Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]#[N:13])[CH:8]=2)[O:3]1.C(O)C.N>CO.[Ni]>[NH2:13][CH2:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[O:3][C:2]([CH3:14])([CH3:1])[CH:11]=[CH:10]2
Reactant: CC1(C)C=Cc2cc(C#N)ccc2O1
Agent: [Ni]
Agent: N
Solvent: CCO
Solvent: CO
Product: CC1(C)C=Cc2cc(CN)ccc2O1
Temperature: 60 °C
Yield: 97.9 %

Procedure:
Add 2,2-dimethyl-2H-chromene-6-carbonitrile (1.5 g, 8.1 mmol) and ethanol wet Raney® activated nickel (0.4 g) to a Parr pressure vessel. Immediately add 7N ammonia in methanol (170 mL) and seal the vessel. Purge the reaction vessel with nitrogen, pressurize the reaction mixture with hydrogen (3400 KPa), seal the vessel, agitate the reaction and heat to 60° C. for 20 h. Turn off the heat and allow the reaction mixture to cool to ambient temperature. Vent the excess hydrogen from the vessel and purge the vessel with nitrogen. Filter the reaction mixture to remove the Raney® nickel. Purify by chromatography on silica gel eluting with DCM/2M ammonia in methanol (9:1) to obtain the title compound (1.5 g, 97%). MS (ES+) m/z: 175 (M+H—NH3)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][CH:2]=1.Cl.[CH3:11][NH:12][O:13][CH3:14].O>C(Cl)Cl>[CH3:14][O:13][N:12]([CH3:11])[C:7](=[O:9])[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: CNOC
Reactant: O=C(O)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CON(C)C(=O)c1ccncc1
Reaction time: 0.67 h

Procedure:
A suspension of 4-picolinic acid (3.00 g, 24.4 mmol) and 1,1-carbonyldiimidazole (4.74 g, 29.2 mmol) in CH2Cl2 (35 mL) was stirred for ˜40 min and became a clear solution. After the addition of N,O-dimethylhydroxylamine hydrochloride (2.85 g, 29.2 mmol), the mixture was stirred at room temperature for 22 hours. Water was added, the organic layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with water once, and the aqueous layer was back extracted with CH2Cl2. The organic phase was dried (Na2SO4), filtered, concentrated, and purified by flash column chromatography (80 g silica gel column, 100% EtOAc) to give the title compound as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])=[N:4][CH:5]=[C:6](Cl)[N:7]=1.[CH3:15][S-:16].[Na+]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:3]([C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])=[N:4][CH:5]=[C:6]([S:16][CH3:15])[N:7]=1
Reactant: CON(C)C(=O)c1ncc(Cl)nc1Cl
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ncc(SC)nc1Cl
Reaction time: 5 h

Procedure:
To a solution of 55B (2 g, 8.47 mmol) in DMF (10 mL), 1 eq. of sodium methanethiolate was added to the solution. After 5 hours, 0.5 eq. of sodium methanethiolate was added to the suspension. The reaction was stirred overnight then diluted with EtOAc and washed with NaHCO3 (aq) and brine. The organic layer was concentrated and purified by flash chromatography to provide the title compound. MS (m/z) 248 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[NH:10][C:9]2[S:13][CH:14]=[CH:15][C:8]=2[C:7]=1Cl)=[O:5])[CH3:2].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[NH:10][C:9]2[S:13][CH:14]=[CH:15][C:8]=2[C:7]=1[N:27]1[CH2:26][CH2:25][N:24]([C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[CH2:29][CH2:28]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)c2ccsc2[nH]c1=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CCOC(=O)c1c(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccsc2[nH]c1=O

Procedure:
In another method, intermediate 4-chloro-6-oxo-6,7-dihydro-thieno[2,3-b]pyrdine-5-carboxylic acid ethyl ester, depicted by formula (42), was reacted with tert-butyl-1-piperazine carboxylate to yield 4-(4-tert-butoxycarbonyl-piperazin-1-yl)-6-oxo-6,7-dihydro-thieno[2,3-b]-pyridine-5-carboxylic acid ethyl ester, depicted by formula (45). This intermediate was either reacted with an appropriate halide (R1—X) or boronic acid (R1—B(OH)2) to yield intermediate of structure (46), which was deprotected and reacted with an appropriate acid chloride (R3—COCl) or acid (R3—COOH) to yield target compounds of structure (III) with R2 as ethyl carboxylate, and R1 and R3 as defined above, as shown in Scheme 24.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][CH2:7][CH2:6][C@@:5]12[C:16]([F:18])([F:17])[CH2:15][O:14][C:13]([NH2:19])=[N:12]1.C(N(CC)CC)C.[CH3:27][O:28][C:29]1[CH:50]=[CH:49][C:32]([C:33](Cl)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)=[CH:31][CH:30]=1>ClCCl>[CH3:41][O:40][C:37]1[CH:36]=[CH:35][C:34]([C:33]([C:32]2[CH:31]=[CH:30][C:29]([O:28][CH3:27])=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[NH:19][C:13]2[O:14][CH2:15][C:16]([F:18])([F:17])[C@:5]3([N:12]=2)[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[S:8][CH2:7][CH2:6]3)=[CH:39][CH:38]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: NC1=N[C@@]2(CCSc3ccc(Br)cc32)C(F)(F)CO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(NC2=N[C@@]3(CCSc4ccc(Br)cc43)C(F)(F)CO2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.7 %

Procedure:
A solution of (R)-6′-bromo-5,5-difluoro-5,6-dihydro spiro[[1,3]oxazine-4,4′-thiochroman]-2-amine (intermediate B6.9) (460 mg, 1.32 mmol) and triethylamine (267 mg, 2.63 mmol) in dichloromethane (10 ml) was cooled to 0° C. and 4,4′-dimethoxytritylchloride (469 mg, 1.38 mmol) was added. The reaction mixture was left to warm to room temperature and stirred for 15 hours. For the workup, the reaction mixture was evaporated and the residue directly purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=0:100 to 60:40 as the eluent. The (R)—N-(bis(4-methoxyphenyl)(phenyl)methyl)-6′-bromo-5,5-difluoro-5,6-dihydrospiro[[1,3]oxazine-4,4′-thiochroman]-2-amine (789 mg, 92% yield) was obtained as a yellow foam. MS (ISP): m/z=651.0 [M+H]+ and 353.0 [M+2+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][OH:19])=[CH:16][C:3]1=2.C(Cl)Cl.[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[C:30](=[O:31])([O:19][CH2:18][CH2:17][C:15]1[CH:14]=[CH:13][C:4]2[O:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:2](=[O:1])[C:3]=2[CH:16]=1)[NH:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C1c2ccccc2COc2ccc(CCO)cc21
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1)OCCc1ccc2c(c1)C(=O)c1ccccc1CO2
Reaction time: 8 h
Yield: 67.8 %

Procedure:
A stirred solution of 2.54 g (0.01 mol) of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)ethanol of Example 1, 20 ml of sieve dried CH2Cl2 and 1.55 g (0.013 mol) of phenylisocyanate was heated 20 hours under reflux with exclusion of moisture. The cooled solution was concentrated on a rotary evaporator to afford an oil which was dissolved in 10 ml of hot toluene. The solution was seeded with product (previously obtained by the method described herein), stirred until a thick suspension formed and allowed to stand overnight (about 16 hours) at ambient temperature. Filtration and drying in vacuo afforded 2.53 g (67.8%) of a colorless solid of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)ethyl carbanilate, m.p. 98°-99° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[N+:10]([O-])([O-:12])=[O:11].[K+]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:4]([CH:3]=1)[CH:5]=[O:6]
Reactant: O=[N+]([O-])[O-]
Reactant: O=Cc1cccc(Br)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=Cc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 51 %

Procedure:
3-Bromobenzaldehyde (18.5 g, 100 mmol) was added dropwise to a solution of potassium nitrate (20.2 g, 200 mmol) in concentrated sulfuric acid (100 mL) cooled to 0° C. by an ice water bath. The solution was stirred for an additional 15 minutes upon complete addition of 3-bromobenzaldehyde whereupon the entire reaction mixture was added to ice (250 g). The precipitate was isolated by filtration, and the solid was washed with de-ionized water until the pH of the wash was neutral. Drying for 12 hours under vacuum gave the yellow solid, 5-bromo-2-nitrobenzaldehyde was (11.8 g, 51% yield).
Reaction SMILES: [OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH:19](=[O:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[OH:22].[Cl:28][CH2:29]/[CH:30]=[CH:31]/[CH2:32]Cl.[OH-].[Na+]>O>[Cl:28][CH2:29]/[CH:30]=[CH:31]/[CH2:32][O:22][C:21]1[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=1[CH:19]=[O:27]
Reactant: ClC/C=C/CCl
Reactant: O=Cc1ccccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=Cc1ccccc1OC/C=C/CCl

Procedure:
To 2 lt of refluxing water, 3 ml of 40% aqueous tetrabutylammonium hydroxide, 250 ml of salicylaldehyde and 280 ml of trans-1,4-dichloro-2-butene are added while vigorously stirring, followed by the dropwise addition of the solution of 83 g of sodium hydroxide in 400 ml of water at such a rate that the pH of the mixture is kept between 7 and 8 (ca 25 minutes). Thereafter the mixture is refluxed for about 6 minutes until the pH is about 7, cooled to 20° and the aqueous layer is extracted with diethyl ether. The extract is combined with the organic layer, washed with 5% aqueous sodium hydroxide, dried, evaporated, the residue distilled and the fraction boiling at 141°-147°/0.7 mmHg collected, to yield the 2-(4-chloro-trans-2-butenyloxy)-benzaldehyde.
Reaction SMILES: [CH:1]1([CH2:6][OH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.O[C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]2=[O:28])[CH:12]=[CH:13][CH:14]=1>>[CH:1]1([CH2:6][O:7][C:13]2[CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][N:18]3[C:19](=[O:28])[C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:26]3=[O:27])[CH:10]=[CH:9][CH:14]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Reactant: OCC1CCCC1
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(OCC2CCCC2)c1

Procedure:
Coupling of cyclopentylmethanol (0.22 g, 2.4 mmol) with compound 58 (0.56 g, 2 mmol) following the method used in Example 2 gave 2-(3-(3-(cyclopentylmethoxy)phenyl)propyl)isoindoline-1,3-dione as a colorless oil. Yield (0.29 g, 40%): 1H NMR (400 MHz, CDCl3) δ 7.78-7.83 (m, 2H), 7.66-7.72 (m, 2H), 7.13 (t, J=7.8 Hz, 1H), 6.71-6.77 (m, 2H), 6.66 (ddd, J=0.6, 2.5, 8.0 Hz), 3.78 (d, J=7.0 Hz, 2H), 3.74 (t, J=7.0 Hz, 2H), 2.65 (t, J=7.6 Hz, 2H), 2.28-2.38 (m, 1H), 1.98-2.07 (m, 2H), 1.77-1.87 (m, 2H), 1.52-1.66 (m, 4H), 1.30-1.40 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:47]=[CH:46][C:29]([O:30][C:31]2[CH:32]=[CH:33][C:34]3[N:35]([CH:37]=[C:38]([NH:40][C:41]([CH:43]4[CH2:45][CH2:44]4)=[O:42])[N:39]=3)[CH:36]=2)=[C:28]([F:48])[CH:27]=1.C(=O)([O-])O.[Na+]>O1CCCC1.CN(C)C=O>[CH:43]1([C:41]([NH:40][C:38]2[N:39]=[C:34]3[CH:33]=[CH:32][C:31]([O:30][C:29]4[CH:46]=[CH:47][C:26]([NH:25][C:16]([C:5]5[C:6](=[O:15])[N:7]([C:8]6[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=6)[C:2]([CH3:1])=[CH:3][CH:4]=5)=[O:18])=[CH:27][C:28]=4[F:48])=[CH:36][N:35]3[CH:37]=2)=[O:42])[CH2:44][CH2:45]1
Reactant: Cc1cccc(-n2c(C)ccc(C(=O)O)c2=O)c1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cccc(-n2c(C)ccc(C(=O)Nc3ccc(Oc4ccc5nc(NC(=O)C6CC6)cn5c4)c(F)c3)c2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution (3 mL) of 6-methyl-1-(3-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (120 mg, 0.50 mmol) in tetrahydrofuran were added oxalyl dichloride (130 mg, 1.0 mmol) and N,N-dimethylformamide (1 drop), and the mixture was stirred at room temperature for 1 hr. The mixture was concentrated under reduced pressure, and the solvent was evaporated. N,N-Dimethylformamide (3.0 mL) and a solution (2.0 mL) of N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (130 mg, 0.40 mmol) in N,N-dimethylformamide were successively added, and the mixture was stirred at room temperature for 5 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the obtained residue was washed with ethyl acetate and collected by filtration to give the title compound (150 mg, 69%) as a brown solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:52][CH:53]2[CH2:57][CH2:56][CH2:55][CH2:54]2)[C:40]([NH:42][C:43]2[CH:47]=[CH:46][N:45]([CH2:48]C(O)=O)[N:44]=2)=[O:41])[CH:32]=[CH:33][C:34]=1S(C)(=O)=O.CN1C=CC(N)=N1.N1C(C)=CC=CC=1C.C(Cl)[Cl:74]>>[CH:53]1([CH2:52][C@H:39]([C:31]2[CH:32]=[CH:33][C:34]([Cl:74])=[C:29]([Cl:28])[CH:30]=2)[C:40]([NH:42][C:43]2[CH:47]=[CH:46][N:45]([CH3:48])[N:44]=2)=[O:41])[CH2:57][CH2:56][CH2:55][CH2:54]1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(=O)O)n2)cc1Cl
Reactant: ClCCl
Agent: Cn1ccc(N)n1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1cccc(C)n1
Product: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(Cl)c(Cl)c2)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 48 %

Procedure:
In a round bottom flask under argon was placed triphenylphosphine (120 mg, 0.46 mmol) and methylene chloride (10 mL) and it was cooled to 0° C. in an ice bath. To this was added N-bromosuccinimide (81 mg, 0.46 mmol) and it was stirred for 15 minutes at 0° C. To this was then added 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionic acid (prepared as in PCT WO 2002/046173 A1, Example 3, 100 mg, 0.35 mmol) and it was stirred for an additional 5 minutes at 0° C. and then warmed to 25° C. and stirred for 10 minutes. The solution was recooled to 0° C. and then 1-methyl-1H-pyrazol-3-ylamine (68 mg, 0.70 mmol) in methylene chloride (500 μL) and 2,6-lutidine (160 μL, 1.4 mmol) were added to the flask and it was stirred at 0° C. and then warmed to 25° C. and stirred for 2.5 h. After this time the reaction was diluted with methylene chloride and then washed with an aqueous 1 N hydrochloric acid solution and saturated aqueous brine solution. Flash chromatography using Biotage system (40S column, Silica gel, 50% ethyl acetate/hexanes) provided a white foam, this material was then lyophilized to afford 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-(1-methyl-1H-pyrazol-3-yl)-propionamide (62 mg, 48%) as a white powder: [α]27589=−15.6° (c=0.27, methanol); ES-HRMS m/e calcd for C18H21N30Cl2 (M+H)+ 366.1135, observed 366.1135; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.01-1.19 (m, 2H, CH2), 1.34-1.80 (m, 8H, 4×CH2), 1.95-2.14 (m, 1H, CH), 3.70 (s, 3H, NCH3), 3.79 (dd, J=8.6, 6.0 Hz, 1H, ArCH), 6.30-6.44 (m, 1H, Ar), 7.34 (dd, Jo=8.4 Hz, Jm=1.3 Hz, 1H, Ar), 7.51 (d, Jm=1.3 Hz, 1H, Ar), 7.54-7.65 (m, 2H, Ar), 10.66 (s, 1H, NH).
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH2:11])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21](Cl)(=[O:23])=[O:22])([O-:14])=[O:13].CCN(CC)CC.N#N>C1COCC1>[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([NH:11][CH:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1)(=[O:23])=[O:22])([O-:14])=[O:13]
Reactant: NC1CCCc2cccnc21
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: N#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NC1CCCc2cccnc21
Yield: 93 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-quinolin-8-ylamine (1.73 g, 12.0 mmol) dissolved in THF (80 mL) was added 2-nitrobenzenesulfonyl chloride (2.92 g, 13.0 mmol) and Et3N (2.4 mL, 18.0 mmol). The mixture was stirred for 16 hours at room temperature under a positive pressure of N2. The reaction mixture was quenched with saturated aqueous NaHCO3 (100 mL) and extracted with CH2Cl2 (2×100 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to afford 2-nitro-N-(5,6,7,8-tetrahydro-quinolin-8-yl)-benzenesulfonamide as a dark brown solid (3.72 g, 94%). 1H NMR (CDCl3) δ 1.59 (m, 1H), 1.89 (m, 2H), 2.50 (m, 1H), 2.76 (m, 2H), 4.35 (m, 1H), 6.86 (m, 1H), 7.04 (m, 1H), 7.35 (m, 1H), 7.74 (m, 2H), 7.99 (m, 1H), 8.12 (m, 1H), 8.26 (m, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH2:10][CH:11]=O)[CH2:3][CH2:4][CH2:5][C:6]([OH:9])([CH3:8])[CH3:7].C#C.[CH3:15][C:16]([CH3:18])=[O:17]>>[CH3:1][CH:2]([CH2:3][CH2:4][CH2:5][C:6]([CH3:7])([OH:9])[CH3:8])[CH2:10][CH:11]=[CH:15][C:16](=[O:17])[CH3:18]
Reactant: CC(C)=O
Reactant: CC(CC=O)CCCC(C)(C)O
Agent: C#C
Product: CC(=O)C=CCC(C)CCCC(C)(C)O

Procedure:
The ethynylation of 212 g of 6,10-dimethylundeca-3-en-2-on-10-ol obtained by aldol condensation of hydroxycitronellal and acetone with acetylene was worked out in the same manner as in example 9 except that hydroxycitronellal was used in place of pseudoionone and 269 g of a crude product was thus obtained.
Reaction SMILES: Cl[C:2]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:3]=1[C:4]([C:6](=[CH:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[H-].[Na+].O>O1CCCC1>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[N:13]1[C:2]2[C:3](=[CH:22][C:23]([F:27])=[C:24]([F:26])[CH:25]=2)[C:4](=[O:5])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12]1
Reactant: CCOC(=O)C(=CNc1ccc(F)cc1F)C(=O)c1cc(F)c(F)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2cc(F)c(F)cc2c1=O
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
The solution of 3.0 g of ethyl 2-(2-chloro-4,5-difluorobenzoyl)-3-(2,4-difluorophenylamino)acrylate in 30 ml of anhydrous tetrahydrofuran was cooled to 10° C. 0.3 g (1.02 eq.) of 60% sodium hydride was added to the reaction mixture, which was refluxed for 4.5 hours. The reaction mixture was cooled to 5˜10° C. 54.6 ml of water was added to the reaction mixture, which was then stirred for 30 minutes. The organic layer was filtered under a reduced pressure and washed with a mixed solution of n-hexane and ether (1/1). The resulting wet cake was dried under a reduced pressure at 40˜45° C. for 6 hours to give 2.26 g of ethyl 1-(2,4-difluorophenyl)-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (Yield: 82.8%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([CH2:23][O:24][C:25]3[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=3[CH:32]([CH3:34])[CH3:33])[CH2:19][CH2:18]2)[N:8]=1)=[O:6].Cl[C:36]1[N:41]=[C:40]([C:42]([NH2:44])=[O:43])[CH:39]=[CH:38][N:37]=1.[K]>C(#N)C>[NH2:44][C:42]([C:40]1[CH:39]=[CH:38][N:37]=[C:36]([NH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][CH:20]([CH2:23][O:24][C:25]4[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=4[CH:32]([CH3:34])[CH3:33])[CH2:19][CH2:18]3)[N:8]=2)=[O:6])[N:41]=1)=[O:43]
Reactant: Cc1ccc(C(C)C)c(OCC2CCN(CCCNc3nccc(C(=O)NCCN)n3)CC2)c1
Reactant: NC(=O)c1ccnc(Cl)n1
Agent: [K]
Solvent: CC#N
Product: Cc1ccc(C(C)C)c(OCC2CCN(CCCNc3nccc(C(=O)NCCNc4nccc(C(N)=O)n4)n3)CC2)c1

Procedure:
2.31 g (4.92 mmol) of N-(2-aminoethyl)-2-[[3-[4-[[5-methyl-2-(1-methylethyl)phenoxy]methyl]piperidin-1-yl]propyl]amino]pyrimidine-4-carboxamide, 0.82 g (5.2 mmol) of 2-chloropyrimidine-4-carboxamide, 0.89 g (6.4 mmol) of potassium carbonateand 75 ml of acetonitrile are introduced, under an argon atmosphere, into a0.25 l round-bottomed flask and the mixture is heated at reflux for 30 h.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][C@@H:6]1[C:11]([O:13]C)=O)=[O:4].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(OCCO)C>[CH2:15]([N:22]1[CH2:2][C:3](=[O:4])[N:5]2[CH2:9][C@@H:8]([OH:10])[CH2:7][C@@H:6]2[C:11]1=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)[C@H]1C[C@H](O)CN1C(=O)CCl
Solvent: CCOCCO
Solvent: CCN(CC)CC
Product: O=C1[C@H]2C[C@H](O)CN2C(=O)CN1Cc1ccccc1

Procedure:
To a solution of Example 65B (200 g, 0.90 mol, 1 equivalent) in 2-ethoxyethanol (3.2 L), benzylamine (120 mL, 1.09 mol, 1.2 equivalents) was added. To this mixture, triethylamine (152 mL, 1.08 mol, 1.28 equivalents) was added, and the mixture was refluxed for 20 hours. The reaction mixture was cooled and concentrated under reduced pressure to afford crude product. This crude material was purified by column chromatography on silica gel using a mixture of methanol-ethyl acetate gradient (0-10%) to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 2.11 (m, 1H), 2.46 (m, 1H), 3.50 (m, 2H), 3.73 (d, 1H, J=16), 3.76 (m, 1H), 4.00 (d, 1H, J=16), 4.45 (d, 1H, J=15), 4.50 (m, 2H), 4.72 (d, 1H, J=15), 7.30 (m, 5H).
Reaction SMILES: [CH2:1]([C:4]1[C:11]([O:12][CH3:13])=[CH:10][C:7]([CH2:8][OH:9])=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1)[CH:2]=[CH2:3].N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:4]1[C:11]([O:12][CH3:13])=[CH:10][C:7]([CH2:8][O:9][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1cc([N+](=O)[O-])c(CO)cc1OC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCc1cc([N+](=O)[O-])c(CO[Si](C)(C)C(C)(C)C)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
229 mg of 4-allyl-5-methoxy-2-nitrobenzyl alcohol was dissolved in 5 ml of N,N-dimethylformamide. Thereafter, 0.17 g of imidazole and 0.23 g of t-butyldimethylsilyl chloride were added to the reaction solution while cooling on ice. The obtained mixture was stirred at room temperature for 2 hours. Thereafter, 34 mg of imidazole and 46 mg of t-butyldimethylsilyl chloride were further added to the reaction solution. The obtained mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate and then washed with a saturated ammonium chloride aqueous solution and a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), so as to obtain 330 mg of the subject compound.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([NH:5][CH2:6][CH2:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:4].[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(O)(=O)C>[C:20]([N:8]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)[CH2:7][CH2:6][NH:5][C:3](=[O:4])[C:2]([F:18])([F:19])[F:1])(=[O:22])[CH3:21]
Reactant: O=C(NCCNc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)N(CCNC(=O)C(F)(F)F)c1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
0.6 g (2.1 mmol) of 4-(2-trifluoroacetylamino-ethylamino)-nitrobenzene are dissolved in 10 ml of glacial acetic acid and after the addition of 2 ml (21.2 mmol) of acetic acid anhydride stirred for 5 hours at 80° C. and overnight at ambient temperature. The solvent is distilled off, the residue is made alkaline with sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic extracts are dried and evaporated down.