6][C:7]21[CH2:12][CH2:13][C:14]1[CH:19]=[N:18][N:17]=[CH:16][C:15]=1[CH2:20][CH2:21]2.[O:32]=[C:29]1[C:30]2[C:26](=[CH:25][CH:24]=[C:23]([C:49]3[CH:50]=[C:45]([CH:46]=[CH:47][CH:48]=3)[C:43]#[N:44])[CH:31]=2)[CH2:27][C:28]21[CH2:42][CH2:41][CH2:40][C:35]1[CH:36]=[N:37][N:38]=[CH:39][C:34]=1[CH2:33]2
Reactant: O=C1c2cc(Br)ccc2CC12CCCc1cnncc1C2
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: O=C1c2cc(Br)ccc2CC12CCc1cnncc1CC2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: N#Cc1cccc(-c2ccc3c(c2)C(=O)C2(CCCc4cnncc4C2)C3)c1
Product: N#Cc1cccc(-c2ccc3c(c2)C(=O)C2(CCc4cnncc4CC2)C3)c1
Temperature: 110 °C
Reaction time: 0.03 h

Procedure:
A 10 mL microwave tube was charged with a mixture of 6′-bromo-5,6,8,9-tetrahydrospiro[cyclohepta[d]pyridazine-7,2′-inden]-1′(3′H)-one and 6′-bromo-5,7,8,9-tetrahydrospiro[cyclohepta[d]pyridazine-6,2′-inden]-1′(3′H)-one (0.1646 g), obtained as described above, 3-cyanophenylboronic acid (0.2530 g, 1.7 mmol), Cs2CO3 (0.6177 g, 1.9 mmol), 1,4-dioxane (4 mL), water (1 mL), and PdCl2(PPh3)2 (0.0360 g, 0.05 mmol). The tube was heated in a CEM microwave reactor at 110° C. for 30 min. The reaction mixture was diluted with CH2Cl2 and dried over Na2SO4. After the solvent was evaporated under reduced pressure, the residue was purified by reversed-phase HPLC (SunFire™ Prep C18 OBD™ 5 μm 19×50 mm column, 10%→90% MeOH/H2O, 0.1% CF3COOH over 8 min and then 90% MeOH/H2O, 0.1% CF3COOH over 2 min, flow rate 20 mL/min) to afford 0.0281 g of 3-(1′-oxo-1′,3′,5,6,8,9-hexahydrospiro[cyclohepta[d]pyridazine-7,2′-inden]-6′-yl)benzonitrile and 0.0925 g of 3-(1′-oxo-1′,3′,5,7,8,9-hexahydrospiro[cyclohepta[d]pyridazine-6,2′-inden]-6′-yl)benzonitrile.
Reaction SMILES: [CH:1]([C:3]1[S:4][CH:5]=[CH:6][C:7]=1[C:8]1[NH:9][C:10]([CH2:19][CH3:20])=[C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:12]=1)=[O:2].[CH3:21][Mg]Br.[Cl-:24].[NH4+]>O1CCCC1>[ClH:24].[ClH:24].[OH:2][CH:1]([C:3]1[S:4][CH:5]=[CH:6][C:7]=1[C:8]1[NH:9][C:10]([CH2:19][CH3:20])=[C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:12]=1)[CH3:21]
Reactant: CCc1[nH]c(-c2ccsc2C=O)nc1-c1cccnc1
Reactant: C[Mg]Br
Reactant: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1[nH]c(-c2ccsc2C(C)O)nc1-c1cccnc1
Product: Cl
Reaction time: 0.5 h

Procedure:
To a solution of 2-(2-formylthiophen-3-yl)-5-ethyl-4-(3-pyridyl)imidazole (68 mg) in tetrahydrofuran (5 ml) was added dropwise 3M methyl magnesium bromide (0.24 ml, diethyl ether solution) under argon atmosphere in an ice bath, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (solvent: chloroform:methanol=20:1) to obtain 2-[2-(1-hydroxyethyl)thiophen-3-yl]-5-ethyl-4-(3-pyridyl)-imidazole dihydrochloride (60 mg) as orange brownish powder.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=C[C:11]=2N=N1.[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][C:45]=3Cl)[C:40]2=[O:49])[C:36]([OH:38])=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][N:52]=1.C1(C[C@H](N2CC3C(=CC=CC=3)C2=O)C(NC2SC=CN=2)=O)CCCCC1>>[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:49])[C:36]([NH:50][C:51]2[CH:56]=[CH:55][C:54]([CH3:11])=[CH:53][N:52]=2)=[O:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: Nc1ccccn1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1Cc2c(Cl)cccc2C1=O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Product: Cc1ccc(NC(=O)[C@H](CC2CCCCC2)N2Cc3ccccc3C2=O)nc1
Yield: 30 %

Procedure:
BOP coupling of (S)-3-cyclohexyl-2-(4-Chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (ca. 1:1 mixture of regioisomers, prepared in Example 36, Step C; 201 mg; 0.62 mmol) and 2-aminopyridine(132 mg; 1.39 mmol) in a manner similar to that used for the preparation of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide as outlined in Example 9, Step B) provided after chromatography (Biotage 40S column, eluent: 30% ethyl acetate/hexanes) 107 mg of (S)-3-Cyclohexyl-2-(4-Chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-N-pyridin-2-yl-propionamide: EI-HRMS m/e calcd for C22H24ClN3O2 (M+) 397.1557, found 397.1563; and 46 mg of regioisomeric (S)-3-Cyclohexyl-2-(7-Chloro-1-oxo-1,3dihydro-isoindol-2-yl)-N-pyridin-2-yl-propionamide: EI-HRMS m/e calcd for C22H24ClN3O2 (M+) 397.1557, found 397.1551.
Reaction SMILES: [CH:1]12[O:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:8]1([OH:13])[CH2:12][CH2:11][CH2:10][CH2:9]1.C(N(CC)CC)C.[C:21](Cl)(=[O:24])[CH:22]=[CH2:23].O>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:21]([O:13][C:8]1([CH:2]2[CH2:3][CH:4]3[O:7][CH:1]2[CH2:6][CH2:5]3)[CH2:9][CH2:10][CH2:11][CH2:12]1)(=[O:24])[CH:22]=[CH2:23]
Reactant: OC1(C2CC3CCC2O3)CCCC1
Reactant: C=CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: C=CC(=O)OC1(C2CC3CCC2O3)CCCC1
Reaction time: 1 h
Yield: 83.5 %

Procedure:
In 80 ml of toluene were dissolved 18.2 g of 1-(7-oxanorbornan-2-yl)cyclopentanol, 15.2 g of triethylamine, and 0.5 g of 4-(N,N-dimethylamino)pyridine. Then 12.5 g of acrylic chloride was added to the solution at 50° C., which was stirred at the temperature for one hour. Water, 50 ml, was added to the solution below 30° C., followed by ordinary post-treatment. Vacuum distillation yielded 19.7 g of 1-(7-oxanorbornan-2-yl)cyclopentyl acrylate. The two-step yield was 84%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[N:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]1[CH3:22].[OH:23][C:24]1[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[CH:28][C:25]=1[CH:26]=O>CC(O)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[N:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]1/[CH:22]=[CH:26]/[C:25]1[CH:28]=[CH:29][CH:30]=[C:31]([O:32][CH3:33])[C:24]=1[OH:23]
Reactant: COc1cccc(C=O)c1O
Reactant: COc1cccc(OC)c1-n1c(C)nc2ccccc2c1=O
Solvent: CC(=O)O
Product: COc1cccc(/C=C/c2nc3ccccc3c(=O)n2-c2c(OC)cccc2OC)c1O
Yield: 39.9 %

Procedure:
A mixture of 80 (170 mg, 0.57 mmol) and 2-hydroxy-3-methoxybenzaldehyde (9, 87 mg, 0.57 mmol) in AcOH (˜5 mL) was refluxed under N2 for 4 days and the reaction was monitored by MS and TLC. Additional 2-hydroxy-3-methoxybenzaldehyde (87 mg, 0.57 mmol) was added and the reaction mixture was refluxed for another 2 days. The solution was concentrated in vacuo and the crude product was purified by flash chromatography on silica gel eluting with EtOAc/hexanes to give the pure 81 as a yellow solid (98 mg, 40%). MS (APCI): m/z 431 (100%, [M+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:12](=[O:34])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([O:26][C:27]([CH3:33])([CH3:32])[C:28]([O:30]C)=[O:29])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.Cl>O1CCCC1.CO>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:12](=[O:34])[C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[CH:17][C:16]([O:26][C:27]([CH3:33])([CH3:32])[C:28]([OH:30])=[O:29])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(C)(C)Oc1ccc2c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccccc3)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(OC(C)(C)C(=O)O)ccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
To a solution of methyl 2-[(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)oxy]-2-methylpropanoate (0.37 g, 0.7 mmol) in tetrahydrofuran (10 ml) and methanol (10 ml) was added 1N sodium hydroxide solution (2 ml). The mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crystals were crystallized from ethyl acetate-diisopropyl ether to give 2-[(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)oxy]-2-methylpropanoic acid (0.32 g, 91.4%) as crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].[Cl:8][C:9]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[C:11]([C:12]([NH:14][C:15]2[NH:19][N:18]=[N:17][N:16]=2)=[O:13])[CH:10]=1>>[ClH:8].[ClH:8].[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][N:5]([CH3:6])[C:9]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[C:11]([C:12]([NH:14][C:15]2[NH:19][N:18]=[N:17][N:16]=2)=[O:13])[CH:10]=1
Reactant: O=C(Nc1nnn[nH]1)c1cc(Cl)c2ccccc2n1
Reactant: CNCCN(C)C
Product: CN(C)CCN(C)c1cc(C(=O)Nc2nnn[nH]2)nc2ccccc12
Product: Cl

Procedure:
4[(2-Dimethylaminoethyl)methylamino]-N(1H-tetrazol-5-yl)quinaldamide, dihydrochloride, m.p. 126° (d) was prepared similarly from N,N,N'-trimethylethylenediamine and 4-chloro-N(1H-tetrazol-5-yl)quinaldamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1.ClC1C=CC=C(C(OO)=[O:28])C=1>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:11])([CH3:12])[CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=3[O-:28])[C:6]=2[CH:19]=1
Reactant: CC1(C)CC(c2ccccn2)c2cc(Br)ccc2O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1(C)CC(c2cccc[n+]2[O-])c2cc(Br)ccc2O1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.1 %

Procedure:
330 mg of 6-bromo-3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran were dissolved in 10 ml of dichloromethane at room temperature and 280 mg of m-chloroperbenzoic acid were added. After stirring at room temperature for 3 days the mixture was washed with sodium bisulphite solution, then with sodium bicarbonate solution and finally with water. The organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using 4% (v/v) methanol/ethyl acetate for the elution to give 250 mg of 2-(6-bromo-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide as a foam. NMR (300 MHz, CDCl3): 8.35-8.30 (1H, m), 7.26-7.15 (3H, m), 7.13-7.05 (1H, m), 6.95 (1H, broad s), 6.75 (1H, d, 9Hz), 5.28 (1H, broad s), 2.42 (1H, dd, 13Hz, 6Hz), 1.7 (1H, broad s), 1.42 (3H, s), 1.37 (3H, s). MS (EI): 335 (M+ [Br81 ], 333 (H+ [Br79 ]), 318 (M+ [Br81 ]-OH), 316 (M+ [Br79 ]-OH)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18](O)=[O:19])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:60][C@H:61]1[CH2:66][CH2:65][C@H:64]([OH:67])[CH2:63][CH2:62]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18]([NH:60][C@H:61]3[CH2:66][CH2:65][C@H:64]([OH:67])[CH2:63][CH2:62]3)=[O:19])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CC[C@H](O)CC1)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of [2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-cyclohexyl-acetic acid (200 mg, 0.54 mmol; example 5.1) in dry DMF (4 mL) was added dry DIPEA (3.2 mmol) followed by HATU (1.6 mmol) at 0° C. Then the reaction mixture was allowed to warm to rt and stirred for 45 min at that temperature. TLC shows total consumption of acid and formation of a new spot. (trans)-4-Amino-cyclohexanol (0.64 mmol) was added to this reaction mixture at 0° C. Then the cooling bath was removed and the reaction mixture was stirred at room temperature for 16 h. TLC shows total consumption of [2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-cyclohexyl-acetic acid and DMF was removed in vacuo at 60° C. It was then diluted with H2O (5 ml). Aqueous layer was extracted with EtOAc (5×5 mL) and combined organic layers were washed with brine (50 ml), dried over Na2SO4 and concentrated in vacuo. Crude product was subjected to column chromatography [SiO2 (230-400 mesh), EtOAc:Hexane 10:90] to give the title compound (40 mg, 24%) as off-white solid. MS: m/e=470.0 [M+H+].
Reaction SMILES: [Na].C(O)C.[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][SH:11])=[CH:8][CH:7]=1.CS(O[C@H:19]1[CH2:24][CH2:23][C@H:22]2[C@H:25]3[C@H:35]([C:36](=[O:38])[CH2:37][C@:20]12[CH3:21])[C@:33]1([CH3:34])[C:28](=[CH:29][C:30](=[O:39])[CH:31]=[CH:32]1)[CH2:27][CH2:26]3)(=O)=O>C(Cl)(Cl)Cl>[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][S:11][C@@H:19]2[CH2:24][CH2:23][C@H:22]3[C@H:25]4[C@H:35]([C:36](=[O:38])[CH2:37][C@:20]23[CH3:21])[C@:33]2([CH3:34])[C:28](=[CH:29][C:30](=[O:39])[CH:31]=[CH:32]2)[CH2:27][CH2:26]4)=[CH:8][CH:7]=1
Reactant: C[C@]12CC(=O)[C@H]3[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1CC[C@@H]2OS(C)(=O)=O
Reactant: SCc1ccc(Cl)cc1
Agent: [Na]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: C[C@]12CC(=O)[C@H]3[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1CC[C@H]2SCc1ccc(Cl)cc1

Procedure:
To 1.38 gm. of sodium metal dissolved in 120 ml. of ethanol is added 6 ml. of 4-chlorobenzylmercaptan followed by 2.26 gm. of 17β-methanesulfonyloxy-1,4-androstadiene-3,11-dione. Heat at reflux for 96 hours. Obtain a residue in a manner similar to that described in Example 1A. Dissolve the residue in a minimum amount of chloroform and pass through a 200 gm. silica gel column. Elute with chloroform following the fractions by TLC. Combine the fractions, reduce, and crystallize the residue from ethyl acetate/hexane to obtain the title compound; m.p. 176°-180° C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H][H].CCC[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O-:18])=O.[CH3:19][CH2:20][CH2:21][CH2:22]CCCC([O-])=O.[Ni+2].C1CCCCC=1.C([Al](CC)CC)C>[Ni]>[CH2:3]([C:2]1[C:13]([CH3:12])=[CH:14][CH:15]=[C:16]([OH:18])[C:1]=1[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC
Reactant: CCCCCCCC(=O)[O-]
Reactant: [H][H]
Agent: [Ni+2]
Agent: [Ni]
Agent: CC[Al](CC)CC
Solvent: C1=CCCCC1
Product: CCCCc1c(C)ccc(O)c1CCCC
Temperature: 54.44444444444444 °C

Procedure:
Five gallons of the block copolymer cement product from Example VI containing about 2500 gms. of polymer is charged to a hydrogenation reactor together with an additional 40 lbs. of dry hexane. The reactor is flushed 6 times by pressuring to 50 psig with hydrogen and then releasing the pressure to about 5 psig. Then the hydrogenation catalyst is added which comprises 25 millimoles of Ni in nickel octoate-cyclohexene-triethyl aluminum in proportions of 1/1/3 respectively. The temperature is raised to 130°F and hydrogen introduced to a pressure of 150 psig. Periodically the system is repressured to 150 psig and samples are removed three times at several hours intervals. The temperature is maintained at 130°-160°F over a period of about 7 hours after which the reaction mixture is cooled to 120°F and vented several times. The product is dropped into a 55 gallon drum containing methanol and a small amount of antioxidant (dibutyl-p-cresol) to provide about 0.5 gm. of A.O. per 100 gms. of polymer. The product is filtered and rinsed several times with hexane. The copolymer is found to be about 100% hydrogenated and to have a glass transition temperature of -59°C and a melting point of 97°C. This product shows excellent impact strength and is used in the tests of Example VIII.
Reaction SMILES: [CH3:1][C:2]1([C:9]([OH:11])=O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.S(Cl)([Cl:14])=O>>[CH3:1][C:2]1([C:9]([Cl:14])=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC1(C(=O)O)CCCCCC1
Reactant: O=S(Cl)Cl
Product: CC1(C(=O)Cl)CCCCCC1
Yield: 99 %

Procedure:
A solution of 1-methyl-cycloheptanecarboxylic acid (156 mg, 0.998 mmol) (Journal of Organic Chemistry (1982), 47(17), 3242-7) in thionyl chloride (5 ml) was stirred at room temperature for 2 days and then concentrated on high vacuum giving 174 mg (99%) of 1-methyl-cycloheptanecarbonyl chloride as a yellow oil.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][N:12]1[C:16](=[O:17])[CH:15]=[C:14]([Br:18])[NH:13]1.[F:19][C:20]([F:35])([C:31]([F:34])([F:33])[F:32])[C:21]([F:30])([F:29])[C:22]([F:28])([F:27])[S:23](F)(=[O:25])=[O:24]>O1CCCC1.O>[CH3:11][N:12]1[C:16]([O:17][S:23]([C:22]([F:27])([F:28])[C:21]([F:29])([F:30])[C:20]([F:19])([F:35])[C:31]([F:34])([F:33])[F:32])(=[O:25])=[O:24])=[CH:15][C:14]([Br:18])=[N:13]1
Reactant: Cn1[nH]c(Br)cc1=O
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1nc(Br)cc1OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.7 %

Procedure:
A solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (1M, 0.70 mL, 0.70 mmol) was added at −78° C. under nitrogen to a stirred solution of 1-methyl-3-bromo-5-pyrazolone from Step 1 (0.10 g, mmol) in dry tetrahydrofuran (2 mL). After 10 min, nonafluorobutanesulfonyl fluoride (0.13 mL, 0.70 mmol) was added dropwise. The resulting gel was warmed to room temperature and stirred for 1 hour. The solution was diluted with water (10 mL) and extracted with ethyl acetate (2×10 mL). The extracts were dried (Na2SO4) and concentrated. Flash column chromatography on silica, eluting with 10% ethyl acetate—isohexane, gave 1-methyl-3-bromo-5-(nonafluorobutanesulfonyloxy)pyrazole (0.204 g, 79%) as a colourless oil. δ (1H, 500 MHz, CDCl3) 3.80 (3H, s), 6.19 (1H, s). Step 3: 1-methyl-3-bromo-5-(5-methylpyridin-2-yl)pyrazole