Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]([OH:18])[C:14]([F:17])([F:16])[F:15])[C:10](C)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:21](=[S:29])[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:21](=[S:29])([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[O:18][CH:13]([C:11]1[CH:10]=[N:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:12]=1)[C:14]([F:15])([F:16])[F:17]
Reactant: S=C(Cl)Oc1ccccc1
Reactant: Cc1nn(Cc2ccccc2)cc1C(O)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: FC(F)(F)C(OC(=S)Oc1ccccc1)c1cnn(Cc2ccccc2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To a solution of 1-(1-benzyl-3-methyl-1H-pyrazol-4-yl)-2,2,2-trifluoroethanol (compound 314.3, 1.15 g, 4.26 mmol) in toluene (15 mL) were added 4-dimethylaminopyridine (1.47 g, 12.0 mmol) and phenyl chloromethanethioate (1.04 g, 6.02 mmol). The reaction mixture was stirred for 1 h at 60° C. under nitrogen, then concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1/15) as the eluent to yield 1.34 g (77%) of the title compound as a light yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][S:26]3(=[O:31])=[O:30])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:32])[CH3:9])=[CH:4][CH:3]=1.[CH3:33][C:34]1[CH:39]=[C:38](B(O)O)[CH:37]=[CH:36][N:35]=1>>[O:30]=[S:26]1(=[O:31])[CH2:27][CH2:28][CH2:29][N:25]1[CH2:24][CH2:23][CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:32])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:38]3[CH:37]=[CH:36][N:35]=[C:34]([CH3:33])[CH:39]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCN2CCCS2(=O)=O)(c2ccccc2)OC1=O
Reactant: Cc1cc(B(O)O)ccn1
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CCCN4CCCS4(=O)=O)(c4ccccc4)OC3=O)cc2)ccn1

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-(1,1-dioxo-isothiazolidin-2-yl)propyl)-6-phenyl-1,3-oxazinan-2-one and 2-methylpyridine-4-boronic acid following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.001, m/z=534.1; 1H NMR (CDCl3) 1.22-1.33 (m, 1H), 1.52 (d, 3H), 1.68-1.81 (m, 1H), 1.83-2.03 (m, 2H), 2.12-2.38 (m, 5H), 2.83-2.91 (m, 5H), 2.93-3.13 (m, 5H), 5.68 (m, 1H), 7.09 (d, 2H), 7.18-7.32 (m, 5H), 7.36 (d, 2H), 7.61 (s, 1H), 7.68 (s, 1H), 8.24 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)=[O:13])[C:9]([OH:24])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[NH:25]1[CH:29]=[CH:28][N:27]=[CH:26]1>CN(C=O)C>[Cl:23][C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([Cl:22])[CH:19]=1)[CH2:15][NH:14][C:12]([C:10]1[C:9]([OH:24])=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)[N:11]=1)=[O:13]
Reactant: O=C(NCc1cc(Cl)cc(Cl)c1)c1nc(Cl)c2cccnc2c1O
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: O=C(NCc1cc(Cl)cc(Cl)c1)c1nc(-n2ccnc2)c2cccnc2c1O

Procedure:
The chloride from Example 44 Step 5 (8.0 mg, 0.021 mmol) and imidazole (80 mg) were fused at 160 C for 1 hr under argon. The residue was dissolved in DMF (0.5 ml) and purified by preparative HPLC. (Gilson semi preparative HPLC system and a YMC Combiprep Pro Column (50×20 mm I.D., C18, S-5 um, 120A) eluting with 5-95% acetonitrile/water (0.1% TFA) at 15 ml/min) to afford the title compound after lyophilization.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+].Cl.C(OCC)(=O)C>O1CCCC1.O>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=2)[C:3]([OH:24])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.4 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid methyl ester (1.17 g, 3.29 mmol) in tetrahydrofuran (6 mL) was treated with a 0.8M aqueous lithium hydroxide solution (6.17 mL, 4.94 mmol). The reaction mixture was stirred at 25° C. for 3 h. The reaction mixture was then diluted with water (50 mL), a 1N aqueous hydrochloric acid solution (10 mL), and ethyl acetate (50 mL). The layers were separated, and the aqueous layer was further extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid (993 mg, 88%) as a yellow foam which contained a small impurity. A small amount of the yellow foam (50 mg) was re-purified using Biotage chromatography (FLASH 40S, Silica, 3/1 then 1/1 hexanes/ethyl acetate) to afford 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid as a white foam: mp 114-118° C. (foam to gel); FAB-HRMS m/e calcd for C15H19NO6S (M+H)+342.1011, found 342.1014.
Reaction SMILES: Br[C:2]1[C:3]([F:36])=[C:4]([CH:12]2[C:17]3([C:25]4[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=4)[NH:19][C:18]3=[O:27])[CH:16]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=3)[CH2:15][C:14](=[O:35])[NH:13]2)[C:5]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1.[C:37]([Si:39]([CH3:42])([CH3:41])[CH3:40])#[CH:38].C(N(CC)CC)C>CN(C)C=O.O>[Cl:26][C:22]1[CH:21]=[C:20]2[NH:19][C:18](=[O:27])[C:17]3([CH:16]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=4)[CH2:15][C:14](=[O:35])[NH:13][CH:12]3[C:4]3[C:5]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=[C:2]([C:38]#[C:37][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:3]=3[F:36])[C:25]2=[CH:24][CH:23]=1
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2c(OCCO)ccc(Br)c2F)N1
Reactant: C#C[Si](C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: C[Si](C)(C)C#Cc1ccc(OCCO)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1F
Temperature: 100 °C
Yield: 40.5 %

Procedure:
To a solution of racemic (2′R,3R,4′S)-2′-[3-bromo-2-fluoro-6-(2-hydroxy-ethoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.12 g, 0.202 mmol) prepared in example 183d in N,N-dimethyl formamide (1 mL) was added ethynyl-trimethyl-silane (0.28 mL, 2.0 mmol) (Aldrich) and triethylamine (0.127 g, 2.0 mmol). After the reaction mixture was degassed for 5 min, dichloro-bis-(triphenyl-phosphine) (14 mg, 0.02 mmol) (Strem) was added and the reaction mixture was heated at 100° C. under nitrogen for overnight. The reaction mixture was cooled to room temperature and diluted with water, extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, filtered and concentrated. The residue was purified with chromatography to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-fluoro-6-(2-hydroxy-ethoxy)-3-trimethylsilanylethynyl-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as brown solid (Yield: 50 mg, 40.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9].Cl.[CH3:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[C:32]1([C:35](O)=[O:36])[CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:35]([C:32]2([N:27]3[CH2:28][CH2:29][CH2:30][CH2:31][CH:26]3[CH3:25])[CH2:34][CH2:33]2)=[O:36])[C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Reactant: CC1CCCCN1C1(C(=O)O)CC1
Agent: Cl
Product: CC1CCCCN1C1(C(=O)N2C[C@H](S(=O)(=O)c3ccccc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)CC1
Yield: 33 %

Procedure:
The reaction of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7H with 1-(2-methylpiperidin-1-yl)cyclopropanecarboxylic acid hydrochloride 16L carried out according to the general procedure L yielded (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(2-methylpiperidin-1-yl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide as a yellow solid (33%). MS ISP (m/e): 519.3 (100) [(M+H)]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=2)[C:10]([OH:12])=O)[CH2:3][CH2:2]1.C(Cl)CCl.[CH3:23][NH2:24].C1COCC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:23][NH:24][C:10](=[O:12])[C:9]1[CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=[C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[CH:8]=1
Reactant: O=C(O)c1cc(N2CCOCC2)cc([N+](=O)[O-])c1
Reactant: CN
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CNC(=O)c1cc(N2CCOCC2)cc([N+](=O)[O-])c1

Procedure:
Prepared according to Procedure U using 3-morpholino-5-nitrobenzoic acid (0.8 g, 3.17 mmol), EDC (1.22 g, 6.34 mmol), DMAP (0.78 g, 6.34 mmol), 2.0M methanamine in THF (2.4 mL, 4.76 mmol), and DCM (12 mL). Purification by column chromatography (silica; 0-75% EtOAc in hexanes) afforded N-methyl-3-morpholino-5-nitrobenzamide as a yellow amorphous solid. Mass Spectrum (ESI) m/e=266.2 (M+1).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:40]=[C:41]([C:53]([O:55][CH3:56])=[O:54])[C:42]3[NH:43][C:44]4[CH:45]=[C:46]([OH:52])[CH:47]=[CH:48][C:49]=4[C:50]=3[N:51]=2)=[CH:35][CH:34]=1.[O:57]1[CH2:62][CH2:61][N:60]([CH2:63][CH2:64][CH2:65]O)[CH2:59][CH2:58]1>C1COCC1>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]2[CH:40]=[C:41]([C:53]([O:55][CH3:56])=[O:54])[C:42]3[NH:43][C:44]4[CH:45]=[C:46]([O:52][CH2:65][CH2:64][CH2:63][N:60]5[CH2:61][CH2:62][O:57][CH2:58][CH2:59]5)[CH:47]=[CH:48][C:49]=4[C:50]=3[N:51]=2)=[CH:37][CH:38]=1
Reactant: OCCCN1CCOCC1
Reactant: COC(=O)c1cc(-c2ccc(Cl)cc2)nc2c1[nH]c1cc(O)ccc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2ccc(Cl)cc2)nc2c1[nH]c1cc(OCCCN3CCOCC3)ccc12
Reaction time: 1 h
Yield: 55.2 %

Procedure:
Diethyl azodicarboxylate (90 μL, 0.57 mmol) was added to a solution of triphenylphosphine (149 mg, 0.567 mmol), methyl 2-(4-chlorophenyl)-7-hydroxy-5H-pyrido[3,2-b]indole-4-carboxylate (100 mg, 0.283 mmol) and 3-morpholinopropan-1-ol (78 μL, 0.57 mmol) in dry THF (1.4 mL) at RT under nitrogen. After 1 hr, the reaction was quenched with a little water and the product was captured on an SCX cartridge, washed with MeOH and DCM, and then released with 2 N NH3 in MeOH. Radial chromatography (step gradient elution with DCM containing 0 to 1% MeOH) afforded impure methyl 2-(4-chlorophenyl)-7-(3-morpholinopropoxy)-5H-pyrido[3,2-b]indole-4-carboxylate (75 mg) as a yellow solid. MS (ESI) m/z 480.0 (M+H).
Reaction SMILES: C1([C@H](NC(=O)[O:15][C@@H:16]([C:30]#[N:31])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:18]=2)C)C2C(=CC=CC=2)C=CC=1.C(N(CC)CC)C.Cl[SiH](Cl)Cl.[Cl-].[NH4+]>C1C=CC=CC=1.ClC(Cl)Cl.CCOCC>[C:30]([C@H:16]([OH:15])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:18]=1)#[N:31]
Reactant: C[C@@H](NC(=O)O[C@@H](C#N)c1cccc(Oc2ccccc2)c1)c1cccc2ccccc12
Agent: Cl[SiH](Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: N#C[C@H](O)c1cccc(Oc2ccccc2)c1

Procedure:
To 1.99 g (4.7 mmol) of (R)-α-cyano-3-phenoxybenzyl (R)-N-1-(1-naphthyl)ethylcarbamate in 20 ml of benzene is added 725 μl (525 mg, 5.2 mmol) of triethylamine. The solution, under nitrogen, is stirred while 505 μl (675 mg, 5.0 mmol) of trichlorosilane is added. The reaction is warmed to 50° for 2.5 hours, and is then poured into saturated ammonium chloride and ether. The organic fraction is washed again with saturated ammonium chloride and then with brine (3×), and is dried over sodium sulfate overnight in the freezer. Solvent is removed by rotoevaporation, and the residue is washed repeatedly with hexane to remove the isocyanate. The urea contamination is removed by dissolving the product in ether/hexane (~1:1), and the solvent is then removed. Purification by thin layer chromatography (tlc) on silica gel plates developed in 30% ethylacetate/hexane yields the product, which is then dissolved in trichloromethane. The solvent is removed, giving (R)-α-cyano-3-phenoxybenzyl alcohol, specific rotation [α]D =+15.2° (c=10 mg/ml in acetone).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[In].[Cl-].[NH4+].C(O)C>O>[CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: Cc1ccc2ccccc2n1
Agent: [Cl-]
Agent: [In]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC1CCc2ccccc2N1
Temperature: 25 °C
Yield: 63.5 %

Procedure:
A mixture of 2-methylquinoline (584 mg, 4.1 mmol), indium powder (4.21 g, 36.7 mmol), saturated aqueous ammonium chloride solution (6.3 ml) and ethanol (21 ml) were heated at reflux for 3 days. On cooling to room temperature, water was added and the mixture was filtered through Keiselguhr. The filtrate was adjusted to pH 9 with 2M sodium hydroxide solution and extracted with DCM (×2). The extracts were dried over MgSO4 and concentrated in vacuo to give the crude product which was purified by flash column chromatography. Elution with 10% EtOAc in 60-80C petroleum ether gave the title compound as a pale yellow oil (383 mg). 1H NMR (400 MHz, CDCl3) δ (ppm): 6.96 (m, 2H), 6.60 (t, 1H), 6.47 (d, 1H), 3.68 (br, 1H), 3.40 (m, 1H), 2.84 (ddd, 1H), 2.72 (ddd, 1H), 1.92 (m, 1H), 1.60 (m, 1H), 1.21 (d, 3H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:6]([NH2:13])=[C:5]([NH2:14])[CH:4]=1.[C:17](O)(=[O:21])[C:18](O)=[O:19]>Cl>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10])[NH:13][C:18](=[O:19])[C:17](=[O:21])[NH:14]2
Reactant: Nc1cc(C(F)(F)F)c(C(F)(F)F)cc1N
Reactant: O=C(O)C(=O)O
Agent: Cl
Product: O=c1[nH]c2cc(C(F)(F)F)c(C(F)(F)F)cc2[nH]c1=O
Temperature: 25 °C
Yield: 35.1 %

Procedure:
A mixture of 102 mg (0.418 mmol) of 4,5-bis(trifluoromethyl)-1,2-phenylenediamine and 37 mg (0.411 mmol) of oxalic acid in 2 mL of 2N HCl was refluxed for 6 h and cooled to room temperature. The mixture was filtered and washed by water, CHCl3 and dried to leave a colorless solid (43 mg, 35%), mp >250° C. 1H NMR (DMSO-d6), 7.629 (s, 2) 12.293 (s, 2). 19F NMR (DMSO-d6), 62.185 (s).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.Cl.[NH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([OH:30])[CH2:26][CH2:25]1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[F:19][C:18]([F:21])([F:20])[O:17][C:13]1[CH:12]=[C:11]([C:8]2[N:6]3[N:7]=[C:2]([NH:23][CH:24]4[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26][CH2:25]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: FC(F)(F)Oc1cccc(-c2cnc3ccc(Cl)nn23)c1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: OC1CCC(Nc2ccc3ncc(-c4cccc(OC(F)(F)F)c4)n3n2)CC1
Temperature: 180 °C
Reaction time: 0.75 h
Yield: 19.8 %

Procedure:
To a solution of 6-chloro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine (200 mg, 0.64 mmol) and trans-4-aminocyclohexanol hydrogenchloride (184 mg, 1.59 mmol) in NMP (2.0 mL) was added NaHCO3 (161 mg, 1.91 mmol), the mixture was stirred at 180° C. for 45 mins under microwave irridation. The mixture was purified by flash chromatograph to give 4-((3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexanol (50 mg, 0.127 mmol, 16%) as a pale yellow solid.
Reaction SMILES: [CH:1]1([C:4]2[C:9]([CH2:10][NH:11][CH3:12])=[CH:8][N:7]=[C:6]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[N:5]=2)[CH2:3][CH2:2]1.[CH2:23]([O:25][C:26]([C:28]([CH3:42])([O:30][C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([O:40][CH3:41])[CH:39]=1)[C:34]([OH:36])=O)[CH3:29])=[O:27])[CH3:24].OC1C=C(C=C(OC)C=1)C=O.C(CC(Br)(C)C([O-])=O)C.Cl([O-])=O.[Na+]>>[CH2:23]([O:25][C:26](=[O:27])[C:28]([O:30][C:31]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[C:33]([C:34](=[O:36])[N:11]([CH2:10][C:9]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[N:5][C:6]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)=[N:7][CH:8]=2)[CH3:12])[CH:32]=1)([CH3:29])[CH3:42])[CH3:24]
Reactant: CCOC(=O)C(C)(C)Oc1cc(OC)cc(C(=O)O)c1
Reactant: CNCc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Agent: CCCC(C)(Br)C(=O)[O-]
Agent: COc1cc(O)cc(C=O)c1
Agent: [Na+]
Product: CCOC(=O)C(C)(C)Oc1cc(OC)cc(C(=O)N(C)Cc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)c1

Procedure:
A] In analogy to the procedures described in example 26B] and 26C], [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethyl]-methyl-amine (example 130C]) was reacted with 3-(1-ethoxycarbonyl-1-methyl-ethoxy)-5-methoxy-benzoic acid (prepared from 3-hydroxy-5-methoxy-benzaldehyde [Journal of Organic Chemistry (1985), 50(13), 2236–40], by reaction with ethyl-bromoisobutyrate followed by oxidation with sodium chlorite in analogy to the procedures described in examples 52A] and 59A]) to give 2-(3-{[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethyl]-methyl-carbamoyl}-5-methoxy-phenoxy)-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([OH:20])=[O:19])[NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[Si](C)(C)C.C(N(C(C)C)CC)(C)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37].Cl>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([OH:20])=[O:19])[NH:17][S:36]([CH3:35])(=[O:38])=[O:37])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: CS(=O)(=O)Cl
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reaction time: 2.5 h

Procedure:
(S)-N6-Benzyloxycarbonyllysine (1.5 kg) was slurried in methylene chloride (7.5 l) and chlorotrimethylsilane (1.36 l) added over 10 minutes. The mixture was heated under reflux for 30 minutes to give a solution which was cooled to 3° C. before simultaneously adding diisopropylethylamine (1.87 l) and methanesulphonyl chloride (435 ml) at such a rate as to keep the temperature below 25° C. The reaction was stirred for a further 2.5 hours then poured into 2 M aqueous hydrochloric acid solution. The layers were separated and the methylene chloride phase was washed with 2 M aqueous hydrochloric acid solution followed by water. The solvent was removed under reduced pressure and replaced with n-butyl acetate. The solution was cooled and the resulting crystalline material was collected by filtration, washed with n-butyl acetate and dried under reduced pressure to provide the title compound (1.63 kg), m.p. 83.5-84° C. [α]D25−13.4° (c=1, methanol). Found: C,50.23; H,6.40; N,7.76.
Reaction SMILES: [CH3:1][C@:2]12[C:11]3=[CH:12][CH2:13][C@@:14]([CH:17]=[CH2:18])([CH3:16])[CH2:15][CH:10]3[CH2:9][CH2:8][CH:7]1[C@@:6]([C:20]([OH:22])=[O:21])([CH3:19])[CH2:5][CH2:4][CH2:3]2.C(Cl)(C(Cl)=O)=O.[CH:29]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>C(Cl)Cl.CN(C=O)C>[CH:29]1([NH-:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.[CH3:1][C@:2]12[C:11]3=[CH:12][CH2:13][C@@:14]([CH:17]=[CH2:18])([CH3:16])[CH2:15][CH:10]3[CH2:9][CH2:8][CH:7]1[C@@:6]([C:20]([OH:22])=[O:21])([CH3:19])[CH2:5][CH2:4][CH2:3]2
Reactant: NC1CCCCC1
Agent: C=C[C@@]1(C)CC=C2C(CCC3[C@](C)(C(=O)O)CCC[C@@]23C)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: [NH-]C1CCCCC1

Procedure:
Acanthoic acid, including compound obtained by the above described methodology, can be dissolved in dry CH2Cl2 and treated with 10 equivalents of (COCl)2 followed by two drops of DMF. When the reaction stops bubbling, the CH2Cl2 solvent and (COCl)2 can be evaporated under vacuum and the reaction residue can be redissolved in dry benzene and then treated with 5 equivalents of cyclohexylamine to yield N-cyclohexylamide derivative of acanthoic acid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21](Br)[CH:20]=2)([C:9]2[CH:14]=[C:13]([CH2:15][CH3:16])[N:12]=[C:11]([CH2:17][CH3:18])[CH:10]=2)[N:3]=1.[F:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][C:29]=1[Sn](CCCC)(CCCC)CCCC>CN(C=O)C.C1(P([Pd-](Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:9]2[CH:14]=[C:13]([CH2:15][CH3:16])[N:12]=[C:11]([CH2:17][CH3:18])[CH:10]=2)([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][C:28]=3[F:27])[CH:20]=2)[N:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccc1F
Reactant: CCc1cc(C2(c3ccc(F)c(Br)c3)N=C(N)N(C)C2=O)cc(CC)n1
Agent: Cl[Pd-]([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCc1cc(C2(c3ccc(F)c(-c4cnccc4F)c3)N=C(N)N(C)C2=O)cc(CC)n1
Temperature: 150 °C
Yield: 9.6 %

Procedure:
A mixture of 2-amino-5-(3-bromo-4-fluorophenyl)-5-(2,6-diethyl-pyridin-4-yl)-3-methyl-3,5-dihydro-imidazol-4-one (0.170 g, 0.405), 4-fluoropyridin-3-yl(tributly)tin (0.235 g, 0.608 mmol) and bis(triphenylphosphino)palladium(II) chloride (0.023 g, 0.032 mmol) in DMF (5 mL) was degassed and heated at 150° C. for 1 h. The mixture was cooled to room temperature and diluted with ethyl acetate (50 mL) and 2% aqueous lithium chloride (20 mL). The organic layer was separated, washed with 2% aqueous lithium chloride, dried over sodium sulfate, filtered, and concentrated. Purification of the resultant residue by flash chromatography (silica, 95:5:0.25 methylene chloride/methanol/concentrated ammonium hydroxide) afforded the title product (0.017 g, 10%) as a white solid, mp 92-100° C.; 1H NMR (300 MHz, CD3OD) δ 8.55-8.45 (m, 2H), 7.56-7.19 (m, 4H), 7.09 (s, 2H), 3.10 (s, 3H), 2.68 (q, J=7.5 Hz, 4H), 1.15 (t, J=7.5 Hz, 6H); ESI MS m/z 436 [C24H23F2N5O+OH]+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Br.[C-:13]#[N:14].[K+].C(O)C>O>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][C:13]#[N:14]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCc1ccccc1C(F)(F)F

Procedure:
A mixture of 75 g. (0.31 mole) of o-trifluoromethylbenzyl bromide, 120 g. (0.55 mole) of potassium cyanide, 150 ml. of water and 600 ml. of absolute ethanol is stirred and heated under reflux for 20 hours. The reaction mixture is diluted with 4 liters of water and is extracted with 500 ml. of ether. The extract is dried over anhydrous potassium carbonate and evaporated. Distillation gives 45 g. of the desired product b.p. 103°-105° C./10 mm.