Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:28])[C:3]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:7]=3[C:6]=2[N:5]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[N:4]=1.[Cl:29]N1C(=O)CCC1=O.C(O)C>C(Cl)(Cl)Cl>[Cl:29][C:12]1[C:8]2=[CH:9][CH:10]=[C:11]3[C:6]([N:5]([C:18]4[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=4)[N:4]=[C:3]3[CH:2]([F:1])[F:28])=[C:7]2[CH:15]=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: COc1ccc2c(c1)CCc1c(C(F)F)nn(-c3ccc(S(N)(=O)=O)cc3)c1-2
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COc1ccc2c(ccc3c(C(F)F)nn(-c4ccc(S(N)(=O)=O)cc4)c32)c1Cl
Temperature: 50 °C

Procedure:
4-[3-(Difluoromethyl)-4,5-dihydro-7-methoxy-1H-benz[g]indazol-1-yl]benzenesulfonamide (1.0 g, 1.23 mmol) from Step 2 was suspended in chloroform (100 ml), and N-chlorosuccinimide (NCS) (329 mg, 1.23 mmol) was added. The reaction was heated to 50° C. for 16 hours. At this point, ethanol (20 ml) was added to dissolve the suspended reagents. The reaction was again heated to 50° C. for 24 hours. At this time, an additional equivalent of NCS (329 mg) was added, and the reaction was heated to 50° C. for an additional 4 days. Upon cooling, a precipitate which had formed was collected. This solid was pure 4-[6-chloro-3-(difluoromethyl)-7-methoxy-1H-benz[g]indazol-1-yl]benzenesulfonamide (350 mg, 65%): 1H NMR (acetone d6) δ=4.0 (s, 3H), 7.2 (t, 1H, j=54.0 Hz), 7.3 (d, 1H j=9.3 Hz), 7.6 (d, 1H j=9.3 Hz), 7.9 (d, 2H j=8.7 Hz), 8.0 (d, 1H j=9.3 Hz), 8.1 (d, 1H j=9.3 Hz), 8.2 (d, 2H j=8.7 Hz); 19F NMR (acetone d6) δ-113.5 ppm (d, 2F).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][NH:11][C:12]1[C:15](=[O:16])[C:14](=[O:17])[C:13]=1OCC)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[NH3:21]>C(O)C>[CH2:1]([O:3][P:4]([CH2:9][CH2:10][NH:11][C:12]1[C:15](=[O:16])[C:14](=[O:17])[C:13]=1[NH2:21])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: N
Reactant: CCOc1c(NCCP(=O)(OCC)OCC)c(=O)c1=O
Solvent: CCO
Product: CCOP(=O)(CCNc1c(N)c(=O)c1=O)OCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
A solution of [2-[(2-ethoxy-3,4-dioxo-1-cyclobuten-1-yl)amino]ethyl]phosphonic acid diethyl ester (1.69 g, 5.5 mmol) in 100% ethanol (40 mL) was placed in flask equipped with an addition funnel and a nitrogen inlet. Saturated ethanolic ammonia (190 mL) was placed in the addition funnel and added dropwise over 1 hour. The reaction mixture was left stirring at room temperature for a total of 24 hours and then concentrated in vacuo. The resulting solid was recrystallized from methanol in ethyl acetate to afford [2-[(2-amino-3,4-dioxo-1-cyclobuten-1-yl)amino]ethyl]phosphonic acid diethyl ester as a yellow solid (1.27 g, 82%, mp=150°-152° C. dec); IR (KBr, cm-1): 1805, 1650; MS (+FAB): 277 (MH+, 100), 182 (20), 109 (15); 1H NMR (DMSO, 400 MHz): δ 7.5 (br s, 3 NH), 4.1-3.9 (m, 4H), 3.7-3.6 (m, 2H), 2.11 (d of t, J=17.5 and 7.5 Hz, 2H), 1.22 (t, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[Li+].Cl>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(NS(C)(=O)=O)ccc1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(NS(C)(=O)=O)cc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Combine methyl 2-methoxy-5-methylsulfonamidobenzoate (1.0 g, 3.86 mmol) and lithium hydroxide (93 mg, 3.86 mmol) in tetrahydrofuran/water (50 mL/10 mL). After 18 hours, add lithium hydroxide (100 mg) and heat to reflux. After 1 hour, cool to ambient temperature and evaporate to remove most of the tetrahydrofuran. Dilute the evaporated reaction mixture with water (about 70 mL) and acidify to pH of about 1 using a 1 M aqueous hydrochloric acid solution. Evaporate to dryness and triturate with dichloromethane (200 mL). Filter and evaporate the filtrate to give the title compound: mp; 160-163° C.
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][N:9]([C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)[CH2:10][CH2:11]OS(C1C=CC(C)=CC=1)(=O)=O.C(N(CC)CC)C.[CH3:39][NH:40][CH2:41][CH2:42][CH2:43][CH3:44]>C1(C)C=CC=CC=1>[CH2:41]([N:40]([CH3:39])[CH2:11][CH2:10][N:9]([CH3:8])[C:23]1[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=1)[CH2:42][CH2:43][CH3:44]
Reactant: Cc1ccc(S(=O)(=O)OCCN(C)c2ccc([N+](=O)[O-])cc2)cc1
Reactant: CCCCNC
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCN(C)CCN(C)c1ccc([N+](=O)[O-])cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of toluene-4-sulfonic acid 2-[methyl-(4-nitro-phenyl)-amino]-ethyl ester TFA salt (74 mg, 0.21 mmol) in toluene (1 mL) is added triethylamine (50 μL) and N-methylbutylamine (75 μL, 0.63 mmol). The mixture is shaken in 70° C. block shaker overnight. The reaction mixture is concentrated and purified by reverse phase high performance liquid chromatography to give N-butyl-N,N′-dimethyl-N′-(4-nitro-phenyl)-ethane-1,2-diamine as a di-TFA salt (71 mg, 68%).
Reaction SMILES: O[CH2:2][C@@H:3]([NH2:8])[CH2:4][CH:5]([CH3:7])[CH3:6].COC(=O)[C@H](CC(C)C)N.OCCN.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[S:32])=[C:26]([CH3:33])[CH:25]=1>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]2[NH:8][C@@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:2][S:32]2)=[C:26]([CH3:33])[CH:25]=1
Reactant: CC(C)C[C@H](N)CO
Reactant: Cc1cc(F)ccc1N=C=S
Agent: COC(=O)[C@@H](N)CC(C)C
Solvent: NCCO
Product: Cc1cc(F)ccc1N=C1N[C@@H](CC(C)C)CS1

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 4-Fluoro-2-methylphenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(4-fluoro -2-methylphenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(4-fluoro-2-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine.
Reaction SMILES: [CH2:1]([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[N:17]=[CH:18][N:19]([CH2:21][CH3:22])[CH:20]=3)[S:15][C:8]=12.CI>O1CCCC1>[Cl:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[N:17]=[C:18]([CH3:1])[N:19]([CH2:21][CH3:22])[CH:20]=3)[S:15][C:8]=12.[Cl:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[N:17]=[CH:18][N:19]([CH2:21][CH3:22])[CH:20]=3)[S:15][C:8]=12
Reactant: [Li]CCCC
Agent: CCn1cnc(-c2cc3nccc(Cl)c3s2)c1
Solvent: C1CCOC1
Solvent: CI
Product: CCn1cc(-c2cc3nccc(Cl)c3s2)nc1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium was added to a solution at −78° C. of 7-chloro-2-(1-ethyl-1H-imidazol-4-yl)thieno[3,2-b]pyridine (13, scheme 4) in tetrahydrofuran and stirred for about 15 minutes. Methyl iodide was added slowly and the reaction mixture was stirred at −78° C. until completion of the reaction. The mixture was quenched with water then allowed to warm to room temperature. The aqueous solution was extracted three times with ethyl acetate. The combined organic extracts were washed with water and brine, then dried over anhydrous MgSO4, filtered and evaporated. The crude product was purified by flash chromatography (eluent: 100% DCM to 2% MeOH/98% DCM) to afford the title compound 107 (as a mixture with about 15% of the starting material 13) as a yellow solid (190 mg, 80% yield). MS (m/z): 278.0 (M+H).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[N:13]=[C:14]([CH2:17][N:18]2[CH:22]=[C:21]([C:23]([O:25]CC)=[O:24])[CH:20]=[N:19]2)[S:15][CH:16]=1.[OH-].[Na+].O>C(O)C.O1CCCC1>[F:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[N:13]=[C:14]([CH2:17][N:18]2[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[CH:20]=[N:19]2)[S:15][CH:16]=1
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3cccc(C(F)(F)F)c3F)cs2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnn(Cc2nc(-c3cccc(C(F)(F)F)c3F)cs2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85226936 %

Procedure:
To a mixed solution of the compound (320 mg, 0.79 nmol) obtained in Example 52a in ethanol/tetrahydrofuran (v/v=1/1, 8 mL) was added 2N aqueous sodium hydroxide solution (1.6 mL, 3.2 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the aqueous layer was washed with diethyl ether, neutralized with 1N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was recrystallized (ethyl acetate-hexane) to give the title compound (250 mg, 84%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(N(CC)CC)C.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25]>ClCCl>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[C:21]([C:20]([F:19])([F:30])[F:31])[CH:22]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-methyl-3-nitroaniline (5 g, 32.2 mmol, 1.0 eq.) and triethylamine (5.38 ml, 38.6 mmol, 1.2 eq.) in dichloromethane (100 ml) is added a solution of 3-trifluoromethylbenzoyl chloride 33.8 mmol, 1.05 eq.) within 30 min. The suspension formed is stirred for 1 h at room temperature. Then, the reaction mixture is diluted with dichloromethane (800 ml) and extracted with water (100 ml), 2M aqueous Na2CO3 (100 ml), 2M HCl (100 ml), water (100 ml). The organic layer is dried over Na2SO4, evaporated to a volume of about 100 ml and diluted with hexanes (100 ml). The precipitate is filtered off, washed with hexanes/dichloromethane 1:1 and hexanes. Vacuum drying over night at room temperatures gives light yellow fine needles: HPLC: tR=6.72 min (purity: >99%, gradient A), ESI-MS: 325.2 [MH]+
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:23][CH2:24][CH2:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1>C(O)CCC>[NH2:30][C:29]1[CH:31]=[CH:32][C:26]([CH2:25][CH2:24][NH:23][C:2]2[C:3]3[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[C:9]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[O:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:27][CH:28]=1
Reactant: NCCc1ccc(N)cc1
Reactant: Clc1ncnc2oc(-c3ccccc3)c(-c3ccccc3)c12
Solvent: CCCCO
Product: Nc1ccc(CCNc2ncnc3oc(-c4ccccc4)c(-c4ccccc4)c23)cc1
Yield: 73.6 %

Procedure:
4-Chloro-5,6-diphenylfuro[2,3-d]pyrimidine (0.200 g) and 4-(2-aminoethyl)aniline (0.107 g) in n-butanol (5 mL) were heated at 80° C. for 16 h. The reaction mixture was concentrated and the residue was partitioned between water and ethyl acetate. The organic layer was concentrated and the crude compound was purified by silica gel column chromatography using a mixture of dichloromethane:methanol (40:1), to give N-(4-aminophenethyl)-5,6-diphenylfuro[2,3-d]pyrimidin-4-amine (0.195 g, 74%).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][C:7](C)=[CH:8]C(Cl)=O.[C:13]([NH2:17])(=O)[CH:14]=[CH2:15]>>[NH:17]1[C:13]2[C:6](=[CH:7][CH:8]=[CH:15][CH:14]=2)[CH2:3][CH2:2][C:1]1=[O:4]
Reactant: C=CC(N)=O
Reactant: CC(C)=CC(=O)Cl
Reactant: C=CC(=O)Cl
Product: O=C1CCc2ccccc2N1

Procedure:
An example for a compound in accordance with Formula 2 is 4-iso-propylaniline that serves as the starting material for the presently preferred compounds of the invention. The aniline derivative of Formula 2 is reacted with an acryloyl chloride derivative of Formula 2A in a basic solvent, such as pyridine, to provide the phenyl amide derivative of the acryloic acid of Formula 3. An example of the acryloyl chloride derivative of Formula 2A that is used for the synthesis of the presently preferred compounds of the invention is commercially available 3,3-dimethylacryloyl chloride. The acryloic acid amide derivative of Formula 3 is cyclized under Friedel Crafts conditions to provide the 1,2,3,4-tetrahydro-quinolin-2-one derivative of Formula 4. The 1,2,3,4-tetrahydro-quinolin-2-one derivative of Formula 4 is reacted with bromine in acetic acid to provide the 8-bromo-1,2,3,4-tetrahydro-quinoline-2-one derivative of Formula 5. The numbering of the quinoline ring system and of the heptatrienoic acid moiety that is attached to it in the 8 position of the quinoline nucleus in the compounds of the invention, is shown in Formula 1. The endocyclic oxo function of the 8-bromo-1,2,3,4-tetrahydro-quinoline-2-one derivative of Formula 5 is reduced by treatment with borane-methyl sulfide to give the 8-bromo-1,2,3,4-tetrahydro-quinoline derivative of Formula 6. An alkyl group, designated R3, where R3 is defined as in connection with Formula 1, is introduced to the nitrogen of the quinoline nucleus by treatment of the compound of Formula 6 with an alkylating agent, such as R3-I, in the presence of base, to give the 1-alkyl-8-bromo1,2,3,4-tetrahydro-quinoline compound of Formula 7. The 1-alkyl-8-bromo1,2,3,4-tetrahydro-quinoline compound of Formula 7 is reacted with dimethylformamide (DMF) in the presence of strong base, such as n-butyl lithium to give a 1-alkyl-1,2,3,4-tetrahydro-quinoline-8-carbaldehyde of Formula 8. The carbaldehyde of Formula 8 is reacted with a Grignard reagent of the formula R5MgBr, where R5 is defined as in connection with Formula 1, to provide a (1-alkyl-1,2,3,4-tetrahydro-quinoline-8-yl)-alkan-1-ol of Formula 9.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13](S(C)(=O)=O)=[N:14][CH:15]=2)[N:10]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][O:29][Si:30]([C:43]([CH3:46])([CH3:45])[CH3:44])([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:23]=2)[C:9]1=[O:47].[NH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>Cl>[NH:48]([C:13]1[N:12]=[C:11]2[N:10]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][O:29][Si:30]([C:43]([CH3:46])([CH3:45])[CH3:44])([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:23]=3)[C:9](=[O:47])[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Br:1])[CH2:17][C:16]2=[CH:15][N:14]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)[Si](OCc1cccc(N2C(=O)N(c3ccccc3Br)Cc3cnc(S(C)(=O)=O)nc32)c1)(c1ccccc1)c1ccccc1
Agent: Cl
Product: CC(C)(C)[Si](OCc1cccc(N2C(=O)N(c3ccccc3Br)Cc3cnc(Nc4ccccc4)nc32)c1)(c1ccccc1)c1ccccc1
Temperature: 180 °C
Yield: 100 %

Procedure:
1.5 g (2 mmol) of 3-(2-bromophenyl)-1-[3-(tert-butyldiphenylsilyloxymethyl)phenyl]-3,4-dihydro-7-methanesulfonyl-pyrimido[4,5-d]pyrimidin-2(1H)-one (prepared in Example 61(h)) was treated with 3 ml of aniline and the mixture heated at 180° C. for 20 minutes and cooled. The mixture was poured into 50 ml of 2M aqueous hydrochloric acid and the precipitated product filtered off, washed with water and dried to afford 1.5 g (100%) of 7-anilino-3-(2-bromophenyl)-1-[3-((tert-butyldiphenylsilyloxy)methyl)phenyl]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a light brown solid. [Mass spectrum (ESI) MH+ =741].
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].[H-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[CH2:12]([O:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:1]#[N:2])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(OCc2ccccc2)c1
Temperature: 90 °C

Procedure:
A stirred solution of 3-cyanophenol (20 g) in dry N,N-dimethylformamide (200 mL) is treated with sodium hydride (5.6 g; 60% dispersion in mineral oil), portionwise during 40 minutes, followed by dropwise addition of benzyl bromide (20 mL). The mixture is heated at 90° C. for 4 hours, cooled and concentrated under reduced pressure. The residue is partitioned between ethyl acetate and water and the organic layer washed with 1 N sodium hydroxide (100 mL) followed by drying over magnesium sulphate and concentration. The residue is recrystallised from methanol to give 3-benzyloxybenzonitrile (24 g), in the form of a cream solid, m.p. 38-40° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:18])[CH:7]=[CH:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])[CH3:4].[C:19](Cl)(=[O:23])[CH:20]([CH3:22])[CH3:21]>O1CCCC1>[C:19]([C:7](=[CH:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])[C:6]([O:5][CH2:3][CH3:4])=[O:18])(=[O:23])[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)C(=O)Cl
Reactant: CCOC(=O)C=CNc1ccccc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=CNc1ccccc1OC)C(=O)C(C)C
Temperature: 25 °C
Yield: 77.6 %

Procedure:
50% Sodium hydride (4.8 g, 0.1 mol) was washed with petroleum ether and suspended in dry tetrahydrofuran (50 ml) under nitrogen at -10° C. Ethyl3-(2-methoxyphenylamino)acrylate (22.4 g. 0.1 mol) in dry tetrahydrofuran (70 ml) was added dropwise to the suspension keeping the temperature to below 0° C. Cooling was removed and the mixture was stirred at ambient temperature until a deep orange colour was obtained. The mixture was recooled to -20° C. and treated dropwise with a solution of isobutyryl chloride (11.0 ml, 0.11 mol) in dry tetrahydrofuran (30 ml). The cooling bath was again removed, and the mixture stirred overnight at room temperature. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with dilute hydrochloric acid and brine, dried, filtered and evaporated. The crude product was chromatographed (silica gel, petroleum ether/dichloromethane) to afford ethyl 2-isobutyryl-3-(2-methoxyphenylamino)acrylate as an oil (22.6 g, 77.5%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CN(C)P(N(C)C)(N(C)C)=O.[CH3:24][CH2:25][O:26][C:27]([CH2:29][N:30]=[C:31]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:28].Br[CH2:45][C:46]1[S:47][C:48]([N+:51]([O-:53])=[O:52])=[CH:49][CH:50]=1>O1CCCC1>[C:32]1([C:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[N:30][CH:29]([C:27]([O:26][CH2:25][CH3:24])=[O:28])[CH2:45][C:46]2[S:47][C:48]([N+:51]([O-:53])=[O:52])=[CH:49][CH:50]=2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=[N+]([O-])c1ccc(CBr)s1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(Cc1ccc([N+](=O)[O-])s1)N=C(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 101 %

Procedure:
To a stirred solution of diisopropylamine (8.81 g, 87.0 mmol) in tetrahydrofuran (300 ml) at 0° C. was added 1.6M n-butyllithium in hexanes (54 ml, 86.4 mmol) over a 10 minute period. The resulting yellow mixture was stirred for 30 minutes, cooled to -78° C. and hexamethylphosphoramide (15.5 g, 86.2 mmol) was added. To this mixture was added ethyl N-(diphenylmethylene) glycinate (23.0 g, 86.0 mmol) in tetrahydrofuran (100 ml) over a 20 minute period. The dark orange mixture was stirred for 1 hour and then a solution of 2-bromomethyl-5-nitrothiophene (19.0 g, 85.6 mmol) in tetrahydrofuran (100 ml) was added over a 20 minute period. The mixture was stirred for 1 hour and then warmed to 0° C. After quenching with approximately 150 ml of ice-cold water, the mixture was concentrated at reduced pressure. The remaining aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulphate. The solvent was removed at reduced pressure and the resulting dark brown oil was filtered through silica gel eluting with 25% ethyl acetate/hexane to remove excess diisopropylamine . The filtrate was concentrated at reduced pressure and the resulting dark brown oil was placed in vacuo overnight. Ethyl N-diphenylmethylene-3-(5-nitro-2-thienyl)-DL-alaninate (35.3 g) was obtained as a viscous dark brown oil. The product was used without further purification.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-]=C=S.[Na+].C(Cl)(=O)C1C=CC=CC=1.[CH:25]([NH2:28])([CH3:27])[CH3:26].[CH2:29]1[O:37][C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[O:30]1>C1C=CC=CC=1>[CH:25]([N:28]([C:34]1[CH:33]=[CH:32][C:31]2[O:30][CH2:29][O:37][C:36]=2[CH:35]=1)[C:10]([NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[S:11])([CH3:27])[CH3:26]
Reactant: CC(C)N
Reactant: c1ccc2c(c1)OCO2
Reactant: O=C(N=C=S)c1ccccc1
Agent: [N-]=C=S
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O=C(Cl)c1ccccc1
Product: CC(C)N(C(=S)NC(=O)c1ccccc1)c1ccc2c(c1)OCO2
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a solution of 16.3 grams benzoyl isothiocyanate, prepared by refluxing 13.6 grams of dried sodium isothiocyanate with 17 grams of benzoyl chloride in 30 ml. of benzene, is slowly added, at room temperature, 28 grams of N-isopropyl-N-(3,4-methylenedioxyphenyl)-amine (prepared as in Example A) in 150 ml. benzene. The reaction mixture is stirred for 30 minutes at 20°C. and a solid forms which is recrystallized from benzene to yield N-isopropyl-N-(3,4-methylenedioxyphenyl)-N'-benzoyl thiourea melting at 152°-154°C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[CH:42]=[CH:41][C:13]([C:14]([NH:16][C@H:17]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:18][NH:19][C:20]([CH:22]2[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]2)=[O:21])=[O:15])=[CH:12][CH:11]=1.C1(OC)C=CC=CC=1>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:16][C@H:17]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:18][NH:19][C:20]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:21])=[O:15])=[CH:41][CH:42]=1
Reactant: COc1ccc(C(=O)N[C@@H](CNC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc2)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C(=O)N[C@@H](CNC(=O)C2CCNCC2)c2ccccc2)cc1
Reaction time: 1 h
Yield: 92 %

Procedure:
(Deprotection Method A) Trifluoroacetic acid was added to a stirring suspension of (R)-N-[2-(4-methoxybenzoylamino)-2-phenylethyl]-1-tert-butoxycarbonylpiperidine-4-carboxamide (2.0 g, 4.2 mmol), methylene chloride (20 mL), and anisole (0.5 g, 4.6 mmol) at room temperature. A solution was obtained and bubbling was observed. After 1 h, the reaction mixture was evaporated at 40° C. The residue was taken up in warm methanol, and to this stirring solution was added ether to precipitate the product. The precipitate was collected by vacuum filtration, washed with ethyl acetate, then dried under vacuum at 60° C. overnight to afford 1.9 g (92%) of a white solid
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][SH:15])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].O1CCOCC1.[F:26][CH:27](Cl)[F:28]>O>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][S:15][CH:27]([F:28])[F:26])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CS)cc1
Reactant: FC(F)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1ccc(Cl)cc1)c1ccc(CSC(F)F)cc1
Temperature: 25 °C
Yield: 36 %

Procedure:
4-chloro-4'-mercaptomethylbenzophenone (14.7 g) and potassium hydroxide (15 g) was added to a solvent comprising dioxane (100 ml) and water (100 ml). Difluoromethyl chloride was blown into this solution at 60° C. until the starting material 4-chloro-4'-mercaptomethylbenzophenone disappeared. The reaction product was cooled to room temperature and then subjected to filtration. The organic layer as the filtrate was dried over anhydrous magnesium sulfate add concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1) to obtain the desired product (6.4 g, melting point: 34° to 35° C., yield: 36%).