Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20]OS(C)(=O)=O)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].[OH:33][CH2:34][C:35]1[O:39][C:38]([CH2:40][N:41]2[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[N:43]=[C:42]2[N:50]2[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)=[CH:37][CH:36]=1>CO>[CH3:32][O:31][C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:53]2[CH2:54][CH2:55][CH2:56][N:50]([C:42]3[N:41]([CH2:40][C:38]4[O:39][C:35]([CH2:34][OH:33])=[CH:36][CH:37]=4)[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=3)[CH2:51][CH2:52]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc(OC)c1OC
Reactant: OCc1ccc(Cn2c(N3CCCNCC3)nc3ccccc32)o1
Solvent: CO
Product: COc1cc(C(=O)N2CCC(CCN3CCCN(c4nc5ccccc5n4Cc4ccc(CO)o4)CC3)(c3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 1.6 using 1-(3,4,5-trimethoxybenzoyl)-3-(2-methanesulfonyloxyethyl)-3-phenylpyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) and 4-(1-(5-hydroxymethylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepane to give, after chromatography on silica gel eluting with methanol, the title compound: Rf=0.41 (silica gel, methanol).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:20]([NH:23][C:24](=[O:37])[C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[CH:27][CH:26]=2)(=[O:22])=[O:21])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH2:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-:3])=[O:2].Cl[C:39]([O:41][CH2:42][CH2:43][O:44][CH3:45])=[O:40]>N1C=CC=CC=1.C(N(CC)CC)C>[N+:1]([C:4]1[CH:5]=[C:6]([S:20]([NH:23][C:24]([C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][N:34]([C:39]([O:41][CH2:42][CH2:43][O:44][CH3:45])=[O:40])[CH2:33][CH2:32]3)=[CH:27][CH:26]=2)=[O:37])(=[O:21])=[O:22])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH2:12][S:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([O-:3])=[O:2]
Reactant: O=C(NS(=O)(=O)c1ccc(NCCSc2ccccc2)c([N+](=O)[O-])c1)c1ccc(N2CCNCC2)cc1
Reactant: COCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COCCOC(=O)N1CCN(c2ccc(C(=O)NS(=O)(=O)c3ccc(NCCSc4ccccc4)c([N+](=O)[O-])c3)cc2)CC1
Reaction time: 18 h

Procedure:
A solution of Example 173A (54.1 mg, 0.1 mmol) in pyridine (2 mL) and triethylamine (1 mL) at room temperature was treated with 2-methoxyethyl chloroformate (0.2 mmol), stirred for 18 hours, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 0-5% methanol/dichloromethane) to provide the desired product. MS (ESI(−)) m/e 642 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ8.66 (t, 1H), 8.55 (d, 1H), 7.89 (dd, 1H), 7.75 (d, 2H), 7.30-7.40 (m, 2H), 7.31-7.25 (m, 2H), 7.21-7.07 (m, 2H), 6.90 (d, 2H), 4.16-4.12 (m, 2H), 3.63 (q, 2H), 3.54-3.43 (m, 4H), 3.31-3.20 (m, 8H), 3.23 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]#[CH:14])[CH:12]=[C:6]2[C:5]=1[NH:15][C@H:16]1[C@@H:20]([CH2:21][CH3:22])[CH2:19][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:17]1)(=[O:3])[NH2:2].C(N(CC)CC)C.[OH:37]/[N:38]=[C:39](\Cl)/[CH3:40]>ClCCl>[C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[O:37][N:38]=[C:39]([CH3:40])[CH:14]=3)[CH:12]=[C:6]2[C:5]=1[NH:15][C@H:16]1[C@@H:20]([CH2:21][CH3:22])[CH2:19][N:18]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:17]1)(=[O:3])[NH2:2]
Reactant: C#Cc1cc2c(N[C@@H]3CN(C(=O)OC(C)(C)C)C[C@@H]3CC)c(C(N)=O)cnn2c1
Reactant: C/C(Cl)=N/O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H]1CN(C(=O)OC(C)(C)C)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cc(C)no3)cc12
Temperature: 40 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
To a solution of (3S,4S)-tert-butyl 3-((3-carbamoyl-6-ethynylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate from Step 2 (88 mg, 0.221 mmol) in dichloromethane (2 mL) and triethylamine (0.046 mL, 0.332 mmol) was added (Z)—N-hydroxyacetimidoyl chloride (25.9 mg, 0.277 mmol). The solution was stirred at 40° C. overnight. After stirring overnight, the reaction was cooled to room temperature and diluted with dichloromethane. This solution was washed once with aqueous potassium carbonate, and once with water. It was then dried over sodium sulfate, filtered and concentrated. The crude material was purified by flash chromatography, eluting with 0-100% ethyl acetate in hexanes. Concentration of the pure fractions afforded the title compound (64 mg, 60.4% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.20 (t, J=9.1 Hz, 1H), 8.31 (s, 1H), 8.24 (d, J=1.3 Hz, 1H), 7.30 (br. s., 1H), 6.72 (s, 1H), 5.01-4.74 (m, 1H), 3.81-3.58 (m, 2H), 3.48-3.34 (m, 1H), 3.10-2.96 (m, 1H), 2.42 (d, J=12.8 Hz, 1H), 2.28 (s, 3H), 1.60-1.46 (m, 2H), 1.37 (d, J=19.1 Hz, 9H), 0.96-0.75 (m, 3H). MS (ES+) m/z: 455.2 (M+H); LC retention time: 3.038 min (analytical HPLC Method O).
Reaction SMILES: O.[C:2]([C:4]1[C:5](=[O:17])[O:6][C:7]2[C:12]([C:13]=1O)=[CH:11][CH:10]=[C:9]([CH3:15])[C:8]=2[CH3:16])#[N:3].CC1C(C)=CC=CC=1[OH:26].CC1C(C)=CC=C(C(O)=O)C=1O.C(OC1C(C)=C(C)C=CC=1C(O)=O)(=O)C.C(OC1C(C)=C(C)C=CC=1C(Cl)=O)(=O)C>CCO>[OH2:6].[C:2]([C:4]1([OH:26])[CH2:13][C:12]2[C:7](=[C:8]([CH3:16])[C:9]([CH3:15])=[CH:10][CH:11]=2)[O:6][C:5]1=[O:17])#[N:3]
Reactant: Cc1ccc2c(O)c(C#N)c(=O)oc2c1C
Reactant: Cc1cccc(O)c1C
Agent: CC(=O)Oc1c(C(=O)Cl)ccc(C)c1C
Agent: CC(=O)Oc1c(C(=O)O)ccc(C)c1C
Agent: Cc1ccc(C(=O)O)c(O)c1C
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(c1C)OC(=O)C(O)(C#N)C2

Procedure:
3-Cyano-7,8-dimethyl-4-hydroxycoumarin monohydrate, m.p. (EtOH -- pet. ether) 255°-6°, (Found; C, 62.04; H, 4.80; N, 6.04. C12H9NO3.H2O requires C, 61.79; H, 4.76; N, 6.01) was prepared from 2,3-dimethylphenol via 3,4-dimethylsalicylic acid (m.p. 192°-3°), 2-acetoxy-3,4-dimethylbenzoic acid (m.p. 42°-4°) and 2- acetoxy-3,4-dimethylbenzoyl chloride by an analogous procedure to that described in Example 10.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([CH:9]([CH2:11][CH3:12])[CH3:10])=[N:5][N:4]=[C:3]1[S:13][CH3:14].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[CH:15](=[N:1][N:2]1[C:7](=[O:8])[C:6]([CH:9]([CH2:11][CH3:12])[CH3:10])=[N:5][N:4]=[C:3]1[S:13][CH3:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccccc1
Reactant: CCC(C)c1nnc(SC)n(N)c1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: CCC(C)c1nnc(SC)n(N=Cc2ccccc2)c1=O
Temperature: 0 °C

Procedure:
21.4 g of 4-amino-6-sec.-butyl-3-methylthio-1,2,4-triazin-5(4H)-one and 11.0 ml of benzaldehyde, dissolved in 50 ml of isopropanol, were briefly heated to the reflux temperature after adding 0.1 g of p-toluenesulfonic acid. On cooling to 0° C, 23.2 g of crude product crystallized out and were purified further by dissolving in 200 ml of boiling toluene. A small amount of a high-melting by-product crystallized out at 0° C and was filtered off and discarded. On concentration on a rotary evaporator, the mother liquor left 21.1 g (70%) of a pale oil which crystallized after trituration with a little methanol. The pure 4-benzylideneamino-6-sec.-butyl-3-methylthio-1,2,4-triazine-5 (4H)-one melted at 73° C.
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.C([Li])CCC.[C:13]1([CH:19]([CH2:24][CH3:25])[C:20]([O:22][CH3:23])=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(Br)C=C>O1CCCC1.CCCCCC.CO>[CH2:24]([C:19]([CH2:7][CH:5]=[CH2:6])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:20]([O:22][CH3:23])=[O:21])[CH3:25]
Reactant: CC(C)NC(C)C
Reactant: CCC(C(=O)OC)c1ccccc1
Agent: [Li]CCCC
Solvent: C=CCBr
Solvent: CO
Solvent: C1CCOC1
Product: C=CCC(CC)(C(=O)OC)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 15.4 ml of diisopropylamine in 400 ml of dry tetrahydrofuran at -20° to -30° under nitrogen atmosphere was added dropwise with stirring 64.3 ml of a 1.71 M solution of butyllithium in hexane. After stirring 15 min., the mixture was cooled to -70° and a solution of 17.8 g of methyl 2-phenylbutyrate in 100 ml of tetrahydrofuran was added dropwise. After stirring 30 min., a solution of 19.9 ml of allyl bromide in 50 ml tetrahydrofuran was added dropwise; the mixture was stirred and allowed to warm to room temperature overnight. After decomposing with methanol, the reaction mixture was concentrated in vacuo and the residue dissolved in diethyl ether. The ether solution was washed successively with dilute hydrochloric acid, water, dilute sodium bicarbonate, and saturated sodium chloride solution, then dried over anhydrous potassium carbonate and concentrated in vacuo. Distillation of the residue yielded 20.2 g of the title compound as a water-white oil, b.p. 84°-86°/0.45 mm, having the following elemental analysis:
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][CH:5]3[C@:18]([CH3:20])([CH2:19][C@@H:2]12)[C@@H:17]1[C@H:8]([C@H:9]2[C@@:13]([CH2:15][CH2:16]1)([CH3:14])[C:12](=[O:21])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.O.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>ClCCl>[OH:1][C@@H:3]1[C@@H:2]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:19][C@@:18]2([CH3:20])[CH:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]2=[O:21])[CH2:4]1
Reactant: C1CNCCN1
Reactant: C[C@]12C[C@H]3O[C@H]3CC1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: ClCCl
Solvent: O
Product: C[C@]12C[C@H](N3CCNCC3)[C@@H](O)CC1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 150 °C
Yield: 64.5 %

Procedure:
To compound 22 (202 mg, 0.70 mmol) was added water (1 mL) and piperazine (3.5 g, 41 mmol). The solution was subsequently heated at 150° C. over a period of 24 h. The resulting mixture was diluted with dichloromethane (50 mL) and washed with water, dried with Na2SO4, filtered and evaporated under reduced pressure. The crude compound was purified by flash chromatography (DCM/MeOH: 9:1 containing 0.5% of TEA) to yield compound 23 (169 mg, 65%). 1H NMR (CDCl3) δ: 0.87 (s, 18-CH3 and 19-CH3), 0.73-2.17 (residual CH and CH2), 2.45, 2.64 and 2.91 (3m, 4×CH2N and 2α-CH), 3.85 (m, 3β-CH).
Reaction SMILES: C(O[C:4](=[O:38])[CH:5]=[C:6]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=1[Cl:37])[CH2:7][NH:8][C@H:9]([C:16](=[O:28])[NH:17][C:18]1[CH:22]=[CH:21][N:20]([CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])[N:19]=1)[CH2:10][C@@H:11]([O:13][CH2:14][CH3:15])[CH3:12])C>O1CCCC1>[OH:27][C:24]([CH3:25])([CH3:26])[CH2:23][N:20]1[CH:21]=[CH:22][C:18]([NH:17][C:16](=[O:28])[C@@H:9]([N:8]2[CH2:7][C:6]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=3[Cl:37])=[CH:5][C:4]2=[O:38])[CH2:10][C@@H:11]([O:13][CH2:14][CH3:15])[CH3:12])=[N:19]1
Reactant: CCOC(=O)C=C(CN[C@@H](C[C@H](C)OCC)C(=O)Nc1ccn(CC(C)(C)O)n1)Oc1cccc(Cl)c1Cl
Solvent: C1CCOC1
Product: CCO[C@@H](C)C[C@@H](C(=O)Nc1ccn(CC(C)(C)O)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Temperature: 160 °C
Yield: 36.3 %

Procedure:
3-(2,3-Dichloro-phenoxy)-4-{(1S,3S)-3-ethoxy-1-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-ylcarbamoyl]-butylamino}-but-2-enoic acid ethyl ester (120 mg) was dissolved in tetrahydrofuran (2 mL). The sealed tube was heated in a microwave at 160° C. for 4 h. The resulting solution was concentrated and the residue was purified by reverse phase column chromatography (acetonitrile in water 25% to 100%) to give (2S,4S)-2-[4-(2,3-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-ethoxy-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide (40 mg) as a white powder: HR-ES-MS m/z calculated for C24H30Cl2N4O5 [M+H]+ 525.1666, observed 525.1669; 1H NMR (300 MHz, CDCl3) δ ppm 1.14 (br. s., 6H), 1.19-1.30 (m, 6H), 1.88-2.09 (m, 1H), 2.18 (ddd, J=14.7, 9.3, 5.9 Hz, 1H), 3.30-3.46 (m, 1H), 3.54 (br. s., 1H), 3.61-3.77 (m, 1H), 3.94 (s, 2H), 4.14 (d, J=17.8 Hz, 1H), 4.47 (d, J=17.8 Hz, 1H), 4.92 (s, 1H), 5.01 (t, J=6.2 Hz, 1H), 6.68 (d, J=1.5 Hz, 1H), 7.16-7.33 (m, 4H), 7.42 (d, J=7.8 Hz, 1H), 9.35 (br. s., 1H).
Reaction SMILES: IC.[C:3](=O)([O-])[O-].[K+].[K+].[CH3:9][N:10]([CH3:21])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1.C(OCC)(=O)C>CN(C=O)C.O>[CH3:21][N:10]([CH3:9])[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][C:18]([O:20][CH3:3])=[O:19])=[CH:15][CH:16]=1
Reactant: O=C([O-])[O-]
Reactant: CN(C)c1ccc(CC(=O)O)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)Cc1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 71 h
Yield: 43.4 %

Procedure:
Iodomethane (0.382 mL) and potassium carbonate (848 mg) were added to a solution of (4-dimethylaminophenyl)acetic acid (1 g) in DMF (10 mL), and the reaction solution was stirred at room temperature for 71 hours. Thereafter, ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 468 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH2:1]([C:4]1([CH2:33][CH:34]=C)[S:9](=[O:11])(=[O:10])[CH2:8][C@:7]([C:13]2[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=2[O:30][CH3:31])[C:5]1=[O:32])[CH:2]=C>ClCCl>[Br:19][C:17]1[CH:16]=[CH:15][C:14]([F:20])=[C:13]([C@@:7]2([CH3:12])[N:6]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[C:5](=[O:32])[C:4]3([CH2:33][CH:34]=[CH:2][CH2:1]3)[S:9](=[O:11])(=[O:10])[CH2:8]2)[CH:18]=1
Reactant: C=CCC1(CC=C)C(=O)N(Cc2ccc(OC)cc2OC)[C@](C)(c2cc(Br)ccc2F)CS1(=O)=O
Solvent: ClCCl
Product: COc1ccc(CN2C(=O)C3(CC=CC3)S(=O)(=O)C[C@@]2(C)c2cc(Br)ccc2F)c(OC)c1
Yield: 79.1 %

Procedure:
To a solution of (R)-2,2-diallyl-5-(5-bromo-2-fluoro-phenyl)-4-(2,4-dimethoxy-benzyl)-5-methyl-1,1-dioxo-1λ6-thiomorpholin-3-one (610 mg, 1.08 mmol, Eq: 1.00) in dichloromethane (20.3 ml) was added under argon [1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium (Grubbs II catalyst) (45.7 mg, 53.8 μmol, Eq: 0.05). The reaction mixture was stirred at reflux for 4 hours. Evaporation and chromatography on 20 g silica gel with 0% to 50% ethyl acetate in heptane gave the (R)-8-(5-bromo-2-fluoro-phenyl)-9-(2,4-dimethoxy-benzyl)-8-methyl-6,6-dioxo-6λ6-thia-9-aza-spiro[4.5]dec-2-en-10-one (460 mg, 854 μmol, 79.3% yield) as a white foam. MS (ISP): m/z=538.2 [M+H]+ and 540.2 [M+2+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)O>ClCCl>[CH3:12][N:2]([CH3:1])[CH2:3][CH2:4][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN(C)CC(O)c1ccccc1
Solvent: ClCCl
Product: CN(C)CCc1ccccc1

Procedure:
As Example 15 but using 2-dimethylamino-1-phenyl-ethanol (13.7 g) instead of 3-acetylpyridine. The crude material is pyrified by column chromatography on aluminium oxide using dichloromethane as eluant. The product is dried in vacuo to constant weight to give 1-(1,3-dithian-2-ylidene)-2-ylidene)-2-dimethylamino-1-phenylethane as an oil at room temperature.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH:6]([OH:9])[CH2:7][OH:8])[CH:2]=[CH2:3].S(O[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=O)(=O)C.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O.C1(C)C=CC=CC=1>[CH2:1]([O:4][CH2:5][CH:6]([O:9][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:7][O:8][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:2]=[CH2:3]
Reactant: C=CCOCC(O)CO
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOS(C)(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCOCC(COCCCCCCCC/C=C\C/C=C\CCCCC)OCCCCCCCC/C=C\C/C=C\CCCCC
Temperature: 25 °C
Reaction time: 80 h
Yield: 73.1 %

Procedure:
A 500 mL round bottom flask was charged with 3-(allyloxy)propane-1,2-diol (2.6 g, 19.8 mmol), linoleyl mesylate (15.0 g, 43.5 mmol), tetrabutylammonium hydrogen sulfate (3.4 g, 9.9 mmol), toluene (600 mL) and 40% NaOH (30 mL). The reagents were vigorously stirred (emulsified) for 80 hours at room temperature. Upon completion, the solution was diluted with water (100 mL) and toluene (100 mL). The toluene was separated and the remaining aqueous solution was extracted with toluene (150 mL). The combine toluene extracts were dried on magnesium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography on silica gel 60 (eluted with 5% diethyl ether in hexanes) to afford (6Z,9Z)-18-(3-(allyloxy)-2-((9Z,12Z)-octadeca-9,12-dienyloxy)propoxy)octadeca-6,9-diene as a colorless oil (9.1 g, 73%).
Reaction SMILES: C([Li])CCC.[Br-].[F:7][C:8]1[CH:9]=[CH:10][C:11]([OH:34])=[C:12]([CH:33]=1)[CH2:13][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:35]([CH:37]([CH2:49][CH2:50][C:51]1[CH:60]=[CH:59][C:54]([C:55]([O:57][CH3:58])=[O:56])=[CH:53][CH:52]=1)[CH2:38][C:39]1[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][CH:40]=1)=O.[Cl-].[NH4+]>CCCCCC.C1COCC1.O.C(OCC)(=O)C>[F:7][C:8]1[CH:9]=[CH:10][C:11]([OH:34])=[C:12](/[CH:13]=[CH:35]/[CH:37]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:47][CH:48]=2)[CH2:49][CH2:50][C:51]2[CH:60]=[CH:59][C:54]([C:55]([O:57][CH3:58])=[O:56])=[CH:53][CH:52]=2)[CH:33]=1
Reactant: COC(=O)c1ccc(CCC(C=O)Cc2ccc(C(=O)OC)cc2)cc1
Reactant: Oc1ccc(F)cc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1ccc(CCC(/C=C/c2cc(F)ccc2O)Cc2ccc(C(=O)OC)cc2)cc1
Reaction time: 0.75 h

Procedure:
At 0° C., 21.65 ml (54.12 mmol) of a 2.5 M solution of n-butyllithium in hexane are slowly added dropwise to a solution of 10.84 g (23.2 mmol) of (5-fluoro-2-hydroxybenzyl)(triphenyl)-phosphonium bromide in 150 ml of THF, and the mixture is stirred at this temperature for 45 min. At this temperature, 6.85 g (19.33 mmol) of dimethyl 4,4′-(2-formylbutane-1,4-diyl)dibenzoate in 100 ml of THF are then metered in slowly. The reaction solution is stirred at 0° C. for 3 h, saturated ammonium chloride solution is then added, the mixture is diluted with water and ethyl acetate, the organic phase is separated off and the aqueous phase is re-extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate and filtered, and the solvent is removed to dryness. The crude product obtained is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 4:1). This gives 8.21 g (17.75 mmol, 76% of theory) of a yellowish oil.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21][C:20](=S)[N:19]([N:23]([CH2:25][CH3:26])[CH3:24])[C:18]2=[O:27])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].C([SnH](CCCC)CCCC)CCC.CC(N=NC(C#N)(C)C)(C#N)C.Cl>C(Cl)(Cl)Cl.CCCCCC.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH3:15][C:12]([C:9]1[CH:8]=[C:7]([CH:16]=[C:17]2[S:21][CH2:20][N:19]([N:23]([CH2:25][CH3:26])[CH3:24])[C:18]2=[O:27])[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])[CH3:14]
Reactant: CCN(C)N1C(=O)C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)SC1=S
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCN(C)N1CSC(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Temperature: 60 °C
Yield: 29.8 %

Procedure:
7.02 g of 5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-3-(ethylmethylamino)-2-thioxo-4-thiazolidinone (from Example 40D) and 86.3 ml of toluene were stirred and heated to 60° C. under a nitrogen atmosphere. To this was added 18.6 ml of tri-n-butyl tin hydride and 0.43 g of AIBN. The resultant mixture was heated to reflux temperature for 30 minutes. At that time an additional 0.43 g of AIBN was added. The resultant mixture was heated at reflux temperature for an additional 30 minutes, cooled and transferred to a separatory funnel. To this was added 100 ml of 1N hydrochloric acid and 100 ml of ethyl acetate. The resultant mixture was shaken and separated. The organic layer was washed with brine, dried over sodium sulfate, filtered, evaporated and subsequently chased with chloroform to give an orange/red oil which was taken up in 50 ml of chloroform and filtered. The filtrate was chromatographed on a silica gel column using an 8000 ml gradient of 10-40% ethyl acetate in hexane. Those fractions identified as containing product were evaporated and chased with chloroform. To these fractions were added 15 ml of hexane and the resultant solution was heated slightly. A precipitate formed which was diluted to about 25 ml with additional hexane. The resultant mixture was triturated for about 2 hours, filtered and then washed with hexane to yield 1.94 g of the desired product, m.p. 133.5°-135° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[C:15]([F:21])[CH:16]=[C:17]([F:20])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH2:4][C@H:3]1[C:23]([O:25][CH3:26])=[O:24].[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1/[CH:35]=[CH:36]/[CH:37]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[C:19]2[C:14]=1[CH:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]1[CH2:6][CH2:7][C@@H:2]([NH:1][CH2:37]/[CH:36]=[CH:35]/[C:29]2[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:28]=2[F:27])[C@H:3]([C:23]([O:25][CH3:26])=[O:24])[CH2:4]1
Reactant: O=C/C=C/c1cc(F)ccc1F
Reactant: COC(=O)[C@@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@H]1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@H]1NC/C=C/c1cc(F)ccc1F
Yield: 43.4 %

Procedure:
Methyl (3R,4R)-4-amino-1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidine-3-carboxylate (Intermediate 38) (195 mg, 0.53 mmol), (2E)-3-(2,5-difluorophenyl)acrylaldehyde (FR 2872164) (90 mg, 0.53 mmol) and sodium triacetoxy borohydride (339 mg, 1.6 mmol) were reacted as described for Example 6. Chromatography on silica gel with dichloromethane/N,N-dimethylformamide (25:1 to 15:1) gave 119 mg (43%) of product as a colorless oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][N:4]1[CH2:9][CH2:8][C:7]([CH3:11])([CH3:10])[CH2:6][CH2:5]1.S>C(O)(=O)C>[CH3:1][CH:2]([CH3:12])[CH2:3][N:4]1[CH2:9][CH2:8][C:7]([CH3:10])([CH3:11])[CH:6]=[CH:5]1
Reactant: CC(C)CN1CCC(C)(C)CC1
Agent: S
Solvent: CC(=O)O
Product: CC(C)CN1C=CC(C)(C)CC1

Procedure:
A solution of 1-(2-Methylpropyl)-4,4-dimethylpiperidine (13.0 g, 0.077 mol) and mercuric acetate (98.8 g, 0.31 mol, 4 molar equivalent) in 5% aqueous acetic acid (300 ml) was boiled for 2.5 hours. On cooling, the white solid (mercurous acetate) was filtered-off, and the filtrate was treated repeatedly with hydrogen sulphide gas (3×), each time the mixture was filtered through a celite pad, the final filtrate made basic to pH 10 with K2CO3. The aqueous layer was extracted with ether (3×100 ml), and the combined organic layers dried over anhydrous MgSO4, concentrated and distilled to give the product, 1-(2-methylpropyl)-4,4-dimethyl-1,4,5,6-tetrahydropyridine, 7.1 g (55%), b.p. 50°-53° C. (2 mmHg). 1HNMR (CDCl3) δ5.73 (IH, d), 4.05 (1H, d), 2.88 (2H, t), 2.55 (2H, d), 1.80 (1H, m), 1.55 (2H, t), 0.95 (6H, s), and 0.85 (6H, d).