Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)(S)=[S:8])C=CC=CC=1.[CH2:16]([O:18][C:19](=[O:24])[CH:20]([C:22]#[N:23])[CH3:21])[CH3:17].CCOC(C)=O>C(O)(C)C>[NH2:23][C:22](=[S:8])[CH:20]([CH3:21])[C:19]([O:18][CH2:16][CH3:17])=[O:24]
Reactant: S=P(S)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(C)C#N
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCOC(=O)C(C)C(N)=S
Yield: 54.8 %

Procedure:
A mixture of diphenylphosphinodithioic acid (ALFAAESAR, 37.4 g, 149 mmol) and 2-cyanopropionic acid ethyl ester (ABCR, 9.90 mL, 74.7 mmol) in isopropanol (350 mL) was heated under reflux for 5 h. TLC (Hex:EtOAc 7:3) showed reaction had gone to completion. Reaction mixture was allowed to cool and was placed in the fridge overnight. Reaction mixture was filtered off and washed with isopropanol. Residue was partitioned between ethyl acetate (250 mL) and 1N NaOH (250 mL). Phases were separated and organic phase was washed with water (300 mL), brine (300 mL), dried over sodium sulfate and concentrated to dryness. Crude was purified by chromatography on silica gel using a hexane/EtOAc gradient. Appropriate fractions were combined and evaporated to yield title compound as a white solid (6.6 g, 40.9 mmol, 54.8% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm: 9.60 (s, 1H), 9.40 (s, 1H), 4.05 (q, 2H), 3.74 (q, 1H), 1.29 (d, 3H), 1.15 (t, 3H). [ES+MS] m/z 162 (MH+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:10]2[C:19]3[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=3)[CH2:13][NH:12][CH2:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9].[CH2:22]=O>[Ni].CO>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([CH:10]2[C:19]3[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=3)[CH2:13][N:12]([CH3:22])[CH2:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: COc1ccc2c(c1)CNCC2c1ccc(Cl)c(Cl)c1
Reactant: C=O
Agent: [Ni]
Agent: Cl
Solvent: CO
Product: COc1ccc2c(c1)CN(C)CC2c1ccc(Cl)c(Cl)c1

Procedure:
The free base prepared from 5.20 g. of rac.-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxyisoquinoline hydrochloride is stirred at room temperature with 75 ml. of methanol and 3.8 ml. of 35% formaldehyde solution for 2 hours and thereupon hydrogenated over 2 g. of Raney nickel. After filtering off, evaporation, acidification with ethanolic hydrogen chloride, crystallization and recrystallization from methanol-ether, there is obtained rac.-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline hydrochloride, m.p. 273°-275°.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]1([CH3:35])[CH:20]([CH:21]=[C:22]([Cl:31])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[CH:19]1[C:32](Cl)=[O:33].N1C=CC=CC=1.Cl>C1(C)C=CC=CC=1.O>[F:16][C:15]1[CH:14]=[CH:13][C:10]([CH2:11][O:12][C:32]([CH:19]2[CH:20]([CH:21]=[C:22]([Cl:31])[C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[C:18]2([CH3:35])[CH3:17])=[O:33])=[CH:9][C:8]=1[O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccc(F)c(Oc2ccccc2)c1
Reactant: COc1ccc(C(Cl)=CC2C(C(=O)Cl)C2(C)C)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COc1ccc(C(Cl)=CC2C(C(=O)OCc3ccc(F)c(Oc4ccccc4)c3)C2(C)C)cc1
Reaction time: 3 h
Yield: 84.2 %

Procedure:
4.4 g (0.02 mol) of 3-phenoxy-4-fluoro-benzyl alcohol and 7.1 g (0.02 mol) of 2,2-dimethyl-3-(2-chloro-2-(4-methoxy-phenyl)-vinyl)-cyclopropanecarboxylic acid chloride were dissolved in 100 ml of anhydrous toluene, and 2.5 g of pyridine, dissolved in 50 ml of anhydrous toluene, were added dropwise at 20°-25° C., whilst stirring. Stirring was then continued at 25°-35° C. for 3 hours. The reaction mixture was poured into 150 ml of water, to which 10 ml of concentrated hydrochloric acid were added, and the organic phase was separated off and washed again with 100 ml of water. The toluene phase was then dried over sodium sulphate and the solvent was distilled off under a water-pump vacuum. Last solvent residues were removed by brief incipient distillation at a bath temperature of 60° C./1 Hg. 8.1 g (84.5% of theory) of 2,2-dimethyl-3-(2-chloro-2-(4-methoxy-phenyl)-vinyl)-cyclopropanecarboxylic acid 4-fluoro-3-phenoxy-benzyl ester were obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([S:8](O)(=[O:10])=[O:9])[CH:7]=1.O=S(Cl)[Cl:17]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([S:8]([Cl:17])(=[O:10])=[O:9])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(F)cc1S(=O)(=O)O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(F)cc1S(=O)(=O)Cl

Procedure:
In a similar fashion using route 39 general procedure 96, 5-fluoro-2-nitro-benzenesulfonic acid 450 (0.6 g, 2.71 mmol), SOCl2 (3.1 ml) and DMF (0.06 ml) at 90° C. for 3 h gave the title compound (3.4 g) which was used in the next step without further purification. The structure was confirmed by 1H NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[C:5]([NH:7][NH:8][C:9](=[O:25])[C@H:10]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([Cl:23])[C:16]=1[CH3:24])[C@@H:11]([OH:13])[CH3:12])=O.C(NP1(N(CC)CC)N(C)CCCN1C)(C)(C)C>C1COCC1>[Cl:23][C:17]1[C:16]([CH3:24])=[C:15]([NH:14][C@@H:10]([C:9]2[O:25][C:5]([C:4]3[CH:26]=[CH:27][C:28]([Cl:29])=[C:2]([Cl:1])[CH:3]=3)=[N:7][N:8]=2)[C@@H:11]([OH:13])[CH3:12])[CH:20]=[CH:19][C:18]=1[C:21]#[N:22]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(Cl)c(Cl)c2)[C@H](C)O)ccc(C#N)c1Cl
Agent: CCN(CC)[PH]1(NC(C)(C)C)N(C)CCCN1C
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(Cl)c(Cl)c3)o2)[C@H](C)O)ccc(C#N)c1Cl
Reaction time: 1 h
Yield: 25.5 %

Procedure:
To a solution of 3,4-dichloro-N′-((2R,3S)-2-(3-chloro-4-cyano-2-methylphenyl-amino)-3-hydroxybutanoyl)benzohydrazide (1.35 g, 2.9 mmol) in anhydrous THF (100 mL) at room temperature was added 2-tert-butylamino-2-diethylamino-1,3-dimethyl perhydro-1,3,2-diazaphosphorine on polystyrene (2.2 mmol base/g) (4.0 g) followed by p-TSCl (621 mg, 3.2 mmol) and the mixture was stirred for 1 h. The mixture was filtered under suction and the residue washed with acetone (50 mL) followed by MeOH (50 mL). The filtrate was then concentrated and subjected to flash column chromatography [EtOAc-Hexanes (1:12)] to give the desired product (324 mg, 25%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 8.07 (d, J=2.1 Hz, 1H), 7.81 (dd, J=2.1 Hz, 8.3 Hz, 1H), 7.59 (d, J=8.3 Hz, 1H), 7.43 (d, J=8.6 Hz, 1H), 6.65 (d, J=8.6 Hz, 1H), 5.22 (d, J=8.3 Hz, 1H), 4.75 (dd, J=2.8 Hz, 8.2 Hz, 1H), 4.66-4.59 (m, 1H), 2.77 (d, J=3.6 Hz, 1H), 2.35 (s, 3H), 1.43 (d, J=6.3 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.C([O-])(O)=O.[Na+]>O1CCOCC1.O.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>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc(-c2ccccc2F)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 77.5 %

Procedure:
A solution of 4-bromo-2-nitro-phenylamine (2.17 g, 10.0 mmol) in dioxane (40 mL) was treated with 2-fluorophenylboronic acid (1.40 g, 10.0 mmol) and NaHCO3 (40.0 mL, 80.0 mmol, 2M aqueous). The mixture was degassed via sonication and flushed with Ar. Pd(PPh3)4 (116 mg, 0.100 mmol) was added, and the mixture was heated to 80° C. for 12 h. The mixture was diluted with water (40 mL) and extracted twice with EtOAc (40 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified on silica (EtOAc/hexanes, 0:1 to 1:1, v/v) to obtain 1.80 g (78%) of the title compound. 1H-NMR (400 MHz, CDCl3) δ: 8.36 (d, J=1.8 Hz, 1H), 7.64 (dt, J=8.6, 2.0 Hz, 1H), 7.45 (td, J=7.8, 1.8 Hz, 1H), 7.30-7.38 (m, 1H), 7.13-7.27 (m, 2H), 6.91 (d, J=8.6 Hz, 1H), 6.18 (br. s., 2H).
Reaction SMILES: OS(O)(=O)=O.O=S(=O)=O.[N+:10]([O-:13])(O)=[O:11].[CH3:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][N+:16]=1[O-:22].C(=O)([O-])[O-].[NH4+].[NH4+]>S(=O)(=O)(O)O>[CH3:14][C:15]1[C:20]([F:21])=[C:19]([N+:10]([O-:13])=[O:11])[CH:18]=[CH:17][N+:16]=1[O-:22]
Reactant: O=[N+]([O-])O
Reactant: Cc1c(F)ccc[n+]1[O-]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: Cc1c(F)c([N+](=O)[O-])cc[n+]1[O-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A nitration mixture of 30% oleum (55 ml) and fuming nitric acid (90 ml) was added dropwise with cooling and stirring to a solution of 2-methyl-3-fluoropyridine-N-oxide (13.3 g) in concentrated sulphuric acid (48 ml) at 10°-15°. The solution was stirred at room temperature for 1.5 hours and then for 2 hours at 100°. After cooling, the mixture was poured onto ice, basified (ammonium carbonate) and extracted with dichloromethane. After drying (K2CO3), the extracts were evaporated to dryness to give 2-methyl-3-fluoro-4-nitropyridine-N-oxide (12.12 g) m.p. 170°-175°.
Reaction SMILES: C(OP(OC(C)C)OC(C)C)(C)C.C[Mg]Cl.Br[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([Mg]Br)=[CH:29][CH:28]=1>O1CCCC1.[Cl-].[Zn+2].[Cl-].C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Ni+2].O>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)=[CH:29][CH:28]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: N#Cc1ccc(Br)cc1
Agent: [Ni+2]
Agent: CC(=O)/C=C(/C)[O-]
Agent: CC(C)OP(OC(C)C)OC(C)C
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 0 °C
Yield: 74.6 %

Procedure:
A solution of 3.02 g (22.2 mmol) zinc chloride and 5.70 g (22.2 mmol) nickel acetylacetonate (moisture content<1%) in 165 mL of tetrahydrofuran was sequentially treated at room temperature with 0.40 mL (22.2 mmol) water, 10.9 mL (44.4 mmol) triisopropylphosphite, and 27.4 mL (44.4 mmol) of 1.62 M methylmagnesium chloride in tetrahydrofuran. The resultant clear, dark reddish solution was then treated with 111.0 g (609.8 mniol) 4-bromobenzonitrile and cooled to 0° C. The reaction mixture was treated with 653 mL (555 mmol) of 0.85 M 4-chlorophenylmagnesium bromide over a 75 minute period, keeping the temperature below 10° C. After the addition of the arylmagnesium reagent was complete, the reaction was stirred at 0° C. for an additional hour before quenching was carried out by adding 550 mL of 1 M aqueous sodium citrate solution. After adding 300 mL of methyl t-butyl ether (MTBE), the reaction mixture was stirred vigorously at room temperature for 1 h while air was bubbled through the solution. The contents of the reaction flask were transferred into a separatory funnel, and flask rinsed with an additional 250 mL of MTBE. The lower green aqueous phase was drained off and the clear yellow organic phase was washed twice with 100 mL of brine. The crude solid product left after concentration was dissolyed in 660 mL of chlorobenzene at 75° C., then 660 mL of heptane was added at a rate which maintained the temperature between 75-85° C. The clear yellow solution was then allowed to cool to ca. 40° C. and seeded with 1 mg of 4-(4'-chlorophenyl)benzonitrile. Crystallization commenced shortly after seeding, and the resultant slurry was cooled to 0-5° C. and stirred for 1 h. The solid product was filtered, washed with a small amount of heptane, and then dried under reduced pressure to afford 88.5 g (74.7%) of 4-(4'-chlorophenyl)benzonitrile as a fine white crystalline solid (m.p.=130.5-131.5° C.; identity confirmed by 1H- and 13C-NMR).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:28]=[CH:27][C:11]([O:12][C:13]2[CH:26]=[CH:25][C:16]([O:17][CH:18]([CH3:24])[C:19](OCC)=[O:20])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1>C(OCC)C>[F:7][C:8]1[CH:28]=[CH:27][C:11]([O:12][C:13]2[CH:26]=[CH:25][C:16]([O:17][CH:18]([CH3:24])[CH2:19][OH:20])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(C)Oc1ccc(Oc2ccc(F)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(CO)Oc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 0 °C

Procedure:
1 g of lithium aluminium hydride is added to 20 ml of absolute diethyl ether and the solution in cooled by means of an ice-bath. While stirring, a solution of 5.8 g of ethyl 2-[p-(p-fluorophenoxy)phenoxy]-propionate in 50 ml of diethyl ether is added dropwise at such a rate that the temperature does not rise above 20° C. The mixture is subsequently allowed to stir at room temperature for 1.5 hours and then cautiously poured into 100 ml of ice-cold ammonium chloride solution. The mixture is extracted twice with diethyl ether, and the extracts are washed with semi-saturated and saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated. The yellow oily residue is distilled in a bulb-tube at 140°-142° C./0.04 Torr to yield pure 2-[p-(p-fluorophenoxy)phenoxy]-propanol.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.FC(F)(F)S(O[CH2:16][CH:17]([F:19])[F:18])(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([O:8][CH2:16][CH:17]([F:19])[F:18])=[CH:6][N:7]=1
Reactant: Cc1cc(Cl)ncc1O
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Product: Cc1cc(Cl)ncc1OCC(F)F
Yield: 95 %

Procedure:
The title compound is prepared in 95% yield (4.14 g, white solid) from 6-chloro-4-methylpyridin-3-ol (3.0 g, 20.9 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate (4.92 g, 23.0 mmol) in a similar manner to Step-1 of Amine-49.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][CH2:14][CH:15]([C:17]([OH:19])=[O:18])[CH2:16][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH:20]([N-]C(C)C)([CH3:22])[CH3:21].[Li+].C([Li])CCC.C(NC(C)C)(C)C.C(I)(C)C.Cl>O1CCCC1.CCCCCC.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH2:13][CH2:14][C@@H:15]([C:17]([OH:19])=[O:18])[C@H:16]([CH:20]([CH3:22])[CH3:21])[C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCc2c(-c3ccc(Cl)cc3)noc2C1
Reactant: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)[C@@H]1c2onc(-c3ccc(Cl)cc3)c2CC[C@H]1C(=O)O
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of 0.865 g (0.0031 mol) of 3-(4-chlorophenyl)-4,5,6,7-tetrahydro-1,2-benzisoxazole-6-carboxylic acid in 20 ml of dry tetrahydrofuran was added slowly at -70° C. to a solution of lithium diisopropylamide prepared by adding 2.65 ml of a 2.5M solution of n-butyllithium in hexane to 0.66 g (0.0065 mol) of diisopropylamine in 20 ml of dry tetrahydrofuran at -70° C. After 0.25 hour a deep red solution had formed. 0.53 g (0.0031 mol) of isopropyl iodide in 5 ml of dry tetrahydrofuran was added and the mixture was stirred at -65° C. to -30° C. for 1 hour and at a temperature up to 5° C. for an additional 1 hour. The resulting yellow solution was poured into an excess of water and acidified with 2N hydrochloric acid. The mixture was extracted four times with diethyl ether and the combined ether extracts were washed with sodium chloride solution and dried over magnesium sulfate. Evaporation gave a yellow solid which, after crystallization from glacial acetic acid, yielded 0.53 g of trans-3-(4-chlorophenyl)-4,5,6,7-tetrahydro-7-isopropyl-1,2-benzisoxazole-6- -carboxylic acid of melting point 180°-182° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:19][CH:18]3[C:20]4([CH2:24][N:23]([CH2:25][CH2:26][CH3:27])[S:22](=[O:29])(=[O:28])[NH:21]4)[CH:15]([CH2:16][CH2:17]3)[CH2:14][C:13]=2[CH:30]=1)C1C=CC=CC=1>CO.CCOC(C)=O.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:19][CH:18]3[C:20]4([CH2:24][N:23]([CH2:25][CH2:26][CH3:27])[S:22](=[O:29])(=[O:28])[NH:21]4)[CH:15]([CH2:16][CH2:17]3)[CH2:14][C:13]=2[CH:30]=1
Reactant: CCCN1CC2(NS1(=O)=O)C1CCC2Cc2cc(OCc3ccccc3)ccc2C1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCN1CC2(NS1(=O)=O)C1CCC2Cc2cc(O)ccc2C1
Reaction time: 4 h
Yield: 91.8 %

Procedure:
To a degassed solution of the product of Example 27 (7.6 g) in methanol/EtOAc (1:1; 300 ml) was added 10% palladium on carbon (1.3 g). The mixture was hydrogenolysed at 50 psi for 4 hrs, filtered and concentrated to give the title compound as a white foam (5.5 g). 1H NMR (d6-DMSO 360 MHz) δH 0.90 (3H, t, J=7.2), 1.03 (2H, m), 1.55 (2H, m), 1.63 (2H, m), 2.24 (2H, brm), 2.40 (2H, m), 2.87 (2H, t, J=7.1), 3.04 (1H, d, J=15.6), 3.10 (1H, d, J=15.6), 3.14 (2H, s), 6.47 (2H, m), 6.84 (1H, d, J=8), 7.60 (1H, s), 9.00 (1H, s).
Reaction SMILES: [CH2:1]([NH:4][S:5]([C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([N+:15]([O-])=O)[C:9]=1[OH:18])(=[O:7])=[O:6])[CH2:2][CH3:3].[H][H]>[Pd]>[CH2:1]([NH:4][S:5]([C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([NH2:15])[C:9]=1[OH:18])(=[O:7])=[O:6])[CH2:2][CH3:3]
Reactant: [H][H]
Reactant: CCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Agent: [Pd]
Product: CCCNS(=O)(=O)c1c(Cl)ccc(N)c1O
Yield: 96.2 %

Procedure:
Following the general hydrogenation procedure outlined in example 15, N-propyl-6chloro-2-hydroxy-3-nitrobenzenesulfonamide (650 mg, 2.2 mmol) was reduced with hydrogen and 10% Pd/C (320 mg) to form the desired product (560 mg, 96%). 1H NMR (MeOD-d4): δ 6.83 (m, 1H), 2.86 (t, 2H), 1.50 (m, 2H), 0.87 (t, 3H).
Reaction SMILES: [Al].[C:2]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[C:13][CH2:14][CH2:15][C:16]#[C:17][CH2:18][CH2:19][CH2:20][CH3:21])(=[O:4])[CH3:3].[H][H]>N1C2C(=CC=CC=2)C=CC=1.[Cu].[Pd].CCCCCC>[C:2]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH3:21])(=[O:4])[CH3:3]
Reactant: [H][H]
Reactant: CCCCC#CCCC#CCCCCCCOC(C)=O
Agent: [Cu]
Agent: [Pd]
Agent: [Al]
Solvent: c1ccc2ncccc2c1
Solvent: CCCCCC
Product: CCCC/C=C\CC/C=C\CCCCCCOC(C)=O

Procedure:
Into a 500 ml Parr hydrogenation flask fitted with an aluminum or copper cooling coil is placed 100 g of 7,11-hexadecadiynyl acetate, 100 ml hexane (olefin free), 1 g palladium on calcium carbonate (Lindlar catalyst) and 10 drops of synthetic quinoline. Hydrogenation is effected at 10- 20 psi and is complete when the theoretical amount of hydrogen for the partial reduction of two triple bonds is absorbed. During the hydrogenation the reaction temperature is maintained between 15°-25° to minimize cis-trans isomeration. The catalyst is then removed by filtration and the product isolated by distillation of the filtrate. bp 130°-132°/1 torr nD21 1.4592. Yield essentially quantitative. Based on IR analysis it is estimated that there is less than 5% of E isomers present.
Reaction SMILES: C(N(CC)CC)C.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH3:29][N:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1[C:32]([OH:34])=O.[CH:38]1[C:46]2[C:45]3[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][C:44]=3[O:43][C:42]=2[CH:41]=[CH:40][C:39]=1[NH2:52]>>[CH3:29][N:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1[C:32]([NH:52][C:39]1[CH:40]=[CH:41][C:42]2[O:43][C:44]3[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][C:45]=3[C:46]=2[CH:38]=1)=[O:34]
Reactant: Nc1ccc2oc3c(c2c1)CCCCC3
Reactant: CN1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: CN1CCC[C@H]1C(=O)Nc1ccc2oc3c(c2c1)CCCCC3
Yield: 69.4 %

Procedure:
Following the procedure of Example 30, triethylamine (0.21 mL, 1.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.24 g, 1.3 mmol), N-hydroxybenzotriazole (0.17 g, 1.3 mmol), N-methyl-L-proline (0.077 g, 0.60 mmol), and 7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan-2-ylamine (0.12 g, 0.60 mmol) provided 1-methyl-N-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-yl-L-prolinamide (0.13 g). MS (ES) m/z 313.2 ([M+H]+); HRMS: calcd for C19H24N2O2+H+, 313.19105; found (ESI, [M+H]+), 313.1918.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([O:11][CH3:12])=[C:4]([F:13])[CH:3]=1.[CH:14]([C:16]([CH3:18])=O)=[CH2:15]>>[F:13][C:4]1[C:5]([O:11][CH3:12])=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]2[C:3]=1[C:16]([CH3:18])=[CH:14][CH:15]=[N:1]2
Reactant: C=CC(C)=O
Reactant: COc1cc([N+](=O)[O-])c(N)cc1F
Product: COc1cc([N+](=O)[O-])c2nccc(C)c2c1F
Yield: 32 %

Procedure:
The intermediate 4-amino-2-fluoro-5-nitroanisole and methyl vinyl ketone were subjected to a Skraup reaction. A 32% yield of crude 5-fluoro-6-methoxy-4-methyl-8-nitroquinoline resulted. It was obtained in pure form by recrystallization from ethyl acetate. The recovery was 73% of product which melted 142°-144°.
Reaction SMILES: CO[C:3]([C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:8]2[CH:19]=[C:20]([Cl:22])[CH:21]=[C:7]2[C:6]=1[OH:23])=[O:4].[NH2:24][C@H:25]([C:27]([OH:29])=[O:28])[CH3:26].C[O-].[Na+]>>[Cl:22][C:20]1[CH:21]=[C:7]2[C:6]([OH:23])=[C:5]([C:3]([NH:24][C@@H:25]([CH3:26])[C:27]([OH:29])=[O:28])=[O:4])[C:10](=[O:11])[N:9]([CH2:12][C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[N:8]2[CH:19]=1
Reactant: C[C@H](N)C(=O)O
Reactant: COC(=O)c1c(O)c2cc(Cl)cn2n(Cc2cccnc2)c1=O
Agent: C[O-]
Agent: [Na+]
Product: C[C@H](NC(=O)c1c(O)c2cc(Cl)cn2n(Cc2cccnc2)c1=O)C(=O)O

Procedure:
Prepared according to the reaction condition used in Example 19 step a) from 6-chloro-4-hydroxy-2-oxo-1-pyridin-3-ylmethyl-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid methyl ester, L-alanine and NaOMe. ESI (m/z): 391 (M+H)+.
Reaction SMILES: ClCCl.[OH:4][N:5]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH:7]([C:12](=[O:14])[NH2:13])[C:6]1([CH3:16])[CH3:15].[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(N(CC)CC)C>[C:17]([O:4][N:5]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH:7]([C:12](=[O:14])[NH2:13])[C:6]1([CH3:16])[CH3:15])(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)CC(C(N)=O)C(C)(C)N1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)ON1C(C)(C)CC(C(N)=O)C1(C)C
Yield: 85.2 %

Procedure:
20 ml of dichloromethane and 3 ml of triethylamine were added to 0.50 g (2.7 mmol) of 1-hydroxy-3-carbamoyl-2,2,5,5-tetramethylpyrrolidine. 0.38 ml (4.0 mmol) of acetic anhydride was added dropwise to the mixture with stirring and ice-cooling, the mixture was stirred for 3 hours. The reaction mixture was washed with water, 3% diluted hydrochloric acid, water, 5% sodium hydrogencarbonate aqueous solution, and water, in this order. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under vacuum. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate to obtain 0.53 g (2.3 mmol) of white crystals (yield: 86%).
Reaction SMILES: [O:1]1[C:5]2([CH2:9][CH2:8][CH:7]=[CH:6]2)[O:4][CH2:3][CH2:2]1.[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12].C1(C=CC(O)=CC=1)O>C(#N)C>[O:1]1[CH2:2][CH2:3][O:4][C:5]21[CH2:9][C@@H:8]1[CH2:7][C@@H:6]2[CH2:12][CH:11]1[C:10]([O:14][CH3:15])=[O:13]
Reactant: C1=CC2(CC1)OCCO2
Reactant: C=CC(=O)OC
Agent: Oc1ccc(O)cc1
Solvent: CC#N
Product: COC(=O)C1C[C@H]2C[C@H]1CC21OCCO1

Procedure:
A reaction mixture of 1,4-dioxaspiro[4.4]non-6-ene (5 g), methyl acrylate (10.24 g), and hydroquinone (0.13 g) was heated at 100° C. in acetonitrile (12 mL) for three days. After cooling, the solvent was removed, and residue was purified by flash chromatography on silica gel eluting with 4:1 hexane/ethyl acetate to provide the title compound as a mixture of two isomers.