Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl[S:15]([OH:18])(=[O:17])=[O:16]>N1C=CC=CC=1>[CH2:1]([NH:13][S:15](=[O:17])(=[O:16])[OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN
Reactant: O=S(=O)(O)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCNS(=O)(=O)O

Procedure:
Dodecyl amine (0.1 mol) is added to a round bottom flask equipped with magnetic stirrer and dissolved in anhydrous pyridine. Next, chlorosulfonic acid (0.1 mol) is added dropwise with stirring to the chilled solution. The resulting product, dodecyl sulfamic acid, is then collected by filtration, washed with water and dried in an oven.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:11])([CH3:10])[CH2:8][OH:9])[O:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>O1CCCC1>[OH:9][CH2:8][C:7]([C:5]1[O:4][N:3]=[C:2]([NH:1][C:19](=[O:20])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=1)([CH3:11])[CH3:10]
Reactant: CC(C)(CO)c1cc(N)no1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(CO)c1cc(NC(=O)Oc2ccccc2)no1
Temperature: 25 °C
Reaction time: 15 h
Yield: 67.9 %

Procedure:
To a stirred mixture of 2-(3-aminoisoxazol-5-yl)-2-methylpropan-1-ol from Step C (100 mg, 0.64 mmol) and potassium carbonate (166 mg, 1.20 mmol) in anhydrous tetrahydrofuran (15 mL) at rt, was added dropwise a solution of phenyl chloroformate (100 mg, 0.64 mmol) in tetrahydrofuran (6 mL). After stirring at rt for 15 h, the mixture was filtered and concentrated under reduced pressure. The residue was dissolved in dichloromethane (50 mL) and washed with water (50 mL), brine (50 mL), separated, and dried over MgSO4. The mixture was filtered and concentrated under reduced pressure. Crystallization from a mixture of ether and hexane afforded afforded phenyl 5-(1-hydroxy-2-methylpropan-2-yl)isoxazol-3-ylcarbamate as a colorless solid (120 mg, 68%). 1H NMR (300 MHz, CDCl3) δ 8.30 (brs, 1H), 7.42-7.43 (m, 2H), 7.26 (m, 1H), 7.16-7.21 (m, 2H), 6.65 (s, 1H), 3.67 (s, 2H), 1.98 (brs, 1H), 1.33 (s, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[OH:13])=[C:10](F)[CH:9]=[C:8]([F:15])[CH:7]=2)#[N:2].[CH3:16][N:17]1[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]1.CC(C)([O-])C.[K+].C(O)(=O)C>O1CCCC1>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[OH:13])=[C:10]([O:23][CH:20]1[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]1)[CH:9]=[C:8]([F:15])[CH:7]=2)#[N:2]
Reactant: CN1CCC(O)CC1
Reactant: N#Cc1cnc2cc(F)cc(F)c2c1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN1CCC(Oc2cc(F)cc3ncc(C#N)c(O)c23)CC1
Temperature: 60 °C
Yield: 59 %

Procedure:
A mixture of 3-cyano-5,7-difluoro-4-hydroxyquinoline (4.12 g), 1-methylpiperidin-4-ol (2.6 g) and potassium tert-butoxide (6.72 g) in anhydrous tetrahydrofuran (250 ml) was stirred and heated at 60° C. for 2 hours. Acetic acid was added until pH6 was reached and then the solution was evaporated to dryness. The residue was dissolved in a mixture of dichloromethane and methanol (2:1) and the solution added to powdered silica gel (15 g). The suspension was evaporated to dryness and powder was packed into a preload cartridge. This was then chromatographed with an Isco Combiflash system and a Biotage 40M silica cartridge using a gradient elution of 0.6% to 30% ammonia (7.0M in methanol) in dichloromethane. The fractions containing the product were combined and evaporated. This gave the title compound as a white foam (3.55 g, 59%); NMR spectrum: (DMSOd6) 1.77 (m, 2H), 1.92 (m, 2H), 2.30 (s, 3H), 2.43 (m, 2H), 2.81 (m, 2H), 4.55 (m, 1H), 6.81 (m, 2H), 8.40 (s, 1H), Mass spectrum: M+H+ 302.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:17])[C:5]([C:12]([O:14]CC)=[O:13])=[CH:6][NH:7]2.[OH-].[Na+].Cl>>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:17])[C:5]([C:12]([OH:14])=[O:13])=[CH:6][NH:7]2
Reactant: CCOC(=O)c1c[nH]c2cccc(C)c2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cccc2[nH]cc(C(=O)O)c(=O)c12
Yield: 33.9 %

Procedure:
Ethyl 5-methyl-4-oxo-1H-quinoline-3-carboxylate (142 mg, 0.61 mmol) was suspended in an aqueous solution of NaOH (1.54 mL of 4% w/v, 1.54 mmol) and the reaction was stirred under reflux for 2 h. After cooling, the reaction mixture was acidified with conc. HCl. The resulting precipitate was collected via filtration, washed with water and dried to yield 5-methyl-4-oxo-1H-quinoline-3-carboxylic acid (42 mg, 34%). 1H NMR (400 MHz, DMSO-d6) δ 15.69 (brs, 1H), 13.81 (brs, 1H), 8.68 (d, J=6.4 Hz, 1H), 7.70-7.64 (m, 2H), 7.27 (d, J=6.4 Hz, 1H), 2.84 (s, 3H). MS (ESI) m/z: 202.2 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[CH2:6][C:5]([CH2:9]I)([CH2:7]I)[CH2:4][C:3]=1[Br:11].C([BH3-])#N.[Na+]>CN(C)P(N(C)C)(N(C)C)=O.O>[Br:1][C:2]1[CH2:6][C:5]([CH3:9])([CH3:7])[CH2:4][C:3]=1[Br:11]
Reactant: BrC1=C(Br)CC(CI)(CI)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1(C)CC(Br)=C(Br)C1
Yield: 70.1 %

Procedure:
Under nitrogen, a stirred solution of 3.7 g (7.3 mmol) of 1,2-dibromo-4,4-di(iodomethyl)cyclopentene (Step 7) and 1.3 g (20.6 mmol) of sodium cyanoborohydride in 15 mL of hexamethylphosphoramide (HMPA) was heated to 100° C. in an oil bath overnight. The reaction was cooled, diluted with 50 mL of water, and extracted 5 times with ethyl acetate/hexane (1:5). The combined extracts were washed 3 times with water, dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500) with hexane gave 1.3 g (70%) of 1,2-dibromo-4,4-dimethylcyclopentene (16 in Synthetic Scheme V) as a colorless oil: NMR (CDCl3) δ1.16 (s, 6H), 2.44 (s, 4H); MS (EI) m/e (rel intensity) 256 (24), 254 (63), 252(44), 175 (26), 173 (29), 94 (100).
Reaction SMILES: COC([C:5]1[CH:17]=[CH:16][C:8]2[NH:9][C:10]([C:12]([Cl:15])([Cl:14])[Cl:13])=[N:11][C:7]=2[CH:6]=1)=O.[CH3:18][O:19][C:20](=[O:29])C1C=CC=C(N)C=1N>>[CH3:18][O:19][C:20]([C:16]1[C:8]2[N:9]=[C:10]([C:12]([Cl:13])([Cl:14])[Cl:15])[NH:11][C:7]=2[CH:6]=[CH:5][CH:17]=1)=[O:29]
Reactant: COC(=O)c1ccc2[nH]c(C(Cl)(Cl)Cl)nc2c1
Reactant: COC(=O)c1cccc(N)c1N
Product: COC(=O)c1cccc2[nH]c(C(Cl)(Cl)Cl)nc12

Procedure:
Methyl-2-trichloromethyl-1H-benzoimidazole-4-carboxylate was prepared similarly to methyl-2-trichloromethyl-1H-benzoimidazole-5-carboxylate as described in example 5 i) starting from 2.53 g (15.1 mmol) methyl-2,3-diamino-benzoate. Yield: 4.15 g MS (ES+): m/e=293, chloro pattern.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][CH2:12][O:11][C:10]2=[O:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[BrH:15].O=S(Cl)Cl.[C:20]1(C)C=CC=CC=1>C(O)(=O)C>[CH3:20][O:11][C:10](=[O:14])[CH:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:13][CH2:12][Br:15]
Reactant: Br
Reactant: O=C1OCCC1c1ccc(Cl)c(Cl)c1
Reactant: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)C(CCBr)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
A mixture of 10.2 g (44 mmol) 3-(3,4-dichloro-phenyl)-dihydro-furan-2-one, 55 mL HBr in acetic acid (33%) in 20 mL acetic acid was stirred at room temperature for 16 h. The mixture was poured onto ice/water and extracted with isopropylethyl acetate. The combined organic phases were washed with NaCl aq., dried with Na2SO4 and evaporated. 26.3 g (221 mmol) SOCl2 and 200 mL toluene was added and heated to 80° C. for 3 h. The mixture was evaporated to dryness and 100 mL methanol was added and stirred at room temperature for 30 min. The mixture was evaporated and subjected to column chromatography on silica eluting with a gradient formed from ethyl acetate and heptane. The combined product fractions were evaporated to yield 12.7 g (88%) of the title compound as light brown oil. MS (m/e): 335.5 (MH−).
Reaction SMILES: CN1CCCCC1.[CH:8]([O:11][C:12]([NH:14][C@H:15]([C:19]([OH:21])=O)[CH:16]([CH3:18])[CH3:17])=[O:13])([CH3:10])[CH3:9].ClC(OCC(C)C)=O.[F:30][C:31]1[CH:42]=[CH:41][C:34]2[S:35][C:36]([CH:38]([NH2:40])[CH3:39])=[CH:37][C:33]=2[CH:32]=1>ClCCl>[F:30][C:31]1[CH:42]=[CH:41][C:34]2[S:35][C:36]([CH:38]([NH:40][C:19](=[O:21])[C@H:15]([CH:16]([CH3:17])[CH3:18])[NH:14][C:12]([O:11][CH:8]([CH3:9])[CH3:10])=[O:13])[CH3:39])=[CH:37][C:33]=2[CH:32]=1
Reactant: CC(C)OC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CC(N)c1cc2cc(F)ccc2s1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCCCC1
Solvent: ClCCl
Product: CC(C)OC(=O)N[C@H](C(=O)NC(C)c1cc2cc(F)ccc2s1)C(C)C
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 63.2 %

Procedure:
5.1 g of N-methylpiperidine was added to a solution containing 10.4 g of N-isopropoxycarbonyl-L-valine dissolved in 200 ml of dichloromethane, at -20° C. and then 7.0 g of isobutyl chloroformate was added dropwise to the mixture. After the mixture was stirred at -20° C. for 10 minutes, 10.0 g of 1-(5-fluorobenzo[b]thiophen-2-yl)ethylamine was added to the mixture at -50° C. After stirring at the same temperature, the mixture was allowed to sit and warm naturally to room temperature and then stirred for 15 hours at room temperature. After the reaction mixture was washed successively with 10% hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, and water, the organic layer was then dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 12.3 g of the desired product in the form of a white powder.
Reaction SMILES: [C:1]([NH:8][C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][CH:13]=1)([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].[N+:20]([O-])([OH:22])=[O:21]>C(OC(=O)C)(=O)C.C(O)(=O)C>[C:1]([NH:8][C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][C:13]=1[N+:20]([O-:22])=[O:21])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)C(=O)Nc1ccc(-c2ccccc2)s1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(=O)Nc1sc(-c2ccccc2)cc1[N+](=O)[O-]
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 81.8 %

Procedure:
2-Ethoxalylamino-5-phenylthiophene (2.75 g, 10 mmol) was dissolved in 20 ml of acetic anhydride, cooled to -15° C., and treated with a solution of 0.63 ml (10 mmol) of fuming nitric acid dissolved in 5 ml of acetic acid over a period of 30 minutes. After 10 minutes at this temperature, the solvents were evaporated, and traces of acetic acid were removed by stripping with toluene. The solid residue was suspended in 50 ml of ethanol, and 50 ml of water was slowly added. The mixture was stirred overnight, and the precipitate was isolated by filtration to yield 2.62 g (82%) of 2-ethoxalylamino-5-phenyl-3-nitrothiophene, melting at 139°-144° C. 1H-NMR (DMSO-D6, δ): 1.3 (t, 3H), 4.4 (q, 2H), 6.9 (t, 1H), 7.0 (t, 2H), 7.8 (d, 2H), 8.0 (s, 1H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:24]=[CH:23][CH:22]=[CH:21][C:11]=1[O:12][C:13]1[N:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=1[Cl:20].[Cl:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[S:36](Cl)(=[O:38])=[O:37]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:24]=[CH:23][CH:22]=[CH:21][C:11]=1[O:12][C:13]1[N:18]=[CH:17][C:16]([NH:19][S:36]([C:27]2[CH:28]=[CH:29][C:30]([C:32]([F:33])([F:34])[F:35])=[CH:31][C:26]=2[Cl:25])(=[O:38])=[O:37])=[CH:15][C:14]=1[Cl:20]
Reactant: Nc1cnc(Oc2ccccc2-c2nc3ccccc3s2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Product: O=S(=O)(Nc1cnc(Oc2ccccc2-c2nc3ccccc3s2)c(Cl)c1)c1ccc(C(F)(F)F)cc1Cl

Procedure:
The title compound was prepared by reacting 6-(2-(benzo[d]thiazol-2-yl)phenoxy)-5-chloropyridin-3-amine (obtained as per procedure described in preparation 4) and 2-chloro-4-(trifluoromethyl)benzene-1-sulfonyl chloride.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][C:4](=[S:7])[N:3]1[CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1.[CH:17]1([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[O:33][C:32]([CH:34]=O)=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(O)C>CO.ClCCl.[Cl-].[NH4+]>[CH:17]1([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[O:33][C:32]([CH:34]=[C:6]4[S:5][C:4](=[S:7])[N:3]([CH:8]5[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]5)[C:2]4=[O:1])=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: O=Cc1ccc(-c2ccc(C3CCCCC3)cc2)o1
Reactant: O=C(O)C1CCCC(N2C(=O)CSC2=S)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CCO
Solvent: ClCCl
Product: O=C(O)C1CCCC(N2C(=O)C(=Cc3ccc(-c4ccc(C5CCCCC5)cc4)o3)SC2=S)C1
Temperature: 25 °C
Reaction time: 65 h
Yield: 65.1 %

Procedure:
3-(4-oxo-2-thioxo-thiazolidin-3-yl)-cyclohexanecarboxylic acid (80 mg, 0.31 mmol), 5-(4-cyclohexyl-phenyl)-furan-2-carbaldehyde (84 mg, 0.33 mmol), and diethylenediamine diacetate (59 mg, 0.33 mmol) were combined in a 20 mL vial with ethanol (5 mL) and stirred at room temperature for 65 h. The reaction mixture was diluted with 10% methanol in dichloromethane (200 mL) and aqueous ammonium chloride (20 mL) and stirred at room temperature for 15 minutes. The layers were separated and the aqueous layer was extracted with 10% methanol in dichloromethane (2×100 mL). The combined organic extracts were washed with 0.6 N sodium hydrogensulfite (1×20 mL) and then brine (1×20 mL), dried (sodium sulfate) and concentrated under vacuum. The residue was triturated with dichloromethane/hexanes (1:5, 30 mL), filtered and dried overnight in a vacuum oven at 55° C. to afford 3-{5-[1-[5-(4-cyclohexyl-phenyl)-furan-2-yl]-methylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-cyclohexanecarboxylic acid (100 mg, 65%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 1.25-1.49 (7H, m), 1.67-1.92 (10H, m), 2.35-2.45 (2H, m), 2.56 (1H, m), 4.97 (1H, m), 7.26 (1H, d, J=3.6 Hz), 7.36 (1H, d, J=3.6 Hz), 7.42 (1H, d, J=8.4 Hz), 7.59 (1H, s), 7.77 (1H, d, J=8.4 Hz), 12.18 (1H, s); APCI-MS: 495.37; HPLC: 90%.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[N:8][NH:9][CH:10]=1)([O-:5])=[O:4].I[CH2:12][CH3:13].[Cl-:14].[NH4+]>CN(C=O)C>[Cl:14][C:10]1[N:9]([CH2:12][CH3:13])[N:8]=[CH:7][C:6]=1[N+:3]([O-:5])=[O:4]
Reactant: CCI
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: [Cl-]
Agent: [H-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1ncc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
To a suspension of sodium hydride (1 equiv, 60% in mineral oil) in DMF (0.64 M) under nitrogen atmosphere was added a solution of 4-nitro-1H-pyrazole (0.83 equiv) in DMF (3.2 M) at 0° C. The reaction mixture was stirred at room temperature for 30 min before a solution of iodoethane (1 equiv) in DMF (3.2 M) was added. The mixture was stirred at room temperature for 2 h. Saturated aqueous ammonium chloride solution (0.32 M) was added, and the solvent was removed under reduced pressure to give the crude product, which was purified by silica gel column chromatography (25% ethyl acetate in petroleum ether) to give the desire product (82.2% yield) as white solid. MS (ESI) m/z 142.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:33])=[CH:4][C:5]([F:32])=[C:6]([C:8]2[C:9](=[O:31])[N:10]([CH2:29][CH3:30])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([N:18]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH3:19])[CH:12]=3)[CH:7]=1.[F:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=1[N:42]=[C:43]=[O:44]>O1CCOCC1>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:18]([CH3:19])[C:13]2[N:14]=[CH:15][CH:16]3[CH:11]([CH:12]=2)[N:10]([CH2:29][CH3:30])[C:9](=[O:31])[C:8]([C:6]2[C:5]([F:32])=[CH:4][C:3]([F:33])=[C:2]([NH:1][C:43]([NH:42][C:36]4[CH:37]=[C:38]([F:41])[CH:39]=[CH:40][C:35]=4[F:34])=[O:44])[CH:7]=2)=[CH:17]3)=[CH:22][CH:23]=1
Reactant: O=C=Nc1cc(F)ccc1F
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2F)cc2cnc(N(C)Cc3ccc(OC)cc3)cc21
Solvent: C1COCCO1
Product: CCN1C(=O)C(c2cc(NC(=O)Nc3cc(F)ccc3F)c(F)cc2F)=CC2C=NC(N(C)Cc3ccc(OC)cc3)=CC21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
A solution of Example A7 (0.12 g, 0.266 mmol) in dioxane (5 mL) was treated with 2,5-difluorophenyl isocyanate (0.034 mL, 0.293 mmol) and stirred at RT overnight. The resulting solid was collected via filtration and dried to yield 1-(5-(7-((4-methoxybenzyl)(methyl)amino)-1-ethyl-2-oxo-1,2,4a,8a-tetrahydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-(2,5-difluorophenyl)urea (129 mg, 80% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.19 (s, 1H), 9.10 (s, 1H), 8.52 (s, 1H), 8.16 (t, 1H), 8.01-7.98 (m, 1H), 7.86 (s, 1H), 7.38 (t, 1H), 7.31-7.27 (m, 1H), 7.18 (d, 2H), 6.87 (d, 2H), 6.82-6.80 (m, 1H), 6.32 (s, 1H), 4.85 (s, 2H), 4.19 (q, 2H), 3.70 (s, 3H), 3.13 (s, 3H), 1.13 (t, 3H); MS (ESI) m/z: 606.3 [M+H]+.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][C:3]=1[CH3:21].[C:22](=[NH:35])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[C:23]1([C:22](=[N:35][C:2]2[N:7]=[CH:6][C:5]([CH:8]3[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]3)=[CH:4][C:3]=2[CH3:21])[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1cc(C2CN(C(=O)OC(C)(C)C)CCO2)cnc1Br
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc(C2CN(C(=O)OC(C)(C)C)CCO2)cnc1N=C(c1ccccc1)c1ccccc1
Temperature: 100 °C
Yield: 46 %

Procedure:
To a stirred solution of tert-butyl (RS)-2-(6-bromo-5-methylpyridin-3-yl)morpholine-4-carboxylate (1.7 g) and benzophenone imine (1.2 ml) in toluene (20 ml) was added sodium tert-butoxide (732 mg). The reaction mixture was purged with argon for 10 min. (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (296 mg) and tris(dibenzylideneacetone)dipalladium(0) (131 mg) were added and the reaction mixture was heated at 100° C. overnight. The reaction mixture was then cooled to room temperature, poured into water and extracted twice with EtOAc. The organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 75% EtOAc in hexanes) to afford tert-butyl (RS)-2-(6-(diphenylmethyleneamino)-5-methylpyridin-3-yl)morpholine-4-carboxylate (1.01 g, 46%) as a yellow foam. MS (ISP): 458.3 ([M+H]+).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=2)[C:11](Cl)=[C:10]([C:20]#[N:21])[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>ClCCl>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=2)[C:11]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[C:10]([C:20]#[N:21])[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(c1)c(Cl)c(C#N)c(=O)n2Cc1ccccc1
Reactant: C1CNCCN1
Solvent: ClCCl
Product: Cc1ccc2c(c1)c(N1CCNCC1)c(C#N)c(=O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
A solution of Compound 21 (1.2 g, 3.9 mmol) in dichloromethane was added slowly to a stirred solution of piperazine (1.67 g, 19.4 mmol) in dichloromethane at room temperature. The solution was stirred overnight at room temperature. The solvent was removed under reduced pressure. The residue was taken in water, sonicated briefly, and filtered. The solids were dissolved in ethyl acetate and washed by water. The organic layer was dried over Na2SO4 and concentrated to yield 1.34 g (96%) of yellow solids. M.P. 152° C. 1H NMR (DMSO-d6): δ 2.34 (s, 3H), 2.94 (m, 4H), 3.54 (m, 4H), 5.44 (s, 2H), 7.16–7.20 (m, 2H), 7.22 (d, J=7.6 Hz, 1H), 7.28–7.31 (m, 3H), 7.40 (d, J=8.8 Hz, 1H), 7.64 (s, 1H). EIMS m/z 359 (M+1).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]1[NH:19][NH:18][C:17]([C:21]([F:24])([F:23])[F:22])(O)[CH2:16]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[N:19]1[C:15]([C:11]2[O:10][CH:14]=[CH:13][CH:12]=2)=[CH:16][C:17]([C:21]([F:24])([F:22])[F:23])=[N:18]1)#[N:5]
Reactant: N#Cc1ccccc1F
Reactant: OC1(C(F)(F)F)CC(c2ccco2)NN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1-n1nc(C(F)(F)F)cc1-c1ccco1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
To a solution of 2-fluorobenzonitrile (0.605 g, 5 mmol) and 5-furyl-3-trifluoromethyl-3-hydroxypyrazoline (1.1 g, 5 mmol) in DMF (10 mL) was added Cs2CO3 (1.63 g, 5 mmol), and the resulting mixture was stirred at 110° C. for 16 hours. The mixture was diluted with EtOAc, washed with brine (×5), dried over MgSO4, and purified by column chromatography with a gradient solvent (hexane to ethyl acetate) to give 1-(2-cyanophenyl)-5-furyl-3-trifluoromethylpyrazole and 1-(2-cyanophenyl)-3-furyl-5-trifluoromethylpyrazole (1.27 g, 83.8%) in a ratio of 95 to 5. 1H NMR (CDCl3) δ7.82 (dd, J=7.7 Hz, J=1.5 Hz, 1H), 7.77 (dd, J=7.7 Hz, J=1.5 Hz, 1H), 7.66 (td, J=7.7 Hz, J=1.1 Hz, 1H), 7.61 (d, J=7.7 Hz, 1H), 7.39 (d, J=1.4 Hz, 1H), 6.96 (s, 1H), 6.37 (dd, J=3.3 Hz, J=1.4 Hz, 1H), 6.04 (d, J=3.3 Hz, 1H); 19F NMR (CDCl3): δ−62.98; ESMS(+): 304 (M+H, 100).
Reaction SMILES: [CH2:1]([N:3]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[S:4]N1C(=O)C2=CC=CC=C2C1=O)[CH3:2].[C:23]1([SH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1C=CC=CC=1>[C:23]1([S:29][S:4][N:3]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:1][CH3:2])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCN(Cc1ccccc1)SN1C(=O)c2ccccc2C1=O
Reactant: Sc1ccccc1
Solvent: c1ccccc1
Product: CCN(Cc1ccccc1)SSc1ccccc1
Temperature: 25 °C
Yield: 94.4 %

Procedure:
N-(N-ethylbenzylaminothio)-phthalimide (6.24 grams, 20 millimoles) was stirred in 100 milliliters of benzene and 2.2 grams (20 millimoles) of benzenethiol was added. The mixture was refluxed one hour, then cooled to room temperature and filtered to remove phthalimide. The filtrate was washed with 10 percent NaOH, then with water, dried (Na2SO4) and concentrated under reduced pressure to afford 5.2 grams (94.5%) of N-(phenyldithio)-N-ethylbenzylamine as a pale yellow liquid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15](=[O:28])[NH:16][C:17]2[C:18](=[O:27])[N:19]([CH3:26])[C:20](=[O:25])[N:21]([CH3:24])[C:22]=2[NH2:23])=[CH:10][CH:9]=1)(C)(C)C.[ClH:30]>O1CCOCC1>[ClH:30].[NH2:23][C:22]1[N:21]([CH3:24])[C:20](=[O:25])[N:19]([CH3:26])[C:18](=[O:27])[C:17]=1[NH:16][C:15](=[O:28])[CH2:14][C:11]1[CH:10]=[CH:9][C:8]([NH2:7])=[CH:13][CH:12]=1
Reactant: Cn1c(N)c(NC(=O)Cc2ccc(NC(=O)OC(C)(C)C)cc2)c(=O)n(C)c1=O
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(N)c(NC(=O)Cc2ccc(N)cc2)c(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Crude {4-[(6-amino-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-ylcarbamoyl)-methyl]-phenyl}-carbamic acid tert-butyl ester (0.65 mmol) was added to a 4M solution of hydrogen chloride in p-dioxane (10 mL) and the mixture stirred at ambient temperature for 2 hrs. The precipitate was isolated by filtration, washed with p-dioxane and ether then dried in vacuo to give crude N-(6-amino-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)-2-(4-amino-phenyl)-acetamide hydrochloride salt as a light beige solid which was of sufficient purity for subsequent use without additional purification (quantitative).
Reaction SMILES: [C:1]([C:3]1[C:8]([CH:9]([CH3:11])[CH3:10])=[CH:7][C:6]([S:12]([NH2:15])(=[O:14])=[O:13])=[C:5]([CH:16]([CH3:18])[CH3:17])[CH:4]=1)#[N:2].[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[C:19]([NH:15][S:12]([C:6]1[CH:7]=[C:8]([CH:9]([CH3:11])[CH3:10])[C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH:16]([CH3:18])[CH3:17])(=[O:14])=[O:13])(=[O:21])[CH3:20]
Reactant: CC(C)c1cc(S(N)(=O)=O)c(C(C)C)cc1C#N
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NS(=O)(=O)c1cc(C(C)C)c(C#N)cc1C(C)C

Procedure:
A mechanically stirred mixture of 8 parts of 4-cyano-2,5-diisopropylbenzenesulfonamide and 50 parts of acetic anhydride was heated near reflux for 6 hours. The reaction was concentrated in vacuo to give a solid which was recrystallized from ethanol-water, and then exhibited a m.p. of 170°-173°.