Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][S:8][C:9]2[C:14]([CH:15]=O)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24](=[O:29])[CH2:25]S(C)=O.N1CCCCC1>C1(C)C=CC=CC=1>[C:1]1([CH2:7][S:8][C:9]2[C:14]([C:15]3[NH:17][C:18]4[C:19]([C:24](=[O:29])[CH:25]=3)=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1cccnc1SCc1ccccc1
Reactant: CS(=O)CC(=O)c1ccccc1N
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: O=c1cc(-c2cccnc2SCc2ccccc2)[nH]c2ccccc12
Reaction time: 3.5 h
Yield: 26.3 %

Procedure:
2-[(Phenylmethyl)thio]pyridine-3-carboxaldehyde (6.01 g, 26.2 mmole, 1 equiv.), 1-(2-aminophenyl)-2-(methylsulfinyl)ethanone (5.17 g, 26.2 mmole, 1 equiv.), and piperidine (1.3 ml, 13.1 mmole, 0.5 equiv.) were combined in toluene (240 ml), and the mixture was heated to reflux under a Dean - Stark trap. After 3.5 hr, the reaction was concentrated to one half volume and cooled in the refrigerator overnight. Filtration of the mixture gave 2-[2-[(phenylmethyl)thio]-3-pyridinyl]-4(1H)-quinolinone (2.37 g, 26%) as a pale yellow solid: mp 219-226 (dec); TLC (50% EtOAc/CHCl3) Rf 0.19; 1H NMR (DMSO-d6) δ11.93 (br s, 1 H), 8.67 (dd, J=4.8, 1.8 Hz, 1 H), 8.10 (dd, J=8.1, 1.1 Hz, 1 H), 7.87 (dd, J=7.7, 1.8 Hz, 1 H), 7.60-7.72 (m, 1 H), 7.58 (d, J=8.0 Hz, 1 H), 7.17-7.45 (m, 7 H), 6.06 (br s, 1 H), 4.44 (s, 2 H); IR (KBr) 2100-3300 (br), 1633, 1595, 1573, 1549, 1534, 1502, 1474, 1440 cm-1 ; MS (NH3), m/e (%) 345.0 (100, (M+H)+), 255.1 (22.7), 253.1 (20.7). Anal. Calcd for C21H16N2OS: C, 73.23; H, 4.68; N, 8.13; S, 9.31. Found: C, 72.98; H, 4.56; N, 8.03; S, 9.20.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@H:14]([NH:21][C:22](=[O:42])[CH2:23][NH:24][C:25](=[O:41])[C:26]2[CH:31]=[C:30]([NH:32][C:33]3[NH:34][CH2:35][CH:36]([OH:39])[CH2:37][N:38]=3)[CH:29]=[C:28]([OH:40])[CH:27]=2)[CH2:15][C:16]([O:18]CC)=[O:17])[CH:5]=[C:6]([C:8]2([CH:11]([F:13])[F:12])[CH2:10][CH2:9]2)[CH:7]=1.O.[OH-].[Li+].ClCCl>C(#N)C.O.O>[Br:1][C:2]1[CH:3]=[C:4]([C@@H:14]([NH:21][C:22](=[O:42])[CH2:23][NH:24][C:25](=[O:41])[C:26]2[CH:31]=[C:30]([NH:32][C:33]3[NH:38][CH2:37][CH:36]([OH:39])[CH2:35][N:34]=3)[CH:29]=[C:28]([OH:40])[CH:27]=2)[CH2:15][C:16]([OH:18])=[O:17])[CH:5]=[C:6]([C:8]2([CH:11]([F:13])[F:12])[CH2:10][CH2:9]2)[CH:7]=1
Reactant: CCOC(=O)C[C@H](NC(=O)CNC(=O)c1cc(O)cc(NC2=NCC(O)CN2)c1)c1cc(Br)cc(C2(C(F)F)CC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: O=C(O)C[C@H](NC(=O)CNC(=O)c1cc(O)cc(NC2=NCC(O)CN2)c1)c1cc(Br)cc(C2(C(F)F)CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of (3S)-ethyl 3-(3-bromo-5-(1-(difluoromethyl)cyclopropyl)phenyl)-3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetamido)propanoate (from step 2 above) (0.635 mmol, crude residue) in a mixture of acetonitrile/water (1:1) (6 mL) was added lithium hydroxide monohydrate (135 mg, 3.217 mmol) and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo to afford a pale yellow crystalline residue. The residue was dissolved in water (25 mL) and stirred with dichloromethane (50 mL) to remove the urea. The aqueous layer was neutralized with TFA (1 mL in 3 mL ACN) and evaporated in vacuo to afford a pale yellow viscous residue. The crude residue was purified by reverse-phase preparative HPLC on a Biotage 40+M (100 g) C18HS column and a gradient 10-60% acetonitrile in water containing 0.05% TFA to give the desired product, after lyophilization, as a colorless lyophilized powder (94.0 mg). LC-MS analysis of the product shows the desired product's mass: m/z 624 (79BrM+H) and m/z 626 (81BrM+H); Calcd for C26H28BrF2N5O6: 624.43.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH2:16]([CH:18]([C:21]1[NH:22][CH:23]=[CH:24][N:25]=1)[CH2:19][CH3:20])[CH3:17].C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:16]([CH:18]([C:21]1[N:22]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=2[N+:13]([O-:15])=[O:14])[CH:23]=[CH:24][N:25]=1)[CH2:19][CH3:20])[CH3:17]
Reactant: CCC(CC)c1ncc[nH]1
Reactant: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccc(-n2ccnc2C(CC)CC)c([N+](=O)[O-])c1

Procedure:
Ethyl 4-fluoro-3-nitrobenzoate 9.16 g, 2-(1-ethylpropyl)-1H-imidazole 5.94 g, N,N-diisopropylethylamine 11.2 mL and acetonitrile 86 mL were mixed and heated under reflux for 15 hours in nitrogen atmosphere. From the reaction liquid the solvent was distilled off, and the residue was dissolved in ethyl acetate and rendered weakly alkaline with saturated aqueous sodium hydrogencarbonate solution. The organic layer was separated, washed with water and dried over magnesium sulfate. Distilling the solvent off, 13.16 g of the title compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.FC(F)(F)[C:13]1[CH:14]=[C:15]([C:19]([CH:21]=O)=[O:20])[CH:16]=[CH:17][CH:18]=1.C1(C(C=O)=O)C=CC=CC=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][CH2:21][CH:19]([OH:20])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: O=CC(=O)c1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(CCN)cc1
Agent: O=CC(=O)c1ccccc1
Product: Cc1ccc(CCNCC(O)c2ccccc2)cc1

Procedure:
The title compound was prepared in the manner described in Example 9, replacing 2-(4-methylphenyl)-1,1-dimethylethanamine by 2-(4-methylphenyl)ethanamine and 3-trifluoromethylphenylglyoxal by phenylglyoxal. The chromatographed material was recrystallised from hexane to give the title compound, mp 95°-97°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]#[C:10][C:11]2[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=2)=[N:4][C:5](Br)=[CH:6][N:7]=1.[CH3:18][S:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O)=[O:20].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>CC#N.CCOC(C)=O.Cl.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[NH2:1][C:2]1[C:3]([C:9]#[C:10][C:11]2[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[S:19]([CH3:18])=[O:20])=[CH:6][N:7]=1
Reactant: Nc1ncc(Br)nc1C#Cc1cccc(O)c1
Reactant: CS(=O)c1ccccc1B(O)O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CS(=O)c1ccccc1-c1cnc(N)c(C#Cc2cccc(O)c2)n1
Temperature: 60 °C
Yield: 27.7 %

Procedure:
3-[2-(3-Amino-6-bromo-pyrazin-2-yl)ethynyl]phenol (72 mg, 0.2482 mmol), (2-methylsulfinylphenyl)boronic acid (54.80 mg, 0.2978 mmol) and K3PO4 (105.4 mg, 0.4964 mmol) were combined in MeCN (2 mL)/water and Pd[P(tBu)3]2 (6.342 mg, 0.01241 mmol) was added. The reaction was heated at 60° C. for 15 hours. The reaction was cooled to ambient temperature and diluted with EtOAc and 1M HCl. The layers were separated and the aqueous layer extracted with EtOAc (×3). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion™, 12 g column, eluting with 0 to 100% EtOAc/Petroleum Ether, dry loaded) and freeze-dried to give the title product as a yellow solid (24 mg, 26% Yield). 1H NMR (400.0 MHz, DMSO) δ 3.34 (s, 3H), 5.15 (d, 1H), 6.88 (dd, 1H), 7.09 (br s, 2H), 7.19 (d, 1H), 7.27 (t, 1H), 7.60-7.69 (m, 2H), 7.89 (d, 1H), 8.17 (d, 1H), 8.60 (s, 1H) and 9.76 (s, 1H) ppm; MS (ES+) 350.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6].[NH2:21][C:22]1[CH:37]=[CH:36][C:25]2[N:26]([CH2:34][CH3:35])[C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:32])([CH3:31])[C:24]=2[CH:23]=1.CC1(C)[C@]2(CS(O)(=O)=O)C(C[C@H]1CC2)=O>COCCO>[Cl:1][C:2]1[C:3]([NH:12][C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15]([NH:21][C:22]3[CH:37]=[CH:36][C:25]4[N:26]([CH2:34][CH3:35])[C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:31])([CH3:32])[C:24]=4[CH:23]=3)[N:14]=2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6]
Reactant: CNC(=O)c1cccc(Cl)c1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)CCC(C)(C)c2cc(N)ccc21
Agent: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: COCCO
Product: CCN1C(=O)CCC(C)(C)c2cc(Nc3ncc(Cl)c(Nc4c(Cl)cccc4C(=O)NC)n3)ccc21
Yield: 10.3 %

Procedure:
Combined 3-Chloro-2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (91 mg, 0.275 mmol), 7-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (64 mg, 0.275 mmol), DL-10-Camphorsulfonic acid (82 mg, 0.353 mmol) and 2-methoxyethanol (3 mL). Heated reaction to 120° C. for 2.5 hours. Evaporated off solvent, dissolved residue in methylene chloride and washed with saturated sodium bicarbonate solution, then brine. Dried with magnesium sulfate, filtered and purified with normal phase chromatography using basic alumina silica gel to yield a yellow solid, 3-Chloro-2-[5-chloro-2-(1-ethyl-5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (15 mg, 10%). LCMS: m/z=527.54 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.12 (d, 1H, J=1.0 Hz), 8.02 (br s, 1H), 7.59 (d, 1H, J=8.1 Hz), 7.51 (m, 2H), 7.28 (m, 1H), 7.21 (m, 2H), 7.02 (d, 1H, J=8.6 Hz), 6.25 (d, 1H, J=4.6 Hz), 4.13 (m, 2H), 3.76 (m, 2H), 2.82 (d, 3H, J=4.3 Hz), 2.22 (m, 2H), 1.27 (m, 9H).
Reaction SMILES: FC1C=C(C(C2C=CC=C(F)C=2)=CC=O)C=CC=1.C(C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(OCC)=O.C([O:46][C:47](=[O:66])/[CH:48]=[CH:49]/[CH:50]=[C:51]([C:59]1[CH:64]=[CH:63][CH:62]=[C:61]([F:65])[CH:60]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[C:54]([F:58])[CH:53]=1)C.[OH-].[Na+]>C(Cl)(Cl)(Cl)Cl.CO>[F:58][C:54]1[CH:53]=[C:52]([C:51]([C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([F:65])[CH:60]=2)=[CH:50]/[CH:49]=[CH:48]/[C:47]([OH:66])=[O:46])[CH:57]=[CH:56][CH:55]=1
Reactant: CCOC(=O)/C=C/C=C(c1cccc(F)c1)c1cccc(F)c1
Agent: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=CC=C(c1cccc(F)c1)c1cccc(F)c1
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CO
Product: O=C(O)/C=C/C=C(c1cccc(F)c1)c1cccc(F)c1

Procedure:
In the manner described in Example 99, 3,3-bis(3-fluorophenyl)-2-propen al (17.8 g) was reacted with (carbethoxymethylene)triphenylphosphine (26.2 g) in carbon tetrachloride (200 mL) at room temperature overnight. The crude product (23 g) obtained from the usual work up was Predominantly (E)-5,5-bis(3-fluorophenyl)-2,4-pentadienoic acid ethyl ester. A stirred solution of the above material (23 g) in hot methanol (200 mL) was treated in one portion with 2N sodium hydroxide solution (75 mL). After 10 minutes at reflux, the reaction had become homogeneous and most of the methanol was distilled off. The cooled solution was diluted with water (300 mL), then was extracted with dichloromethane (3×200 mL). The organic extracts were discarded and the aqueous phase was added in a fine stream to a stirred mixture of 2N hydrochloric : acid (20mL) and ice (300 g). The resulting precipitate was filtered off then washed with water and dried. Triturating of the crude acid with hot hexane (150 mL) furnished 18.2 g of (E)-5,5-bis(3-fluorophenyl)-2,4-pentadienoic acid mp 162°-164° C. The analytical sample was obtained from 2-propanol. mp 163.5°-165° C.- Anal Calculated for C17H12F2O2 : C, 71.32; H, 4.22; F. 13.27 Found: C, 71.17; H. 4.23; F, 13.37.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](O)=[O:12])=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[S:8][C:7]=2[CH:22]=1.S(Cl)([Cl:25])=O.CN(C)C=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([Cl:25])=[O:12])=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[S:8][C:7]=2[CH:22]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)O)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)Cl)cc1
Yield: 97.2 %

Procedure:
To a slurry of 6-methoxy -2-(4-methoxyphenyl)benzo[b]thiophene-3-carboxylic acid (0.0484 g, 0.154 mmol) in methylene chloride (5 ml) is added thionyl chloride (0.025 ml, 0.356 mmol), and a catalytic amount of N,N-dimethylformamide. The reaction is heated to reflux for 2 hours, then cooled and concentrated in vacuo. The residual material is dissolved in toluene (10 ml), and reconcentrated in vacuo. This dissolution/reconcentration procedure is repeated two more times to afford 0.0498 g (97%) of title compound as a solid: mp 135.5-137.9° C. IR (KBr) 2965, 1678, 1610, 1525, 1478, 1253, 815; 1H NMR (CDCl3): δ8.13 (d, 1 H, J=9 Hz), 7.48 (d, 2 H, J=8.7 Hz), 7.27 (d, 1 H, J=2.4 Hz), 7.13 (dd, 1 H, J=9.0, 2.4 Hz), 7.00 (d, 2 H, J=8.7 Hz); 13C NMR (CDCl3): d 163.4, 161.0, 158.2, 139.1, 131.3, 131.2, 129.1, 128.3, 125.1, 124.6, 115.9, 114.2, 104.4, 55.7, 55.5; Exact mass calcd. for C18H16O4S (in situ-derived methyl ester): 328.0769. Found: 328.0760.
Reaction SMILES: [CH3:1][C:2]([CH3:5])=[C:3]=[O:4].[C:6]1([CH2:12][CH:13]=[O:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C([O-])(O)=O.[Na+]>C(OC(=O)C)C.[Cl-].[Zn+2].[Cl-]>[CH2:12]([CH:13]1[O:14][C:3](=[O:4])[C:2]1([CH3:5])[CH3:1])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)=C=O
Reactant: O=CCc1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC1(C)C(=O)OC1Cc1ccccc1
Temperature: 0 °C
Yield: 84.1 %

Procedure:
2-Methylprop-1-en-1-one (0.04 g, 5.0 mmol) and 2-phenylacetaldehyde (0.60 g, 5.0 mmol) were dissolved in ethylacetate (3.5 mL) and stirred at 0° C. under nitrogen. Zinc(II) chloride (0.03 g, 0.25 mmol) was added quickly and the reaction mixture was kept at 0° C. for a short period and then at room temperature overnight (monitored by TLC). The reaction mixture was then treated at room temperature with a solution of NaHCO3(aq). The organic layers were combined, dried, and concentrated in vacuo, and the crystallization in CH2Cl2:hexane=1:1 gave 4-benzyl-3,3-dimethyloxetan-2-one (0.80 g, 84%).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[C:35]([CH3:36])=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[C:35]([CH3:36])=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: Cc1cc2ccccc2nc1Cl
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc2ccccc2nc1Sc1ccc2c(c1)CC[C@H]1N(C)C(=O)CC[C@]21C
Yield: 16 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (37 mg, 0.14 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-3-methyl-quinoline (30 mg, 0.17 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80 ethyl acetate/hexanes eluent) to give 9 mg (16%) of the title compound as an amorphous foam. mp 185°-193°. FDMS: m/e=402.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.B(O)(O)[C:33]1[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=1>COCCOC>[C:18]1([N:13]2[C:12]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(-c3ccccc3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: Cc1ccc(B(O)O)cc1
Solvent: COCCOC
Product: Cc1ccc(-c2c3c(nn2-c2ccccc2)CCNCC3)cc1
Yield: 14.1 %

Procedure:
The title compound (17.5 mg) was prepared from 188.9 mg of 2-phenyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 176, Step B) and 93.3 mg of p-tolylboronic acid as in Example 199, using DME as the solvent. MS (ESI): exact mass calculated for C20H21N3, 303.17; found, m/z 304.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.26-7.23 (m, 2H), 7.21-7.16 (m, 3H), 7.15-7.12 (m, 2H), 7.04-7.01 (m, 2H), 3.11-3.07 (m, 2H), 3.04-3.00 (m, 2H), 2.98-2.96 (m, 2H), 2.68-2.65 (m, 2H), 2.35 (s, 3H).
Reaction SMILES: CO[C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:6][C:5]=1[NH2:20].[C:22](O)(=[O:24])[CH3:23].O.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>O1CCOCC1.C1(C)C=CC=CC=1>[OH:21][C:3]1[C:4]2[C:5](=[CH:6][C:7]([C:10]3[C:15]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:13]=[CH:12][N:11]=3)=[CH:8][CH:9]=2)[NH:20][C:22](=[O:24])[CH:23]=1
Reactant: CC(=O)O
Reactant: COC(=O)c1ccc(-c2ncccc2C(F)(F)F)cc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: O=c1cc(O)c2ccc(-c3ncccc3C(F)(F)F)cc2[nH]1
Reaction time: 8 h

Procedure:
Heat a solution of 2-amino-4-(3-trifluoromethyl-pyridin-2-yl)-benzoic acid methyl ester (296 mg, 1.0 mmol) and acetic acid (1 mL) in dioxane (2 mL) at 60° C. for 3 hours. Cool the mixture, add water (1 mL) and evaporate to dryness. Dissolve the solid in THF (4 mL) and add drop wise to a solution of potassium bis(trimethylsilyl)amide (600 mg, 3.0 mmol) in toluene (6 mL) at −78° C. Allow the reaction to return to room temperature overnight. Add water (10 mL) and extract with ethyl acetate. Acidify the aqueous layer with hydrochloric acid and collect the precipitate by filtration. Air-dry to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][N:3]=1.[F:11][C:12]1([F:19])[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1.CC([O-])(C)C.[K+]>O1CCOCC1>[F:11][C:12]1([F:19])[CH2:17][CH2:16][C:15](=[C:8]([C:5]2[CH:4]=[N:3][C:2]([CH3:1])=[N:7][CH:6]=2)[C:9]#[N:10])[CH2:14][CH2:13]1
Reactant: Cc1ncc(CC#N)cn1
Reactant: O=C1CCC(F)(F)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ncc(C(C#N)=C2CCC(F)(F)CC2)cn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 23.5 %

Procedure:
To a solution of 2-(2-methylpyrimidin-5-yl)acetonitrile (1 g, 7.52 mmol) and 4,4-difluorocyclohexanone (1.1 g, 8.27 mmol) in 1,4-dioxane (40 mL) was added t-BuOK (0.8 g, 8.27 mmol) in two portions. After the addition was completed, the reaction was heated to 60° C. and stirred overnight. The reaction solution was cooled to 0° C., quenched by saturated NH4Cl aq. solution and extracted with EtOAC (50 m×3). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated to get the crude product, which was purified by column chromatography on silica gel (Petroleum ether: EtOAc=4:1˜2:1) to afford 2-(4,4-difluorocyclohexylidene)-2-(2-methylpyrimidin-5-yl)acetonitrile (440 mg, yield: 23.5%). 1H NMR (CDCl3 varian 400 MHz): δ8.61 (s, 2H), 2.97 (t, J=8.0 Hz, 2H), 2.80 (s, 3H), 2.55 (t, J=8.0 Hz, 2H), 2.27-2.17 (m, 2H), 2.09-1.98 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[O:14][N:15]=[C:16]([C:17]([OH:19])=O)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1)=[O:22]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[O:14][N:15]=[C:16]([C:17]([N:32]3[CH2:31][CH2:30][N:29]([C:26]4[CH:25]=[CH:24][C:23]([C:21](=[O:22])[CH3:20])=[CH:28][CH:27]=4)[CH2:34][CH2:33]3)=[O:19])[C:10]=2[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCc2onc(C(=O)O)c2C1
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3noc4c3CN(C(=O)OC(C)(C)C)CC4)CC2)cc1
Yield: 42.4 %

Procedure:
In a manner similar to general method 1, 1.1 g (4.1 mmol) of 6,7-dihydro-4H-isoxazolo[4,5-c]pyridine-3,5-dicarboxylic acid 5-tert-butyl ester were reacted with 838 mg (4.1 mmol) of 4-piperazinoacetophenone to yield 790 mg (42% of theoretical) of 3-[4-(4-acetyl-phenyl)-piperazine-1-carbonyl]-6,7-dihydro-4H-isoxazolo[4,5-c]pyridine-5-carboxylic acid tert-butyl ester, which were obtained in the form of a yellow-orange oil.
Reaction SMILES: [CH:1]12[CH2:9][CH:5]([CH:6]=[CH:7][CH2:8]1)[CH2:4][N:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:2]2.B.C1C[O:19]CC1.[OH-].[Na+].OO>C1COCC1.O>[OH:19][CH:6]1[CH2:7][CH2:8][CH:1]2[CH2:9][CH:5]1[CH2:4][N:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:2]2
Reactant: CCOC(=O)N1CC2C=CCC(C2)C1
Reactant: C1CCOC1
Agent: B
Agent: OO
Agent: [Na+]
Solvent: O
Product: CCOC(=O)N1CC2CCC(O)C(C2)C1
Temperature: 10 °C
Reaction time: 3.5 h
Yield: 80.6 %

Procedure:
A solution of ethyl 3-azabicyclo[3.3.1]non-6-ene-3-carboxylate (2.50 g, 12.8 mmol) in 75 mL of THF was cooled in an ice bath and borane-THF (1M in THF, 19 mL, 19 mmol) was added drop-wise. The reaction was stirred at about 10° C. for 3.5 h, then cooled in ice bath. A solution of sodium hydroxide (2.4 g, 60 mmol) in 10 mL water was added drop-wise, followed immediately by an additional 50 mL of THF and 10 mL of water. Hydrogen peroxide (30% aqueous, 8.5 g, 75 mmol) was then added, and the mixture stirred overnight at ambient temperature. The mixture was extracted with ether (2×50 mL), and the combined extracts were washed with water and brine (25 mL each). Drying over anhydrous magnesium sulfate, followed by filtration and concentration under reduced pressure, gave the product as a colorless, viscous oil (2.2 g, 80%).
Reaction SMILES: [N+:1]([C:4]1[CH:41]=[CH:40][C:7]([CH2:8][C:9]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=2)([CH2:21][C:22](=[O:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br)[C:10]([C:13](=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br)([OH:12])[OH:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:42]([C@H:45]1[CH2:50][CH2:49][C@H:48]([C:51]2[CH:56]=[CH:55][C:54]([OH:57])=[CH:53][CH:52]=2)[CH2:47][CH2:46]1)[CH2:43][CH3:44]>>[N+:1]([C:4]1[CH:41]=[CH:40][C:7]([CH2:8][C:9]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=2)([CH2:21][C:22](=[O:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:57][C:54]2[CH:55]=[CH:56][C:51]([C@H:48]3[CH2:49][CH2:50][C@H:45]([CH2:42][CH2:43][CH3:44])[CH2:46][CH2:47]3)=[CH:52][CH:53]=2)[C:10]([C:13](=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:57][C:54]2[CH:55]=[CH:56][C:51]([C@H:48]3[CH2:47][CH2:46][C@H:45]([CH2:42][CH2:43][CH3:44])[CH2:50][CH2:49]3)=[CH:52][CH:53]=2)([OH:12])[OH:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(CCCCCBr)CC(Cc1ccc([N+](=O)[O-])cc1)(Cc1ccc([N+](=O)[O-])cc1)C(O)(O)C(=O)CCCCCBr
Reactant: CCC[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Product: CCC[C@H]1CC[C@H](c2ccc(OCCCCCC(=O)CC(Cc3ccc([N+](=O)[O-])cc3)(Cc3ccc([N+](=O)[O-])cc3)C(O)(O)C(=O)CCCCCOc3ccc([C@H]4CC[C@H](CCC)CC4)cc3)cc2)CC1

Procedure:
The preparation was carried out analogously to Synthesis Example 4 using 3.14 g (4.48 mmol) 2,2-bis(4-nitrobenzyl)-1,3 di(6-bromohexanoyl)propanediol and 1.96 g (8.98 mmol 4-(trans-4-propylcyclohexyl)phenol yield 2,2-bis(4 -nitrobenzyl)-1,3-di{6-[4-(trans-4-propylcyclohexyl)phenoxy]hexanoyl}propanediol.