Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][C:17]([O-:19])=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[N+:45]([C:48]1[CH:53]=[CH:52][C:51]([NH:54][CH:55]2[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)=[CH:50][C:49]=1[C:61]([F:64])([F:63])[F:62])([O-:47])=[O:46].C(N(C(C)C)CC)(C)C.[O-2].[Al+3].[O-2].[O-2].[Al+3]>O1CCCC1.CN(C)C=O>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][CH:12]([CH2:15][CH2:16][C:17]([N:58]3[CH2:59][CH2:60][CH:55]([NH:54][C:51]4[CH:52]=[CH:53][C:48]([N+:45]([O-:47])=[O:46])=[C:49]([C:61]([F:62])([F:63])[F:64])[CH:50]=4)[CH2:56][CH2:57]3)=[O:19])[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(NC2CCNCC2)cc1C(F)(F)F
Reactant: O=C([O-])CCC1CCN(c2ccc(Cl)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCC1CCN(c2ccc(Cl)cc2)CC1)N1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reaction time: 3 h
Yield: 24 %

Procedure:
To a solution of 3-[1-(4-chloro-phenyl)-piperidin-4-yl]-propionic acid lithium salt (14 mg; 0.05 mmol, prepared in accordance with Example 143) in tetrahydrofuran (0.5 mL) is added tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (19 mg; 0.05 mmol) in dimethylformamide (0.25 mL). A solution of (4-nitro-3-trifluoromethyl-phenyl)-piperidin-4-yl-amine hydrochloride (16 mg; 0.05 mmol, prepared in accordance with Example 8) in dimethylformamide (0.25 mL) and diisopropylethyl amine (25 μL; 0.15 mmol) are then added and the reaction is stirred. After 3 hours at room temperature, aluminium oxide (90 active basic) is added and stirring is continued for 40 minutes. The solids are removed by filtration and the filtrate is concentrated under high vacuum. The obtained residue is purified by preparative HPLC to afford the desired compound (6 mg; 0.012 mmol). The structure was confirmed using Protocol I-D. Calculated mass=539; observed mass=539; HPLC retention time=1.88 min.
Reaction SMILES: [C:1]1([CH2:7][CH:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)[C@H](C1C=CC=CC=1)O>>[C:1]1([CH2:7][C@H:8]([NH:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(Cc1ccccc1)NCc1ccccc1
Agent: O=C(O)[C@@H](O)c1ccccc1
Product: C[C@H](Cc1ccccc1)NCc1ccccc1
Yield: 28.6 %

Procedure:
A sample of 2.62 g (11.6 mmol) of 1-phenyl-2-benzylaminopropane (38) was reacted with 1.77 g (11.6 mmol) of (S)-(+)-mandelic acid to give 747 mg (57% based on enantiomeric abundance) of the free amine after workup. 1H NMR (CDCl3) δ□□ 1.13 (d, 3H, J=6.0 Hz), 2.62-2.84 (m, 2H), 2.92-2.99 (m, 1H), 3.81 (dd, 2H, J=13.2, 34.5 Hz) 7.14-7.29 (m, 10H); MS (APCI+) m/z (rel): 226 (100); [α]D=−24.5° (c=1.10 MeOH).
Reaction SMILES: [C:1]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[N:16]2[C:11]([C:12]([O:17][CH2:18][C:19]([O:21]C)=[O:20])=[CH:13][CH:14]=[CH:15]2)=[C:10]([C:23](=[O:27])[C:24]([NH2:26])=[O:25])[C:9]=1[CH:28](C)C>C(Cl)(Cl)Cl>[C:1]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[N:16]2[C:11]([C:12]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:13][CH:14]=[CH:15]2)=[C:10]([C:23](=[O:27])[C:24]([NH2:26])=[O:25])[C:9]=1[CH3:28]
Reactant: COC(=O)COc1cccn2c(Cc3ccccc3-c3ccccc3)c(C(C)C)c(C(=O)C(N)=O)c12
Solvent: ClC(Cl)Cl
Product: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cccn2c1Cc1ccccc1-c1ccccc1
Yield: 62.1 %

Procedure:
Mp, 221-224° C. 62.1% Yield. IR νmax (nujol) 3448, 3344, 1735, 1635 (sh), 1615 cm−1. 1H NMR (CDCl3) δ 2.40 (3H, s), 4.14 (2H, s), 4.74 (2H, s), 6.38 (1H, d, J=8.1 Hz), 6.54 (1H, t, J=6.9 Hz), 6.81 (1H, d, J=7.5 Hz), 7.05-7.53 (8H, m). Analyses: Calc'd for C26H22N2O5.0.5H2O: C, 69.17; H, 5.13; N, 6.20. Found: C, 69.07; H, 5.06; N, 6.17. 2-(3-(Biphenyl-2-ylmethyl)-8-carbomethoxymethyloxy-2-isopropylindolizin-1-yl)glyoxylamide 58c. Mp, 139-141° C. 59% Yield. IR νmax (CHCl3) 3462, 3382, 3292, 1737, 1686, 1639 cm−1. 1H NMR (CDCl3) δ 1.32 (6H, d, J=7.0 Hz), 3.42 (1H, sept, J=7.0 Hz), 4.19 (2H, s), 4.59 (2H, s), 6.23 (1H, d, J=7.4 Hz), 6.45 (1H, t, J=7.0 Hz), 6.69 (1H, d, J=7.8 Hz), 6.91 (1H, br.s), 7.03-7.58 (l1H, m). Analyses: Calc'd for C28H26N2O5.1.3H2O: C, 68.09; H, 5.84; N, 5.67. Found: C, 68.02; H, 5.74; N, 5.65.
Reaction SMILES: CC([O-])(C)C.[K+].[Cl:7][C:8]1[CH:9]=[C:10]([OH:15])[CH:11]=[CH:12][C:13]=1[Cl:14].C(S([C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])=[CH:23][N:22]=1)(=O)=O)C>C1COCC1.CS(C)=O>[Cl:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:13]=1[Cl:14])[O:15][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH2:30][CH3:31])(=[O:28])=[O:29])=[CH:23][N:22]=1
Reactant: CCS(=O)(=O)c1ccc(S(=O)(=O)CC)nc1
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCS(=O)(=O)c1ccc(Oc2ccc(Cl)c(Cl)c2)nc1
Temperature: 0 °C

Procedure:
To 6.7 g of t-BuOK in a mixture of 50 ml of THF and 50 ml of DMSO was added 8.2 g of 3,4-dichlorophenol and then 7.9 g of 2,5-bis(ethylsulfonyl)pyridine, and the resulting mixture heated at 55° C. for 3 hrs. The reaction mixture was cooled and then poured into ice-water. A precipitate formed which was collected by filtration and then washed with water. The recovered solid was then dissolved in CH2Cl2 and dried over MgSO4. The solution was diluted with an equal volume of hexane and treated with silica gel and then filtered. The solution was then concentrated to 50 ml, cooled and 6.5 g of 2-(3,4-dichlorophenoxy)-5-ethylsulfonyl)pyridine recovered as a white powder, m.p. 117°-118° C.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:35][O:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][C:46]=1[O:47][CH3:48])[N:43]=[CH:42][N:41]=[C:40]2[O:49][C:50]1[CH:51]=[C:52]([CH:54]=[CH:55][CH:56]=1)[NH2:53]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:53][C:52]2[CH:54]=[CH:55][CH:56]=[C:50]([O:49][C:40]3[C:39]4[C:44](=[CH:45][C:46]([O:47][CH3:48])=[C:37]([O:36][CH3:35])[CH:38]=4)[N:43]=[CH:42][N:41]=3)[CH:51]=2)=[O:19])[N:7]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[N:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(C2CCCCC2)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4C4CCCCC4)c3)c2cc1OC
Temperature: 25 °C
Yield: 38.8 %

Procedure:
A stirred solution of phenyl 3-tert-butyl-1-cyclohexyl-1H-pyrazol-5-Ylcarbamate (200 mg), N,N-Diisopropylethylamine (67 mg, 0.52 mmol) and 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (prepared as described in Example 113A) (80 mg, 0.26 mmol) in THF (1.0 mL) was heated at 60° C. for 15 h. After cooling to rt, the reaction solution was partitioned between dichloromethane and a saturated aqueous solution of sodium carbonate. The organic phase was separated and concentrated under reduced pressure. The crude product was purified via silica gel column chromatography (eluting with a gradient of 40:1 to 20:1 dichloromethane:methanol) then reverse-phase preparative HPLC to afford 1-(3-tert-butyl-1-cyclohexyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (55 mg, 10% over two steps) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.57 (s, 1H), 8.47 (s, 1H), 7.57-7.60 (m, 2H), 7.37-7.41 (m, 2H), 7.24 (m, 1H), 6.93 (m, 1H), 6.01 (s, 1H), 4.00 (s, 3H), 3.99 (s, 3H), 3.94 (m, 1H), 1.62-1.82 (m, 8H), 1.24-1.35 (m, 2H), 1.24 (s, 9H); LC-MS (ESI) m/z 545 (M+H)+.
Reaction SMILES: [Mg].II.[CH2:4]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19]Br)=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:21]1(=[O:25])[CH2:24][CH2:23][CH2:22]1.Cl>C1COCC1>[CH2:4]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:21]2([OH:25])[CH2:24][CH2:23][CH2:22]2)=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C1CCC1
Reactant: BrCCc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: OC1(CCc2ccc(OCc3ccccc3)cc2)CCC1
Temperature: 50 °C
Reaction time: 6 h
Yield: 20.6 %

Procedure:
To a mixture of magnesium (35 mg) and THF (1.5 mL) was added one grain of iodine under nitrogen flow, followed by warming in an oil bath at 50° C. A solution of 1-(benzyloxy)-4-(2-bromoethyl)benzene (400 mg) in THF (3 mL) was added dropwise to the mixture over 20 minutes, and then the reaction liquid was heated under reflux for 4 hours. The reaction liquid was ice-cooled, and a solution of cyclobutanone (100 mg) in THF (4 mL) was added dropwise over 15 minutes, followed by stirring at room temperature for another 6 hours. The reaction liquid was adjusted to an acidic pH by adding 1M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=9:1-1/1) to obtain 1-{2-[4-(benzyloxy)phenyl]ethyl}cyclobutanol (80 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6](=[O:21])[CH2:7][NH:8][C:9]([C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])=O.[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>O1CCCC1>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[O:21][C:9]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([O:16][CH3:17])=[O:15])=[N:8][CH:7]=1
Reactant: COC(=O)CCC(=O)CNC(=O)c1cccc(C(=O)OC)c1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)CCc1cnc(-c2cccc(C(=O)OC)c2)o1

Procedure:
Methyl 3-{[(5-methoxy-2,5-dioxopentyl)amino]carbonyl}benzoate (520 mg, 1.7 mmol) is dissolved in anhydrous tetrahydrofuran (4 mL), and (methoxycarbonylsulfamoyl)triethylammonium hydroxide, inner salt (810 mg, 3.4 mmol). The reaction is microwaved (100 W. 2 min) in a sealed vessel, cooled, filtered, and concentrated under reduced pressure. Purification by flash chromatography (silica gel, 40% ethyl acetate/hexanes) gives the title compound. ESI MS m/z 290.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[C:30]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)([OH:32])=[O:31]>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][C:36]1[CH:37]=[CH:38][C:33]([C:30]([OH:32])=[O:31])=[CH:34][CH:35]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Product: O=C(O)c1ccc(Oc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from [4-(3-hydroxy-phenyl)-8-trifluoromethylquinolin-3-yl]-phenyl methanone and 4-carboxyphenyl boronic acid, following the procedure of Example 519: MS (ESI) m/z 514; MS (ESI) m/z 512.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:27]=[C:28]([NH:36][C:37]([C@H:39]2[C:48]3[C:43](=[CH:44][C:45]([O:49][CH3:50])=[CH:46][CH:47]=3)[CH2:42][CH2:41][NH:40]2)=[O:38])[CH:29]=[CH:30][C:31]=1[Si:32]([CH3:35])([CH3:34])[CH3:33].CCN(C(C)C)C(C)C.[C:60]([O:64][C:65](=[O:74])[CH2:66][C@H:67]1[CH2:70][C@H:69]([C:71](O)=[O:72])[CH2:68]1)([CH3:63])([CH3:62])[CH3:61]>CN(C=O)C.O>[F:25][C:26]1[CH:27]=[C:28]([NH:36][C:37]([C@H:39]2[C:48]3[C:43](=[CH:44][C:45]([O:49][CH3:50])=[CH:46][CH:47]=3)[CH2:42][CH2:41][N:40]2[C:71]([C@H:69]2[CH2:68][C@H:67]([CH2:66][C:65]([O:64][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:74])[CH2:70]2)=[O:72])=[O:38])[CH:29]=[CH:30][C:31]=1[Si:32]([CH3:33])([CH3:35])[CH3:34]
Reactant: COc1ccc2c(c1)CCN[C@H]2C(=O)Nc1ccc([Si](C)(C)C)c(F)c1
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@H](C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)CCN(C(=O)[C@H]1C[C@H](CC(=O)OC(C)(C)C)C1)[C@H]2C(=O)Nc1ccc([Si](C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
HATU (86 mg, 0.23 mmol) was added to a solution of (R)—N-(3-fluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide (70 mg, 0.19 mmol), DIEA (0.064 mL, 0.38 mmol) and trans-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (42.3 mg, 0.20 mmol) in DMF (2.0 mL) at room temperature, and the mixture was stirred at room temperature for 5 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 20→50% ethyl acetate/hexane) to give tert-butyl 2-(trans-3-((R)-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutyl)acetate (92.3 mg, 0.162 mmol, 86%) as a white solid.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:17]=[CH:16][CH:15]=[CH:14][C:8]=2[C:9]([O:11][CH2:12]C)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(C(CC)CNC1N=CC=CC=1C(OCC)=[O:26])C>>[CH:1]1([N:6]2[C:7]3[N:17]=[CH:16][CH:15]=[CH:14][C:8]=3[C:9](=[O:10])[O:11][C:12]2=[O:26])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cccnc1NC1CCCC1
Reactant: CCOC(=O)c1cccnc1NCC(CC)CC
Product: O=c1oc(=O)n(C2CCCC2)c2ncccc12

Procedure:
The title compound was prepared according to the procedure of Example 3B substituting the product of Example 68A for the product of Example 3A (0.130 g, 56%). MS (ESI+) m/z 221.08 (M+H)+; 1H NMR (300 MHz, CDCl3) δ 1.66 (m, 1H), 1.99 (m, 4H), 2.21 (m, 2H), 5.79 (m, 1H), 7.25 (dd, J=8.09, 4.78 Hz, 1H), 8.42 (dd, J=7.72, 2.21 Hz, 1H), 8.70 (dd, J=4.78, 1.84 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:24])=[C:6]([C:8]2[CH2:12][N:11]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:9]=2)[CH:7]=1.[CH3:25][N:26](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:24][C:5]1[CH:4]=[CH:3][C:2]([N+:26]#[C-:25])=[CH:7][C:6]=1[C:8]1[CH2:12][N:11]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:9]=1
Reactant: CN(C)C(=O)N1CC(c2cc(Br)ccc2F)=CC1c1ccccc1
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: [C-]#[N+]c1ccc(F)c(C2=CC(c3ccccc3)N(C(=O)N(C)C)C2)c1

Procedure:
A deoxygenated solution of 4-(5-bromo-2-fluorophenyl)-N,N-dimethyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide (2-11, 50 mg, 0.13 mmol, 1 equiv), zinc cyanide (10 mg, 0.85 mmol, 0.66 equiv), tris(dibenzylideneacetone)-dipalladium (12 mg, 0.013 mmol, 0.10 equiv), and 1,1′-bis(diphenylphosphino)-ferrocene (17 mg, 0.031 mmol, 0.24 equiv) in DMF (3 mL) was heated at 110° C. for 3 hours. The reaction mixture was partitioned between brine (50 mL) and ethyl acetate (50 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (CH2Cl2 initially, grading to 10% EtOAc in CH2Cl2) to provide 4-(2-fluoro-5-isocyanophenyl)-N,N-dimethyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide (13-1) as a pale yellow solid. 1H NMR (500 MHz, CDCl3) δ 7.62 (dd, 1H, j=6.8, 2.0 Hz), 7.59 (m, 1H), 7.33 (m, 4H), 7.26 (m, 1H), 7.22 (dd, 1H, J=10.7, 8.8 Hz), 6.49 (br s, 1H), 6.16 (m, 1H), 4.89 (ddd, 1H, J=13.7, 5.6, 2.0 Hz), 4.55 (d, 1H, J=13.7 Hz), 2.89 (s, 6H). LRMS m/z (M+H) 336.05 found, 336.14 required.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SC)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[OH:31][C@H:32]1[CH2:36][NH:35][C@H:34]([C:37]([OH:39])=[O:38])[CH2:33]1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:35]5[CH2:36][C@H:32]([OH:31])[CH2:33][C@H:34]5[C:37]([OH:39])=[O:38])=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:28])([F:30])[F:29])[CH:3]=1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Product: O=C1N=C(N2C[C@H](O)C[C@H]2C(=O)O)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-4-(R)-hydroxy-pyrrolidine-2-(S)-carboxylic acid was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 4-(R)-hydroxy-pyrrolidine-2-(S)-carboxylic acid following General Procedure C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][C:10]3([CH2:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21](C)(=[O:23])=[O:22])=[CH:17][CH:16]=2)[CH2:12][CH2:11]3)=[CH:4][CH:3]=1.C[Li].C(B(CCCC)CCCC)CCC.C([O-])(=O)C.[Na+].[NH2:45]OS(O)(=O)=O>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][C:10]3([CH2:12][CH2:11]3)[CH2:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH2:45])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1
Reactant: NOS(=O)(=O)O
Reactant: CS(=O)(=O)c1ccc(C2=C(c3ccc(F)cc3)CC3(CC3)C2)cc1
Agent: CC(=O)[O-]
Agent: CCCCB(CCCC)CCCC
Agent: [Li]C
Solvent: O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(C2=C(c3ccc(F)cc3)CC3(CC3)C2)cc1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 28.2 %

Procedure:
Under nitrogen, a solution of 90 mg (0.248 mmol) of 5-(4-fluoro phenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene from step 11 in 1 mL of THF at -78° C. was treated with 0.21 mL (0.27 mmol) of methyllithium (1.3M in ether) over a period of 2 minutes. The reaction was stirred at ambient temperature for 25 minutes, cooled to -78° C., and treated with 0.3 mL (0.3 mmol) of tributylborane (1.0M in THF). The resulting dark brown solution was stirred at ambient temperature for 20 minutes and then at reflux for 16 hour prior to the addition of 350 mg (4.27 mmol) of sodium acetate, 2 mL of water, and 250 mg (2.21 mmol) of hydroxylamine-O-sulfonic acid. The resulting light orange mixture was stirred at ambient temperature for 3 hours and the aqueous phase extracted with ethyl acetate. The combined extracts were washed with water, brine, dried (MgSO4), and concentrated in vacuo. The residue was chromatographed on silica gel to give 24 mg (27%) of 4-[6-(4-fluorophenyl)spiro[2.4]hept-5-en-5-yl]benzenesulfonamide as a colorless solid: mp 131.0°-133.0° C.; NMR (CDCl3) δ 0.68 (s, 4H), 2.90 (s, 3H), 4.81 (s, 2H), 6.92 (t, J=9 Hz, 2H), 7.11 (dd, J=6 and 9 Hz, 2H), 7.27 (d, J=9 Hz, 2H), 7.74 (d, J=9 Hz, 2H). HRMS. Calc'd for C19H18FNO2S: 344.1121. Found: 344.1122. Anal. Calc'd for [C19H18FNO2S+0.1 CH3CO2 CH2CH3 ]: C, 66.16; H, 3.98; S, 9.11. Found: C, 65.86; H, 5.52; N, 3.92; S, 9.57.
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][O:3]1.[CH:17]1([C:20]2[CH:21]=[C:22]([CH3:32])[C:23]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[N:24][CH:25]=2)[CH2:19][CH2:18]1>>[CH:17]1([C:20]2[CH:21]=[C:22]([CH3:32])[C:23]([N:26]3[CH2:27][CH2:28][N:29]([C:12]([C:11]4[CH:10]=[CH:9][C:8]([N:7]5[CH2:6][CH2:5][CH2:4][O:3][C:2]5=[O:1])=[CH:16][CH:15]=4)=[O:14])[CH2:30][CH2:31]3)=[N:24][CH:25]=2)[CH2:19][CH2:18]1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: O=C(O)c1ccc(N2CCCOC2=O)cc1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCOC3=O)cc2)CC1
Yield: 74.4 %

Procedure:
Using 4-(2-oxo[1,3]oxazinan-3-yl)benzoic acid (111 mg) and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (109 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Example 87, the title compound (157 mg) was obtained.
Reaction SMILES: [NH3:1].[C:2]([C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:14]=1[OH:15])[C:9](O)=[O:10])([CH3:5])([CH3:4])[CH3:3]>>[C:2]([C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:14]=1[OH:15])[C:9]([NH2:1])=[O:10])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: N
Product: CC(C)(C)c1cc(C(N)=O)cc(C(C)(C)C)c1O

Procedure:
In the manner of Example 7, ammonia was reacted with 3,5-di-t-butyl-4-hydroxybenzoic acid to produce 3,5-di-t-butyl-4-hydroxybenzamide; melting point 263°-265°C. When tested by the procedure of Example 2, this compound lasted 1000 hours, about 2.5 times as long as the control.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[Cl:8][CH2:9][C:10](=O)[CH2:11][C:12](OCC)=[O:13]>>[Cl:8][CH2:9][C:10]1[N:7]=[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]2[C:12](=[O:13])[CH:11]=1
Reactant: Nc1ccccn1
Reactant: CCOC(=O)CC(=O)CCl
Product: O=c1cc(CCl)nc2ccccn12
Temperature: 0 °C

Procedure:
37.7 g 2-pyridinamine was dissolved in about 250 g polyphosphoric acid, at 40°-50°, using a mechanically driven stirrer. To this mixture was added, dropwise, 54 ml ethyl 4-chloroacetoacetate. After the addition, the mixture was heated to about 125° for 1/2 hour. After cooling to about 50°, the mixture was poured into 1500 ml of ice water, and the mixture was extracted with an equal volume of chloroform. After drying and evaporation of chloroform, about 45 g 2-(chloromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (m.p. 171°-174°) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH:9]=O)[CH:4]=1.Cl.N1C=CC=CC=1.[K+].[C:19]([O:25][CH3:26])(=[O:24])[CH2:20]C([O-])=O.N1CCCCC1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH:9]=[CH:20][C:19]([O:25][CH3:26])=[O:24])[CH:4]=1
Reactant: COc1ccnc(C=O)c1
Reactant: COC(=O)CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COC(=O)C=Cc1cc(OC)ccn1
Temperature: 120 °C

Procedure:
A mixture of 45 g of 4-methoxypyridine-2-carbaldehyde (Ashimori et al., Chem. Pharm. Bull. 38, 2446–2458 (1990)), 75.80 g of pyridine hydrochloride, 102.45 g of monomethyl malonate potassium salt and 4.1 ml of piperidine in 700 ml of pyridine are slowly heated, with stirring, to 120° C. When the evolution of gas starts, the heating source is temporarily removed to stop the reaction from becoming too violent. Once the reaction has subsided, the mixture is stirred at 120° C. for a further 2.5 h, and the pyridine is then distilled off under reduced pressure. The residue is partitioned between ethyl acetate/water and the organic phase is washed with water and dried. The residue obtained after concentration is chromatographed on a silica gel column using ethyl acetate/petroleum ether 2:1. This initially gives 43.2 g of the title compound as a yellow oil which crystallizes on standing and then shows a m.p. of 80–82° C. The mass spectrum shows the molecular peak MH+ at 194 Da.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][C:7]([C:9]1[C:10](=[O:21])[O:11][C:12]2[C:17]([C:18]=1[OH:19])=[CH:16][CH:15]=[C:14](Br)[CH:13]=2)=[O:8])[CH3:2].[CH3:23][Sn](C)(C)C>CN(C)C=O.C(OCC)(=O)C.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>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][C:7]([C:9]1[C:10](=[O:21])[O:11][C:12]2[C:17]([C:18]=1[OH:19])=[CH:16][CH:15]=[C:14]([CH3:23])[CH:13]=2)=[O:8])[CH3:2]
Reactant: CCOC(=O)CNC(=O)c1c(O)c2ccc(Br)cc2oc1=O
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CNC(=O)c1c(O)c2ccc(C)cc2oc1=O
Temperature: 120 °C
Yield: 61.7 %

Procedure:
A mixture of [(7-bromo-4-hydroxy-2-oxo-2H-chromene-3-carbonyl)-amino]-acetic acid ethyl ester (212 mg, 0.563 mmol), tetramethyltin (0.158 mL, 1.14 mmol) and Pd(PPh3)2Cl2 (20 mg, 0.029 mmol) in N,N-dimethylformamide (2 mL) was heated in a 120° C.-oil bath under nitrogen for 1 h; then cooled, diluted with ethyl acetate, washed with water, saturated NaCl solution, and ethyl acetate phase was dried over Na2SO4, filtered, concentrated and column purified to give desired product (106 mg). ESI (m/z): 306 (M+H)+.