Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH:9]2[NH:12][O:13][CH3:14])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:22][CH:23]([F:33])[C:24]1[C:28]([C:29](Cl)=[O:30])=[CH:27][N:26]([CH3:32])[N:25]=1>ClCCl.O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH:9]2[N:12]([O:13][CH3:14])[C:29]([C:28]2[C:24]([CH:23]([F:33])[F:22])=[N:25][N:26]([CH3:32])[CH:27]=2)=[O:30])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: CONC1CCCc2ccc(Cl)cc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C(=O)c1cn(C)nc1C(F)F)C1CCCc2ccc(Cl)cc21
Temperature: 22 °C
Reaction time: 14 h
Yield: 91.8 %

Procedure:
To a stirred solution of N-(7-chloro-1,2,3,4-tetrahydro-naphthalen-1-yl)-O-methyl-hydroxylamine (0.60 g; 2.80 mmol), prepared as described in example P1b and triethylamine (0.80 ml; 5.70 mmol) in dichloromethane (10 ml) under nitrogen at 15° C. was added dropwise 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (0.545 g; 2.80 mmol) in dichloromethane (5 ml). The reaction mixture was stirred at 22° C. for 14 h under nitrogen. The mixture was poured in water and extracted three times with dichloromethane. Combined organics were dried over sodium sulfate and the solvent was removed in vacuo. The crude was subject to flash chromatography (eluant: c-hexane/ethyl acetate 60:40) to afford 0.95 g (91% of theory) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid (7-chloro-1,2,3,4-tetrahydro-naphthalen-1-yl)-methoxy-amide as a yellow oil, that crystallized.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]#[C:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)[CH3:2].[C:18]([O:22][C:23]([N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([CH2:35][CH2:36][O:37][C:38]3[CH:39]=[C:40]4[C:44](=[CH:45][CH:46]=3)[NH:43][CH:42]=[CH:41]4)[N:33]=2)[CH2:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([CH2:35][CH2:36][O:37][C:38]3[CH:39]=[C:40]4[C:44](=[CH:45][CH:46]=3)[N:43]([C:6]([C:7]3[CH:16]=[CH:15][C:14]5[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=5)[CH:8]=3)=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[O:17])[CH:42]=[CH:41]4)[N:33]=2)[CH2:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4[nH]ccc4c3)nc21
Reactant: CCOC(=O)C#Cc1ccc2ccccc2c1
Product: CCOC(=O)C=C(c1ccc2ccccc2c1)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21
Yield: 88 %

Procedure:
The title compound was synthesized from naphthalene-2-yl-propynoic acid ethyl ester and 7-[2-(1H-indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester using the procedure described in Example 16, step (d1), in 88% yield as an E/Z isomeric mixture. 1H NMR (CDCl3) δ 7.85 (m, 4H), 7.50 (m, 2.6H), 7.33 (m, 1.6H), 7.12 (m, 1.8H), 6.95 (m, 1.4H), 6.74 (m, 1.6H), 6.61 (d, 0.6H, J=0.4 Hz), 6.50 (d, 0.4H, J=0.4 Hz), 6.35 (s, 0.6H), 6.23 (s, 0.4 Hz), 4.36 (t, 2H, J=8.0 Hz), 4.05 (m, 2H), 3.76 (m, 2H), 3.20 (t, 2H, J=8.0), 2.73 (t, 2H, J=8.0 Hz), (m, 2H), 1.51 (s, 9H), 1.07 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]([CH3:20])([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[CH3:23][C:24]1[O:28][C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:26][C:25]=1[CH2:35][CH2:36]O>>[CH3:20][C:7]([O:6][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:36][CH2:35][C:25]2[N:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:28][C:24]=2[CH3:23])=[CH:22][CH:21]=1)([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(C)(Cc1ccccc1)Oc1ccc(O)cc1
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Product: CCOC(=O)C(C)(Cc1ccccc1)Oc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1

Procedure:
Mitsunobu coupling of 2-(4-hydroxyphenoxy)-2-methyl-3-phenylpropionic acid, ethyl ester and 2-(5-methyl-2-phenyloxazol-4-yl)ethanol [Hulin, et al., J. Med. Chem. (1992) 35(10), 1853-64] in the manner described in Example 2, Step A. 1H NMR (300 MHz, CDCl3) δ 7.89-7.93 (m, 2H), 7.33-7.41 (m, 3H), 7.19-7.23 (m, 5H), 6.74 (d, 2H), 6.70 (d, 2H), 4.17 (q, 2H), 4.13 (t, 2H), 3.24 (d, 1H), 3.09 (d, 1H), 2.91 (t, 2H), 2.32 (s, 3H), 1.25 (s, 3H), 1.21 (t, 3H); MS(EI): 486 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[C:11]([CH3:23])=[C:10]([C:24](=[O:27])[CH2:25][CH3:26])[CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:35](OC(=O)C)(=[O:37])[CH3:36]>C1COCC1.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[C:35]([NH:22][S:19]([C:16]1[CH:15]=[CH:14][C:13]([N:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:9][C:10]([C:24](=[O:27])[CH2:25][CH3:26])=[C:11]2[CH3:23])=[CH:18][CH:17]=1)(=[O:20])=[O:21])(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(S(N)(=O)=O)cc2)c1C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(S(=O)(=O)NC(C)=O)cc2)c1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-[5-(4-chloro-phenyl)-2-methyl-3-propionyl-pyrrol-1-yl]-benzenesulfonamide (Example 31, 0.12 g, 0.31 mmol) in dry THF (5 mL) was added triethylamine (0.4 mmol, 0.06 mL) and DMAP (0.031 mmol, 4 mg) at room temperature. 10 Minutes later acetic anhydride (0.62 mmol, 0.06 mL) was added drop wise and the mixture stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate (100 mL), washed with sodium bicarbonate (saturated solution, 50 mL), water (50 mL) and brine (50 mL). The organic phase was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified over silica using CH2Cl2:MeOH (95:5) as eluant to provide the titled compound. 1H NMR (CDCl3) δ ppm 1.18 (3H), 2.05 (3H), 2.16 (3H), 2.45 (2H), 3.39 (2H), 6.90 (1H), 7.33-7.90 (8H), 8.50 (1H); MS (ESI) m/z 445 (M+H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:8](=[O:20])[CH:7]=1)=O)C.O.[NH2:22][NH2:23]>C(O)C>[O:20]=[C:8]1[CH:7]=[C:6]([C:4]([NH:22][NH2:23])=[O:3])[CH:11]=[CH:10][N:9]1[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: CCOC(=O)c1ccn(COCC[Si](C)(C)C)c(=O)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: C[Si](C)(C)CCOCn1ccc(C(=O)NN)cc1=O
Temperature: 78 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
The title compound of example 19.1 (9.5 g, 32 mmol) was stirred in ethanol (100 mL) at 78° C. Hydrazine hydrate (7.8 mL, 159.7 mmol) was added and the reaction mixture was stirred at 78° C. for 3 hours. The reaction mixture was cooled to room temperature and concentrated to dryness. The residue was stirred in diethyl ether and filtered to give a yellow solid (8.5 g, 94%).
Reaction SMILES: [F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:20]=[CH:19][C:18]=2[F:30])=[C:13]([F:31])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=[O:7].O[Li].O.O>C1COCC1.O>[F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:20]=[CH:19][C:18]=2[F:30])=[C:13]([F:31])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Temperature: 60 °C
Yield: 98.7 %

Procedure:
Ethyl 2-[2,4-difluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]phenoxy]acetate (100 mg, 0.2 mmol, 1.0 eq) was dissolved in a mixture of THF (15 mL) and H2O (10 mL). LiOH.2H2O (55 mg, 0.8 mmol, 4.0 eq) was added and the solution heated at 60° C. overnight. The THF was removed under reduced pressure and the aqueous phase extracted with EtOAc. The organic extract was discarded and the aqueous layer acidified with 1M HCl and extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to give the title compound (I(b)) as a white solid (80 mg, 99%).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[F:6][C:7]([F:19])([F:18])[C:8]1[C:16]2[C:11](=[N+:12]([O-])[CH:13]=[CH:14][CH:15]=2)[NH:10][N:9]=1.[OH-].[Na+]>>[Cl:3][C:15]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:10][N:9]=[C:8]([C:7]([F:19])([F:18])[F:6])[C:16]=12
Reactant: [O-][n+]1cccc2c(C(F)(F)F)n[nH]c21
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: FC(F)(F)c1n[nH]c2nccc(Cl)c12
Temperature: 100 °C
Reaction time: 1 h
Yield: 27 %

Procedure:
Phosphorus oxychloride (76.4 g) was gradually added to compound (1b) (33.2 g), followed by stirring at 100° C. for 1 hr. The reaction solution was poured into ice water, and sodium hydroxide was added thereto to adjust the pH to 10. The precipitate was collected by filtration to obtain compound (1c) (9.76 g, 27%) as a light pink solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[S:12][C:3]=12.C(OCCO)C.[Br:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27].Cl.N1C=CC=CC=1>>[Br:23][C:24]1[CH:25]=[C:26]([NH:27][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]3[C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[S:12][C:3]=23)[CH:28]=[CH:29][CH:30]=1
Reactant: N#Cc1cnc2c(sc3ccccc32)c1Cl
Reactant: Nc1cccc(Br)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: N#Cc1cnc2c(sc3ccccc32)c1Nc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 58 %

Procedure:
A solution of 150 mg (0.61 mmol) of 4-chlorobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile in 3 mL of 2-ethoxyethanol containing 80 mg (0.74 mmol) of 3-bromoaniline and 71 mg of pyridine hydrochloride is heated at reflux temperature for 4 hours, then allowed to stir at room temperature for 3 days. The reaction mixture is partitioned between ethyl acetate and saturated sodium bicarbonate and the organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. Diethyl ether is added to the residue and the resultant solid is collected by filtration to give 139 mg (58%) of a white solid, mp 240–242° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:9][C:10]2[CH:22]=[CH:21][C:13]([O:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:12]([CH3:23])[CH:11]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1.[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)#[CH:25].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C1CCCCC1.C(NC(C)C)(C)C>O1CCCC1.[Cu]I>[Br:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[CH:22]=[CH:21][C:13]([O:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:12]([CH3:23])[CH:11]=2)[CH:3]=[C:2]([C:25]#[C:24][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH:7]=1
Reactant: CCOC(=O)COc1ccc(Sc2cc(Br)cc(Br)c2)cc1C
Reactant: C#Cc1ccccn1
Agent: [Cu]I
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCOC(=O)COc1ccc(Sc2cc(Br)cc(C#Cc3ccccn3)c2)cc1C
Temperature: 40 °C
Reaction time: 8 h

Procedure:
In nitrogen atmosphere, ethyl [4-(3,5-dibromophenylsulfanyl)-2-methylphenoxy]-acetate (460 mg, 1 mmol; prepared as described in example 1) and 2-ethynylpyridine (110 μL, 1.1 mmol) were dissolved in anhydrous tetrahydrofuran (7 mL). 0.15 M Solution of tri-tert-butylphosphine in cyclohexane (0.6 mL, 0.06 mmol) was added via syringe. Copper(I) iodide (3.8 mg, 0.02 mmol), dichloro(bisbenzonitrile)palladium (11 mg, 0.03 mmol) and diisopropylamine (155 μL, 1.1 mmol) were added. Traces of the air were removed and mixture was stirred under nitrogen at 40° C. overnight. The mixture was diluted with ethyl acetate (10 mL) and filtered through a short path of silica gel. The filtrate was concentrated and purified by column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 90:10-85:15) yielding ethyl [4-[3-bromo-5-[(pyridin-2-yl)ethynyl]phenylsulfanyl]-2-methylphenoxy]acetate beside of 144 mg (30%) of unchanged starting dibromo derivative.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:25][CH2:24][CH:23]([N:26](C)[C:27](=O)OC(C)(C)C)[CH2:22]3)=[N:19][CH:20]=1)=[N:11][C:10]([C:35]1[CH:40]=[C:39]([Cl:41])[C:38]([OH:42])=[C:37]([Cl:43])[CH:36]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>>[ClH:41].[ClH:41].[ClH:41].[Cl:41][C:39]1[CH:40]=[C:35]([C:10]2[N:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]=[CH:5][C:4]([C:1](=[O:3])[CH3:2])=[C:13]3[NH:14][C:15]2[CH:20]=[N:19][C:18]([N:21]3[CH2:25][CH2:24][CH:23]([NH:26][CH3:27])[CH2:22]3)=[CH:17][CH:16]=2)[CH:36]=[C:37]([Cl:43])[C:38]=1[OH:42]
Reactant: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCC(N(C)C(=O)OC(C)(C)C)C2)nc1
Solvent: O=C(O)C(F)(F)F
Product: CNC1CCN(c2ccc(Nc3c(C(C)=O)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)nc34)cn2)C1
Product: Cl
Yield: 196.9 %

Procedure:
Following general procedure D-1, tert-butyl 1-{5-[3-acetyl-6-(3,5-dichloro-4-hydroxy-phenyl)-1,5-naphthyridin-4-ylamino]pyridin-2-yl}pyrrolidin-3-yl(methyl)carbamate (0.183 mmol) was reacted with TFA (2 mL) followed by formation of the trihydrochloride salt to afford the desired product (57 mg, 49% over two steps) as an orange-yellow solid: 1H NMR (500 MHz, CD3OD) δ 9.37 (s, 1H), 8.49 (d, J=8.9 Hz, 1H), 8.40 (d, J=8.9 Hz, 1H), 8.24 (d, J=2.5 Hz, 1H), 7.88 (dd, J=9.4, 2.5 Hz, 1H), 7.57 (s, 2H), 6.96 (d, J=9.4 Hz, 1H), 4.13-4.00 (m, 2H), 3.92-3.79 (m, 2H), 3.66-3.73 (m, 1H), 2.83 (s, 6H), 2.72-2.60 (m, 1H), 2.45-2.34 (m, 1H); ESI MS m/z 523 [M+H]+; HPLC>99% (AUC), tR=8.97 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12][CH3:13])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12][CH3:13])=[S:29]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)c1cccc(OCc2cccc(Cl)c2)c1
Solvent: Cc1ccccc1C
Product: COC(=S)c1cccc(OCc2cccc(Cl)c2)c1
Yield: 145.9 %

Procedure:
In an analogous manner to that described in Example 1(B). 36.5 g (131.9 mmol) of methyl 3-[(3-chlorobenzyl)oxy]benzoate were heated at reflux for 16 hours with 26.7 g (66 mmol) of Lawesson reagent in xylene and thereafter chromatographed on silica gel. Elution with hexane/toluene (2%, 5% and 10%) yielded 28.2 g (73%) of O-methyl 3-[(3-chlorobenzyl)oxy]thiobenzoate as an orange, crystallizing oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:8])[O:4][C:5](=[O:7])[CH:6]=1.[C:9]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=O)#[N:10].[O:19]1[CH2:24][C:23](=O)[CH2:22][C:21](=[O:26])[CH2:20]1>C(O)C>[CH3:8][N:3]1[C:2]2[NH:1][C:23]3[CH2:24][O:19][CH2:20][C:21](=[O:26])[C:22]=3[CH:14]([C:13]3[CH:12]=[C:11]([CH:18]=[CH:17][CH:16]=3)[C:9]#[N:10])[C:6]=2[C:5](=[O:7])[O:4]1
Reactant: Cn1oc(=O)cc1N
Reactant: N#Cc1cccc(C=O)c1
Reactant: O=C1COCC(=O)C1
Solvent: CCO
Product: Cn1oc(=O)c2c1NC1=C(C(=O)COC1)C2c1cccc(C#N)c1
Temperature: 25 °C

Procedure:
The product from Example 45A (0.085 g, 0.75 mmol), 3-cyanobenzaldehyde (0.14 g, 0.75 mmol) and 2H-pyran-3,5(4H,6H)-dione (0.085 g, 0.75 mmol) were heated in 2 mL of ethanol for 2 days. The resulting mixture was allowed to cool to ambient temperature and filtered to provide the title compound as the filter cake (0.09 g). 1H NMR (300 MHz, DMSO-d6) δ 3.28 (s, 3H), 4.05 (s, 2H), 4.59 (q, 2H), 4.81 (s, 1H), 7.5 (t, 1H), 7.6 (m, 1H), 7.62 (m, 1H), 7.64 (d,1H), 10.8 (s, 1H); MS (ESI) m/z 322 (M−H)−; Anal. Calcd for C17H13N3O4.0.25H2O: C, 62.48; H, 3.86; N, 12.86. Found: C, 62.55; H, 4.07; N, 12.61.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][C@H:5]([C@H:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:8]([OH:10])=O)[C:4](=[O:15])[O:3]1.C(OC(C)C)(=O)[C@@H](CC(OC(C)C)=O)O.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.FC(N(C)C)=[N+](C)C.[CH3:56][O:57][C:58]1[CH:63]=[CH:62][C:61]([N:64]2[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]2)=[CH:60][CH:59]=1>C(Cl)Cl>[CH3:56][O:57][C:58]1[CH:59]=[CH:60][C:61]([N:64]2[CH2:69][CH2:68][N:67]([C:8]([C@H:7]([C@H:5]3[O:6][C:2]([CH3:1])([CH3:16])[O:3][C:4]3=[O:15])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH2:66][CH2:65]2)=[CH:62][CH:63]=1
Reactant: CC(C)C[C@H](C(=O)O)[C@H]1OC(C)(C)OC1=O
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: CC(C)OC(=O)C[C@@H](O)C(=O)OC(C)C
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(N2CCN(C(=O)[C@@H](CC(C)C)[C@H]3OC(C)(C)OC3=O)CC2)cc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a cold solution (0° C.) of (2S)-2-[(4R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanoic acid (prepared according to WO 94/02447 or similarly to Seebach et al., 1990, Org. Syntheses, Coll. Vol. III, p 153-159 but starting from diisopropyl (R)-(+)-malate, 150 mg, 0.65 mmol) in anhydrous DCM (3 mL) were added DIEA (115 μL, 0.69 mmol) and fluoro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (190 mg, 0.72 mmol, Aldrich). The reaction mixture was stirred at 0° C. for 40 min. Then a solution of 1-(4-methoxyphenyl)-piperazine (138 mg, 0.72 mmol, Chess) and DIEA (115 μL, 0.69 mmol) in anhydrous DCM (1 mL) was added. The reaction mixture was stirred for 1 hour is at RT and then poured on a silica column (30 g, wet with c-Hex/EtOAc 4:1). Purification was performed with a gradient cHex/EtOAc 4:1 to c-Hex/EtOAc 1:1 in 30 min to give 158 mg of a white powder. Recrystallization from iPrOH gave 112 mg (43%) of the title compound as a white powder. HPLC, Rt: 3.02 min (purity: 99.0%). LC/MS, M+(ESI): 405.3. 1H NMR (CD3OD, 300 MHz) δ 7.00 (d, J=9.2 Hz, 2H), 6.89 (d, J=9.2 Hz, 2H), 4.56 (d, J=8.7 Hz, 1H), 3.87 (m, 3H), 3.78 (s, 3H), 3.73 (m, 1H), 3.50 (m, 1H), 3.15-3.00 (m, 4H), 1.93-1.72 (m, 2H), 1.66 (s, 3H), 1.58 (m, 1H), 1.56 (s, 3H), 0.98 (d, J=6.4 Hz, 6H).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[N+]([O-])(O)=O.[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([CH:28]([O:31][N+:32]([O-:34])=[O:33])[CH2:29][NH2:30])=[CH:24][CH:23]=1)([O-:21])=[O:20].C[O-].[Na+]>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:30][CH2:29][CH:28]([C:25]1[CH:26]=[CH:27][C:22]([N+:19]([O-:21])=[O:20])=[CH:23][CH:24]=1)[O:31][N+:32]([O-:34])=[O:33])#[N:2]
Reactant: NCC(O[N+](=O)[O-])c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)OC(=NC#N)c1cccnc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=[N+]([O-])O
Product: N#CNC(=NCC(O[N+](=O)[O-])c1ccc([N+](=O)[O-])cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 30 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.22 g, 1.2 mmol) was dissolved in methanol (10 ml), and 2-(4-nitrophenyl)-2-nitroxyethylamine nitrate (0.40 g, 1.4 mmol) and sodium methoxide (0.14 g, 2.6 mmol) were added. The mixture was stirred at room temperature for 17 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate was extracted with chlofororm (100 ml×3). The chloroform layer was washed with water (150 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residual concentrate was subjected to chromatography on a silica gel column (WAKO GEL C-200, 30 g) eluting with chloroform-methanol (50:1). The eluted fractions were concentrated under reduced pressure and crystallized from methanol-diethyl ether to give the title compound (0.13 g, 0.36 mmol, yield: 31%) as colorless crystals.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:13][C:14]1[C:22]([Cl:23])=[CH:21][CH:20]=[C:19]2[C:15]=1[C:16](=[O:27])[CH2:17][CH:18]2[C:24](Cl)=[O:25]>C(N(CC)CC)C>[ClH:13].[Cl:13][C:14]1[C:22]([Cl:23])=[CH:21][CH:20]=[C:19]2[C:15]=1[C:16](=[O:27])[CH2:17][CH:18]2[C:24]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]1[CH2:6][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:25]
Reactant: C1CCC(CN2CCCC2)NC1
Reactant: O=C1CC(C(=O)Cl)c2ccc(Cl)c(Cl)c21
Solvent: CCN(CC)CC
Product: Cl
Product: O=C1CC(C(=O)N2CCCCC2CN2CCCC2)c2ccc(Cl)c(Cl)c21
Yield: 57.1 %

Procedure:
From 1.18 g of 2-(pyrrolidin-1-ylmethyl)piperidine, 2.03 g of 4,5-dichloro-3-oxoindan-1-carbonyl chloride and 1.47 ml of triethylamine. 0.95 g of the title compound was obtained, melting at 148°-150° C. (dec) using a procedure similar to that in Example 2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][C:15]=2[CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:31](=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.CB1OB(C)OB(C)O1>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.C(OCC)(=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:31])=[CH:16][C:15]=2[CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)CC(c2cc(Br)ccc2N2CCN(C(=O)OC(C)(C)C)CC2)CC(C)(C)C1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C2CC(C)(C)CC(C)(C)C2)c1
Temperature: 25 °C
Reaction time: 9 h
Yield: 71.7 %

Procedure:
A mixture of 4-[4-bromo-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine-1-carboxylic acid t-butyl ester (200 mg, 0.417 mmol) produced in Example (99a), cesium carbonate (408 mg, 1.25 mmol), tetrakis(triphenylphosphine)palladium(0) (50 mg, 0.0417 mmol) and dimethylformamide (4 mL) was stirred at room temperature under a nitrogen atmosphere. Trimethylboroxine (0.06 mL, 0.417 mmol) was added to the mixture, and stirring was continued for 9 hours at an external temperature of 100° C. Ethyl acetate and water were added to the reaction mixture and extraction was performed with ethyl acetate. The separated organic layer was washed with water and brine in that order and then dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 124 mg of the title compound as colorless crystals.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[S:18]([N:28]1[CH2:32][CH2:31][CH:30](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:29]1)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>C1(C)C=CC=CC=1>[C:8]([C:7]([CH:31]1[CH2:30][CH2:29][N:28]([S:18]([C:21]2[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:32]1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)#[N:9]
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(S(=O)(=O)c3ccc(C)cc3)C2)cc1
Reactant: N#CC(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)N2CCC(C(C#N)(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 25 °C

Procedure:
Diphenylacetonitrile (17.1 g) was added to a stirred suspension of sodium hydride (4 g of a 60% suspension in mineral oil) in anhydrous toluene (250 ml) and the mixture was heated under reflux for 2 hours. On cooling to room temperature, 1-tosyl-3-(R,S)-tosyloxypyrrolidine (28 g - see Preparation 5) was added in portions and the mixture heated under reflux for 3 hours. The mixture was diluted with toluene (150 ml), washed with 5% aqueous sodium hydroxide (2×100 ml) and brine (150 ml) then dried (MgSO4) and concentrated in vacuo to give a solid which was purified by trituration with methanol to give the title compound as a colourless microcrystalline powder, yield 18 g, m.p. 186°-187° C.