Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[S:21][C:20]([NH:22][CH2:23][C:24]5[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=5)=[N:19][N:18]=4)[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)[CH:5]=[N:4][CH:3]=1.[O-:42][CH2:43][CH3:44].[Na+]>CCO>[CH2:43]([O:42][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[S:21][C:20]([NH:22][CH2:23][C:24]5[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=5)=[N:19][N:18]=4)[CH:15]=3)[NH:10][CH:9]=2)[CH:5]=[N:4][CH:3]=1)[CH3:44]
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cncc(Cl)n3)cn4S(=O)(=O)c3ccc(C)cc3)s2)cc1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1cncc(-c2c[nH]c3ccc(-c4nnc(NCc5ccc(OC)cc5)s4)cc23)n1
Temperature: 120 °C

Procedure:
A glass microwave reaction vessel was charged with 5-(3-(6-chloropyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-thiadiazol-2-amine (90.0 mg, 0.149 mmol) and sodium ethoxide, 21 wt % solution in EtOH (0.152 mL, 0.448 mmol, Aldrich) in EtOH (1 mL). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 120° C. for 1 h. Then the solvent was removed to give the crude material, which was used in the next step without further purification. MS (ESI, pos. ion) m/z: 459 (M+1).
Reaction SMILES: COC1C=C2C(=CC=1)NC1C3C=CNC=3CCC2=1.C[O:20][C:21]1[CH:22]=[C:23]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH3:34])[C:29]1[C:28]3[CH:35]=[CH:36][N:37]([CH3:38])[C:27]=3[CH2:26][CH2:25][C:24]2=1>>[CH3:38][N:37]1[C:27]2[CH2:26][CH2:25][C:24]3[C:23]4[C:31]([N:30]([CH3:34])[C:29]=3[C:28]=2[CH:35]=[CH:36]1)=[CH:32][CH:33]=[C:21]([OH:20])[CH:22]=4
Reactant: COc1ccc2c(c1)c1c(n2C)-c2ccn(C)c2CC1
Agent: COc1ccc2[nH]c3c(c2c1)CCc1[nH]ccc1-3
Product: Cn1ccc2c1CCc1c-2n(C)c2ccc(O)cc12

Procedure:
Following the procedure described in Example 125, using 7-methoxy-3,4,5,10-tetrahydro-pyrrolo[3,2-a]carbazole (474 mg, 2.0 mmol) as the starting material, 7-methoxy-3,10-dimethyl-3,4,5,10-tetrahydro-pyrrolo[3,2-a]carbazole as prepared as a crude product. The crude product was thn recated according to the procedure as described in Example 126 to yield the title compound as a brown solid.
Reaction SMILES: [CH2:1]([NH2:19])[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][CH2:17][CH3:18].[I:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24].Cl.C(N)CCCCCCCCCCCCCCCCC>CCOCC.C(O)C>[CH2:1]([NH:19][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=1[I:20])[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][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: O=C(Cl)c1ccccc1I
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCNC(=O)c1ccccc1I
Yield: 8 %

Procedure:
A solution of 17.9 g of octadecylamine in a mixture of 300 ml of ether and 10 ml of ethanol was reacted with a solution of 8.0 g of o-iodobenzoyl chloride in 25 ml of ether for 10 minutes. The precipitate which formed contained octadecylamine hydrochloride. This precipitate was recovered and discarded. The volume was thereafter reduced to approximately half at 65° on a water bath. The resulting precipitate was recovered in accordance with the procedure of Example 3. The crude product was recrystallized from benzene to yield 1.2 g of N-octadecyl-o-iodobenzamide as a white microcrystalline solid, m.p. 94°-96°, Rf 0.77.
Reaction SMILES: [C:1]1(=O)[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH2:2]1.Cl.[NH2:16]O.C([O-])(=O)C.[Na+]>C(O)C.O>[CH:1]1([NH2:16])[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCc2c1[nH]c1ccccc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC1CCCc2c1[nH]c1ccccc21
Reaction time: 0.25 h

Procedure:
To a solution of 2,3,4,9-tetrahydro-1H-carbazol-1-one (1.5 g, 8.10 mmol) in ethanol (20 mL) was added a solution of hydroxylamine hydrochloride (1.13 g, 16.2 mmol) in water (10 mL) and a solution of sodium acetate (2.19 g, 26.7 mmol) in water (10 mL). The reaction mixture was heated at reflux for 2 h, cooled, and concentrated. The residue was diluted with water and extracted with ethyl acetate (2×100 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated to a brown solid. The oxime was dissolved in THF (80 mL) and lithium aluminum hydride (1.0 M in THF, 24.3 mL) was added dropwise. The reaction was heated at reflux for 7 h and cooled in an ice bath. Methanol was added dropwise until bubbling ceased. The mixture was diluted with aqueous Na/K tartrate, stirred vigorously for 15 min and extracted with ethyl acetate (2×100 mL). The extracts were combined, dried over sodium sulfate, filtered and concentrated. The crude amine was purified by flash chromatography on silica (2% to 5% methanol/methylene chloride gradient) to provide 2,3,4,9-tetrahydro-1H-carbazol-1-amine as a brown oil. The oil was diluted in diethyl ether and HCl (1.0 M in diethyl ether) was added. The resulting precipitate was collected by filtration to provide 2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride (760 mg, 42%) as a light brown solid. 1H-NMR (CD3OD): δ 7.54 (d, 1H), 7.42 (d, 1H), 7.22 (t, 1H), 7.09 (t, 1H), 4.66 (t, 1H), 2.95-2.73 (m, 2H), 2.39-2.28 (m, 1H), 2.18-2.03 (m, 3H); MS m/z (M+1) 170.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:28]=[C:27]([Cl:29])[C:12]([CH2:13][C@@H:14]2[CH2:18][CH2:17][N:16]([C@H:19]3[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21][CH2:20]3)[C:15]2=[O:26])=[C:11]([Cl:30])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([Cl:30])[C:12]([CH2:13][C@@H:14]2[CH2:18][CH2:17][N:16]([C@H:19]3[CH2:20][CH2:21][C@H:22]([O:25][S:39]([CH3:38])(=[O:41])=[O:40])[CH2:23][CH2:24]3)[C:15]2=[O:26])=[C:27]([Cl:29])[CH:28]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1[C@H](Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCN1[C@H]1CC[C@H](O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(OCc4ccccc4)cc3Cl)C2=O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dissolve (R)-3-(4-Benzyloxy-2,6-dichloro-benzyl)-trans-1-(4-hydroxy-cyclohexyl)-pyrrolidin-2-one (1.291 g, 2.86 mmol) in 25 ml of dry dichloromethane at 0° C. Add triethylamine (0.73 ml, 5.77 mmol) followed by methanesulfonyl chloride (0.25 ml, 3.17 mmol). Stir at room temperature for 3 hours. Quench with 1N HCl and extract with ethyl acetate. Wash the extract with 1N HCl, NaHCO3 and brine. Dry over magnesium sulfate, filter, and concentrate. Purify by column chromatography to receive 1.315 g of the title compound: Mass spectrum (apci) m/z=526 (M+H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][NH:4][CH:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.CC1(C)[C@]2(CS(O)(=O)=O)C(C[C@H]1CC2)=O.Cl[C:35]1[N:40]=[C:39]([NH:41][C@H:42]2[C@H:47]3[CH2:48][C@H:44]([CH2:45][CH2:46]3)[C@H:43]2[C:49]([NH2:51])=[O:50])[C:38]([Cl:52])=[CH:37][N:36]=1>>[Cl:52][C:38]1[C:39]([NH:41][C@H:42]2[C@H:47]3[CH2:48][C@H:44]([CH2:45][CH2:46]3)[C@H:43]2[C:49]([NH2:51])=[O:50])=[N:40][C:35]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][CH:5]([NH:4][CH2:3][C:2]([F:17])([F:18])[F:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:36][CH:37]=1
Reactant: NC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)CCC(NCC(F)(F)F)CC2
Agent: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Product: NC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1Nc1nc(Nc2ccc3c(c2)CCC(NCC(F)(F)F)CC3)ncc1Cl
Yield: 29.7 %

Procedure:
In an analogous procedure to Example 651, part c, N*7*-(2,2,2-Trifluoro-ethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine (75 mg, 0.290 mmol) was combined with DL-10-camphorsulfonic acid (101 mg, 0.436 mmol) and (1S,2R,3S,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid amide (86.9 mg, 0.290 mmol) to prepare (1S,2R,3S,4R)-3-{5-Chloro-2-[7-(2,2,2-trifluoro-ethylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino]-pyrimidin-4-ylamino}-bicyclo[2.2.1]heptane-2-carboxylic acid amide (45.07 mg, 30% yield) as a white powder. Product was purified on a 12 g Isco cartridge using methelene chloride/methanol as the eluent. 1H-NMR (CDCl3) δ 7.86 (s, 1H), 7.40 (d, J=8.2 Hz, 1H), 7.28 (s, 1H), 7.03 (d, J=8.1 Hz, 1H), 6.84 (m, 2H), 6.33 (m, 2H), 5.54 (br s, 1H), 5.32 (br s, 1H), 4.36 (t, J=7.8 Hz, 1H), 3.24 (q, J=18.9, 9.5 Hz, 2H), 3.06 (s, 1 h), 2.80 (m, 4H), 2.68 (m, 2H), 2.47 (d, J=8.5 Hz, 1H), 2.22 (d, J=9.5 Hz, 1H), 2.08 (m, 2H), 1.64 (m, 1H), 1.34 (m, 2H), 0.88 (m, 1H). LC/MS (ESI+)=521 (M+H). MP=217.5-218.5° C.
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3](O)=[O:4].C(N(C(C)C)CC)(C)C>C(#N)C>[CH:3]([C@@H:2]1[CH2:6][CH2:7][CH2:8][N:1]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Temperature: 50 °C
Reaction time: 10 h
Yield: 124.2 %

Procedure:
A mixture of 3 (11.80 g, 38.8 mmol), N-Boc-L-Pro-OH (10.02 g, 46.6 mmol), and diisopropylethylamine (7.02 g, 54.3 mmol) in acetonitrile (200 mL) was stirred at 50° C. for 10 h. The solvent was evaporated and the residue was partitioned between methylene chloride and H2O. The organic layer was separated and concentrated to dryness. The crude product was purified by silica gel column chromatography (hexanes/ethyl acetate=1/7 to 1/4 (v/v)) to provide 4 (11.53 g, 68% yield) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.84 (m, 1H), 7.48 (m, 2H), 5.58 (m, 1H), 4.40 (m, 1H), 3.60 (m, 1H), 3.40 (m, 1H), 3.18 (m, 1H), 3.04 (m, 1H), 2.37 (m, 2H), 2.04 (m, 1H), 1.96 (m, 1H), 1.46 (ds, 9H) ppm.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH:2]=[CH:3][CH2:4][CH2:5][CH3:6].[OH-].[Na+].[S:11](=[O:14])([OH:13])[O-:12].[Na+].S(=O)(O)[O-]>>[S:11]([CH:3]([CH2:4][CH2:5][CH3:6])[CH2:2][C:1]([OH:8])=[O:7])([OH:14])(=[O:13])=[O:12]
Reactant: CCCC=CC(=O)O
Reactant: O=S([O-])O
Agent: [Na+]
Agent: [OH-]
Product: CCCC(CC(=O)O)S(=O)(=O)O

Procedure:
114 g. of 2-hexenoic acid is neutralized with aqueous sodium hydroxide and reacted with 204 g. of a 50% wt. aqueous solution of sodium bisulfite at 25° C. Complete addition of bisulfite to the double bond requires several hours. The product is concentrated to approximately 50% wt. solids and then treated with a strong acid ion exchange resin to obtain an aqueous solution of 3-sulfohexanoic acid. This is dried by vacuum stripping and converted into 3-propyl-1,2-oxathiolane-5-one-2,2-dioxide with refluxing thionyl chloride at 80° C. for 3 hours. Equivalent weight is 93.
Reaction SMILES: [CH3:1][N:2]([C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1)=[O:20])[CH2:3][CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][CH2:13]OS(C)(=O)=O)[CH2:7][CH2:6]1.[CH2:32]([NH:35][CH3:36])[CH:33]=[CH2:34]>CN(C)C(=O)C.CCOCC>[F:29][C:28]([F:31])([F:30])[C:25]1[CH:26]=[CH:27][C:22]([O:21][C:19](=[O:20])[N:2]([CH2:3][CH2:4][C@H:5]2[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][CH2:13][N:35]([CH2:32][CH:33]=[CH2:34])[CH3:36])[CH2:7][CH2:6]2)[CH3:1])=[CH:23][CH:24]=1
Reactant: C=CCNC
Reactant: CN(CC[C@H]1CC[C@H](CCCOS(C)(=O)=O)CC1)C(=O)Oc1ccc(C(F)(F)F)cc1
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: C=CCN(C)CCC[C@H]1CC[C@H](CCN(C)C(=O)Oc2ccc(C(F)(F)F)cc2)CC1

Procedure:
A solution of 200 mg (0.43 mmol) trans-methanesulfonic acid 3-(4-{2-[methyl-(4-trifluoromethyl-phenoxycarbonyl)-amino]-ethyl}-cyclohexyl)-propyl ester and 0.204 ml (2.15 mmol) of allyl methyl amine in 2 ml of N,N-dimethylacetamide was stirred over night at 60° C. The reaction mixture was then taken up in ether and the ether phases were washed with water. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure and the residue then chromatographed on silica gel with a 9:1 v/v mixture of dichloromethane and 1N ammonia in methanol as the eluent giving 124 mg (65.5%) trans-(2-{4-[3-(allyl-methyl-amino)-propyl]-cyclohexyl}-ethyl)-methyl-carbamic acid 4-trifluoromethyl-phenyl ester as colorless viscous oil, MS: 441 (MH+).
Reaction SMILES: [OH:1][CH:2]=[C:3]([C:8]1[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:12][CH:13]=1)[C:4]([O:6][CH3:7])=[O:5].S(OC)(O[CH3:22])(=O)=O>[OH-].[Na+].O>[CH3:22][O:1][CH:2]=[C:3]([C:8]1[CH:9]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:11]=[CH:12][CH:13]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)C(=CO)c1cccc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC=C(C(=O)OC)c1cccc(C(F)(F)F)c1
Reaction time: 40 h

Procedure:
ba) 26 g of methyl 3-hydroxy-2-(α,α,α-trifluoro-m-tolyl)acrylate were dissolved in 1N sodium hydroxide solution while cooling in an ice-bath and treated with 10.6 ml of dimethyl sulfate. The mixture was stirred at about 0° for about 40 hours and an additional 40 ml of 1N sodium hydroxide solution and 3.8 ml of dimethyl sulfate were added. After the reaction was completed, the mixture was diluted with water and extracted with methylene chloride. After drying with sodium sulfate, the extract was distilled, whereby methyl 3-methoxy-2-(α,α,α-trifluoro-m-tolyl)-acrylate was obtained as a colorless oil of b.p. 75°-90°/0.2 mm.
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1Br.[Li]CCCC.CN([CH:19]=[O:20])C>C1COCC1>[F:1][C:2]1[C:7]([CH3:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[CH:19]=[O:20]
Reactant: CN(C)C=O
Reactant: Cc1c(F)ccc(Br)c1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1c(F)ccc(C=O)c1F
Temperature: -78 °C

Procedure:
A cooled (−78° C.) solution of 2,4-difluoro-3-methylbromobenzene (2.000 g; 9.661 mmol) in anhydrous THF (36 ml) was treated dropwise (over 10 min.) with a solution of 1.6M n-BuLi in hexanes (6.04 ml; 9.661 mmol) while maintaining the temperature below −70° C. This mixture was further stirred at −78° C. for 2 min. before anhydrous DMF (1.49 ml; 19.326 mmol) was added dropwise (over 10 min.) while maintaining the temperature below −70° C. After completion of the addition, the resulting light brown solution was further stirred at −78° C. for 1 h30. The resulting mixture was then quenched at −78° C. with aq. sat. NH4Cl (10 ml), and was then allowed to warm-up to rt. Ether (50 ml) and water (20 ml) were added, and the organic layer was dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure (caution: rotary evaporation bath at 30° C. because the aldehyde is volatile). The crude was purified by FC (DCM) to give the pure product 2,4-difluoro-3-methyl-benzaldehyde as a pale yellow oil (1.250 g; 83%).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:40])[CH2:15][C:16]1[CH:17]=[C:18]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[CH:19]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].Br[CH2:52][C:53]([CH3:55])=[CH2:54]>C1COCC1>[CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:40])[CH:15]([C:16]1[CH:17]=[C:18]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([F:38])([F:39])[F:37])=[CH:34][CH:35]=2)[CH:19]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=1)[CH2:54][C:53]([CH3:55])=[CH2:52])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1)N1C(=O)OCC1Cc1ccccc1
Reactant: C=C(C)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(C)CC(C(=O)N1C(=O)OCC1Cc1ccccc1)c1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
To a colorless solution of 4-benzyl-3-[2-(5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetyl]-oxazolidin-2-one (6.0 g, 11.00 mmol) in dry THF (22 ML) at −78° C. was added sodium hexamethyl disilazide (NaHMDS) (1 M in THF solution, 12.11 mL, 12.11 mmol), drop-wise, maintaining the internal temperature below −75° C. The resulting red solution was stirred at −78° C. for 30 minutes. To this was added 3-bromo-2-methyl propene (4.44 mL, 44 mmol) maintaining the temperature below −75° C. When the addition was at near completion, the reaction mixture turned green. At this point the dry-ice bath was quickly removed and replaced with water-ice bath and the addition was completed. The reaction mixture was stirred at 0° C. for an additional 30 min and quenched with saturated aqueous NH4Cl solution. The system was diluted with EtOAC (100 mL) and the organic phase was washed with saturated aqueous NaHCO3 solution (3×50 mL) and dried (MgSO4). Solvent was removed in vacuo and the crude mixture was purified by ISCO silica gel column to yield 4-benzyl-3-[2-(5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pent-4-enoyl]-oxazolidin-2-one (6.3 g, 95%)
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[CH:8][CH:9]=1.C(N(CC)CC)C.Br[C:19]1[C:20]2[N:21]([C:26]([CH3:29])=[CH:27][N:28]=2)[N:22]=[C:23]([Cl:25])[CH:24]=1.ClC1C=C(Cl)C2N(C(C)=CN=2)N=1>CCO>[Cl:25][C:23]1[CH:24]=[C:19]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:2][CH3:1])=[CH:5][CH:6]=2)[C:20]2[N:21]([C:26]([CH3:29])=[CH:27][N:28]=2)[N:22]=1
Reactant: CCOc1ccc(N)cc1
Reactant: Cc1cnc2c(Br)cc(Cl)nn12
Agent: Cc1cnc2c(Cl)cc(Cl)nn12
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOc1ccc(Nc2cc(Cl)nn3c(C)cnc23)cc1
Temperature: 90 °C
Reaction time: 30 h

Procedure:
p-Phenetidine (0.068 g, 0.5 mmol) and triethylamine (0.15 ml, 1.1 mmol) were added to a mixture of 8-bromo-6-chloro-3-methylimidazo[1,2-b]pyridazine and 6,8-dichloro-3-methylimidazo[1,2-b]pyridazine (0.011 g, 0.5 mmol) both from 1a in EtOH (10 mL). The mixture was heated to 90° C. and stirred for 30 hrs. The solution was then concentrated in vacuo to give crude 6-chloro-N-(4-ethoxyphenyl)-3-methylimidazo[1,2-b]pyridazin-8-amine.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].S(Cl)(Cl)=O.[C:16](=O)(O)[O-].[Na+]>CO>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:16])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(=O)O)ccc1O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)c1ccc(O)c(C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 4-hydroxy-3-methylbenzoic acid (Matrix Scientific, 1 g) was dissolved in methanol and cooled in an ice-bath under a nitrogen atmosphere. Thionyl chloride (5 mL) was added slowly. The reaction was stirred at 0° C. for one hour and then warmed to room temperature and stirred for 16 hours. Solid sodium bicarbonate was then added to neutralize the acid and the mixture was evaporated to dryness. The residue was partitioned between ethyl acetate (75 mL and water (100 mL). The ethyl acetate layer was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to afford 1.0 g of product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH2:25][CH3:26])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[S:27]1(=[O:34])(=[O:33])[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]1>>[O:33]=[S:27]1(=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH2:25][CH3:26])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: O=S1(=O)CCCCN1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCCS4(=O)=O)cc3C#N)CC2)c(C)c1
Yield: 86.6 %

Procedure:
Using 5-bromo-2-[4-(5-ethyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (827 mg) described in Preparation Example 246 and [1,2]thiazinane 1,1-dioxide (351 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (810 mg) was obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[N:9]=1)[C:5]#[N:6].[Cl:19][C:20]1[C:21](B(O)O)=[CH:22][C:23]([F:26])=[N:24][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.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>[Cl:19][C:20]1[C:21]([C:2]2[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[C:8]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[N:9]=2)=[CH:22][C:23]([F:26])=[N:24][CH:25]=1
Reactant: OB(O)c1cc(F)ncc1Cl
Reactant: N#Cc1cc(Cl)nc(NCc2cccc(F)c2)c1
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: COCCOC
Solvent: CCOC(C)=O
Product: N#Cc1cc(NCc2cccc(F)c2)nc(-c2cc(F)ncc2Cl)c1
Temperature: 110 °C
Yield: 46.5 %

Procedure:
To a degassed suspension of 2-chloro-6-(3-fluorobenzylamino) isonicotinonitrile (150 mg, 0.573 mmol) and 5-chloro-2-fluoropyridin-4-ylboronic acid (151 mg, 0.860 mmol) in DME (5 ml) was added Na2CO3 (1.433 ml, 2M, 2.87 mmol) and Pd(Ph3P)4 (66.2 mg, 0.057 mmol). The reaction mixture was capped and heated to 110° C. in an oil bath for 2 hr. The reaction mixture was diluted with EtOAc and washed with sat NaHCO3, and then sat NaCl. The organic layer was dried over Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography on silica gel (0-20% EtOAc/Hexane) to give 5′-chloro-2′-fluoro-6-(3-fluorobenzylamino)-2,4′-bipyridine-4-carbonitrile (95 mg, 47%). LCMS (m/z): 357.0 (MH+), retention time=1.09 min
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][O:11][S:23]([CH3:22])(=[O:25])=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
A solution of 22.0 gm (125.6 mMol) (R)-N-tert-butoxycarbonyl-2-amino-1-propanol and 19.5 gm (150.7 mmol) diisopropylethylamine in 450 mL dichloromethane was cooled to 0° C. To this solution was added dropwise 10.7 mL (138.2 mMol) methanesulfonyl chloride at a rate to maintain the temperature of the reaction mixture at from 0° C. to 10° C. Once the addition was complete the reaction mixture was stirred at 0° C. for about one hour. The reaction mixture was washed twice with 200 mL portions of water, once with 200 mL saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 1:1 hexane:ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure. The residue was crystallized from hexane and ethyl acetate to provide 19.4 gm (61%) of the desired compound in two crops (m.p.=65–68° C.)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.Cl.[CH3:17][N:18]([CH3:23])[CH2:19][C:20](O)=[O:21].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN1CCCC1=O.C(N(CC)CC)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:20](=[O:21])[CH2:19][N:18]([CH3:23])[CH3:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: CN(C)CC(=O)O
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CN(C)CC(=O)N1CCN(c2ccc(N)cc2)CC1

Procedure:
1-(4-nitrophenyl)piperazine and N,N-dimethylglycine hydrochloride were allowed to undergo the reaction using WSC hydrochloride and HOBt in 1-methyl-2-pyrrolidone in the presence of triethylamine. The resulting compound was subjected to-catalytic hydrogenation in the same manner as shown in Reference Example 3 to obtain 1-[4-(4-aminophenyl)piperazin-1-yl]-2-dimethylaminoethanone. NMR2: 2.30 (6H, s), 3.74-3.76 (4H, m), 6.64-6.68 (2H, m).