Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH2:10][CH:9]1[C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[C:13]([C:22]2[CH:31]=[C:30]3[C:25]([C:26]([CH3:36])([CH3:35])[CH2:27][C:28](=[O:34])[N:29]3[CH2:32][CH3:33])=[CH:24][C:23]=2[CH3:37])[CH:12]=1)=[O:7])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:32]([N:29]1[C:30]2[C:25](=[CH:24][C:23]([CH3:37])=[C:22]([C:13]3[CH:12]=[C:11]([CH:9]4[CH2:10][CH:8]4[C:6]([OH:7])=[O:5])[CH:16]=[CH:15][C:14]=3[O:17][C:18]([F:20])([F:19])[F:21])[CH:31]=2)[C:26]([CH3:36])([CH3:35])[CH2:27][C:28]1=[O:34])[CH3:33]
Reactant: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(C4CC4C(=O)OC(C)(C)C)ccc3OC(F)(F)F)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(C4CC4C(=O)O)ccc3OC(F)(F)F)cc21

Procedure:
A solution of Compound 40A in CH2Cl2 (2 mL) and TFA (1 mL) was stirred at r.t. overnight afterwhich the solvent was removed in vacuo to obtain the desired product (Compound 40) as pale yellow powder (0.036 g). The compound is racemic (i.e. mixture of both enantiomers). The designated “trans” stereochemistry merely describes the relative stereochemistry for the two substituents on the cyclopropane ring. MS (electrospray): mass calculated for C25H26F3NO4, 461.18; m/z found 462 [M+H]+.
Reaction SMILES: C([O:4][CH2:5][CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)(=O)C.Cl[Si]([CH2:22][CH3:23])(CC)CC.C1(C)C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1C[O:44]CC1>>[Cl:15][C:10]1[CH:9]=[C:8]([CH:7]([CH:22]=[CH2:23])[CH2:6][C:5]([OH:4])=[O:44])[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: CC(=O)OCC=Cc1ccc(Cl)c(Cl)c1
Reactant: C1CCOC1
Reactant: CC[Si](Cl)(CC)CC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=CC(CC(=O)O)c1ccc(Cl)c(Cl)c1
Temperature: 23 °C
Reaction time: 3 h

Procedure:
Treat a solution of the product of Step 3 (15 g, 61 mmol, dried by azeotropic distillation with toluene, 1×50 mL) in dry THF (250 mL) at -78° C. with chlorotriethylsilane (20.2 mL, 120 mmol), rapidly followed by the addition of 0.5M toluene solution of potassium bis(trimethylsilyl)amide (183 mL, 91.5 mmol) via addition funnel over 50 min. Allow the mixture to warm to 23° C., then heat to reflux for 3 h. Allow the solution to gradually cool overnight, then quench with saturated NH4Cl (150 mL). Stir the resulting mixture vigorously for 3 h, treat with 1M HCl (150 mL) and extract with Et2O (500 mL). Extract the aqueous layer with Et2O (400 mL) and wash the combined organic layers with 300 mL of 5% NaOH followed by 8×150 mL of 5% NaOH. Cool the combined aqueous layers to 5° C. and carefully (temperature kept to 5°-10° C.) acidify with conc. HCl (ca 175 mL) to pH 1. Extract the aqueous layer with CH2Cl2 (2×800 mL), dry (Na2SO4) and concentrate to give 3-(3,4-di-chlorophenyl)-4-pentenoic acid as a faint yellow oil, 13.4 g (54.5 mmol, 89%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].[C:23](=O)([O-])[O-].[Cs+].[Cs+].BrC[CH2:31][CH2:32][CH2:33][CH3:34]>O1CCOCC1>[C:32]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22])([CH2:33][CH3:34])([CH3:23])[CH3:31]
Reactant: CCCCCBr
Reactant: O=C([O-])[O-]
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCC(C)(C)N1C(=O)[C@@]2(COc3cc4c(cc32)OCCO4)c2ccccc21
Temperature: 25 °C
Yield: 71.6 %

Procedure:
A suspension of (S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (1.0 g, 3.4 mmol), cesium carbonate (3.3 g, 10.2 mmol) and 1-bromopentane (1.02 g, 6.77 mmol) in anhydrous 1,4-dioxane (25 mL) was heated at reflux under nitrogen for 2 h. The reaction mixture was allowed to cool to ambient temperature, filtered and concentrated in vacuo. Purification of the residue by column chromatography and eluted with a 15% to 50% gradient of ethyl acetate in hexanes, followed by recrystallization from methanol afforded (S)-t-pentyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one as an off-white solid (0.89 g, 72%): mp 111-113° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.23-7.30 (m, 1H), 7.13 (dd, J=7.4, 0.9 Hz, 1H), 7.00-7.03 (m, 1H), 6.89 (d, J=7.8 Hz, 1H), 6.46 (s, 1H), 6.19 (s, 1H), 4.73 (ABq, 2H), 4.19-4.05 (m, 4H), 3.86-3.59 (m, 2H), 1.82-1.62 (m, 2H), 1.43-1.28 (m, 4H), 0.89 (t, J=6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ177.2, 155.2, 144.5, 142.4, 138.2, 132.5, 128.7, 123.9, 123.0, 121.1, 111.4, 108.5, 99.3, 80.1, 64.5, 63.9, 58.0, 40.3, 29.0, 27.1, 22.3, 14.0; MS (ES+) m/z 366.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.N1C=CC=[CH:18][CH:17]=1>ClCCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[CH2:8][C:9](=[O:11])[CH2:18][CH2:17]2
Reactant: c1ccncc1
Reactant: O=C(O)Cc1ccc(F)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: O=C1CCc2cc(F)ccc2C1
Reaction time: 0.5 h

Procedure:
To a solution of 30 g of 4-fluorophenylacetic acid and 48.9 g of thionyl chloride in 60 ml of 1,2-dichloroethane was added a catalytic quantity of pyridine, and the solution was then refluxed for 5 hours under an atmosphere of nitrogen. Following removal of the 1,2-dichloroethane, the product was added dropwise to an ice cooled suspension of 48.6 g of aluminum chloride in 200 ml of dichloromethane. Following stirring for 30 minutes, ethylene gas was blown into the reaction vessel, and after a further 5 hours of stirring, dilute hydrochloric acid was added, and following separation of the organic layer, the aqueous layer was extracted with toluene. The toluene extract was combined with the organic layer and washed subsequently with water, a saturated aqueous solution of sodium bicarbonate, water, and a saturated aqueous solution of sodium chloride, and was then dried over anhydrous sodium sulfate and the solvent removed by evaporation, and subsequently purified by distillation (75° C., 2 Torr) to obtain 19.4 g of 6-fluoro-3,4-dihydro-2(1H)-naphthalenone.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]3[N:15](C(OC(C)(C)C)=O)[CH2:14][C:13]4([CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:10]3=[N:11][CH:12]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]3[NH:15][CH2:14][C:13]4([CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:10]3=[N:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CC2(CCOCC2)c2ncc(N3CCOCC3)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1nc2c(cc1N1CCOCC1)NCC21CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of tert-butyl 6′-morpholino-2,3,5,6-tetrahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine]-1′(2′H)-carboxylate (5.8 g, 15.45 mmol) in DCM (30 mL) was added TFA (23.80 mL, 309 mmol) and the reaction was stirred at rt for 3 h. After this time the reaction was evaporated under reduced pressure and dried under vacuum overnight. After this time the reaction was partitioned between EtOAc (80 mL) and 1.0M aqueous HCl (200 mL). The separated aqueous layer was washed with EtOAc (40 mL). The aqueous layer was then basified to pH 14 with aqueous NaOH and extracted with EtOAc (2×200 mL) and DCM (100 mL). The combined organic layers were dried over MgSO4, filtered and evaporated in vacuo to give 6′-morpholino-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] as a white solid. Mass Spectrum (ESI) m/e=276.2 (M+1)
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:3]=1[C:4]([NH:6][CH2:7][C:8](=[O:14])[NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:5].[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O>C(O)(=O)C.C(O)C>[Br:19][C:16]1[CH:15]=[C:3]2[C:2](=[CH:18][CH:17]=1)[NH:1][CH:24]([C:23]1[CH:26]=[CH:27][CH:28]=[C:21]([Cl:20])[CH:22]=1)[N:6]([CH2:7][C:8]([NH:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[O:14])[C:4]2=[O:5]
Reactant: O=Cc1cccc(Cl)c1
Reactant: CC(C)(C)NC(=O)CNC(=O)c1cc(Br)ccc1N
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)NC(=O)CN1C(=O)c2cc(Br)ccc2NC1c1cccc(Cl)c1
Temperature: 85 °C
Reaction time: 16 h
Yield: 60.5 %

Procedure:
In a capped 20 mL scintillation vial, a solution of 2-amino-5-bromo-N-(tert-butylcarbamoylmethyl)benzamide (0.65 g, 2.0 mmol), 3-chlorobenzaldehyde (0.27 mL, 2.4 mmol) and catalytic glacial acetic acid (2 drops) in anhydrous ethanol (10 mL) was heated with stirring at 85° C. for 16 h. The resulting white suspension was cooled to room temperature, the white solid collected by suction filtration and washed with cold EtOH to give 2-[6-bromo-2-(3-chlorophenyl)-4-oxo-1,4-dihydro-2H-quinazolin-3-yl]-N-tert-butylacetamide (0.53 g, 1.21 mmol, 58%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:10])[C:3]=1[N+:11]([O-:13])=[O:12].C1(O)C=CC=CC=1.[CH3:21][O:22][C:23](=[O:27])[CH:24](Br)[CH3:25]>>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH:24]([CH3:25])[C:23]([O:22][CH3:21])=[O:27])=[C:3]([N+:11]([O-:13])=[O:12])[C:4]=1[CH3:10])=[O:7]
Reactant: COC(=O)C(C)Br
Reactant: Cc1c(C=O)ccc(O)c1[N+](=O)[O-]
Solvent: Oc1ccccc1
Product: COC(=O)C(C)Oc1ccc(C=O)c(C)c1[N+](=O)[O-]

Procedure:
Using 4-hydroxy-2-methyl-3-nitrobenzaldehyde as the phenol and methyl-2-bromopropanoate as the alkylating agent in the general procedure for alkylation of substituted-2-nitrophenols gives the title compound as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51 (d, J=6.82 Hz, 3 H) 2.50 (s, 3H) 3.69 (s, 3H) 5.40 (q, J=6.82 Hz, 1H) 7.29 (d, J=9.09 Hz, 1H) 8.00 (d, J=8.84 Hz, 1H) 10.12 (s, 1H). ESI-MS: m/z 268.2 (M+H)+.
Reaction SMILES: I[CH2:2][C:3]1([CH3:19])[O:18][C:6]2=[C:7]([CH3:17])[C:8]3[CH2:9][C:10]([CH3:16])([CH3:15])[NH:11][C:12]=3[C:13]([CH3:14])=[C:5]2[CH2:4]1.[C:20]1([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[K].O>CN(C)C(=O)C>[CH3:19][C:3]1([CH2:2][N:29]2[CH2:30][CH2:31][CH:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:27][CH2:28]2)[O:18][C:6]2=[C:7]([CH3:17])[C:8]3[CH2:9][C:10]([CH3:16])([CH3:15])[NH:11][C:12]=3[C:13]([CH3:14])=[C:5]2[CH2:4]1
Reactant: Cc1c2c(c(C)c3c1NC(C)(C)C3)OC(C)(CI)C2
Reactant: c1ccc(C2CCNCC2)cc1
Agent: [K]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1c2c(c(C)c3c1NC(C)(C)C3)OC(C)(CN1CCC(c3ccccc3)CC1)C2
Temperature: 180 °C
Reaction time: 3 h
Yield: 61.5 %

Procedure:
A suspension of 3,5,6,7-tetrahydro-2-(iodomethyl)-2,4,6,6,8-pentamethyl-2H-furo[2,3-f]indole (1.11 g, 2.99 mmol), 4-phenylpiperidine (723 mg, 4.48 mmol) and potassium carboante (826 mg, 5.98 mmol) in N,N-dimethylacetamide (6 ml) was stirred for 3 hours at 180° C. under nitrogen atmosphere. To the reaction mixture was added water, and extracted three times with ethyl acetate. The organic layers were combined, washed with water and saturated brine, dried over magnesium sulfate, treated with an active charcoal, filtered and then concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to obtain 744 mg of the title compound.
Reaction SMILES: ClC1C([N:8]2[C:12]([C:13]#N)=[C:11]([C:15]([F:18])([F:17])[F:16])[C:10]([C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])=[N:9]2)=NC=CC=1.[OH-:26].[Na+].C[OH:29]>O>[F:24][C:19]([F:25])([C:10]1[C:11]([C:15]([F:18])([F:17])[F:16])=[C:12]([C:13]([OH:29])=[O:26])[NH:8][N:9]=1)[C:20]([F:23])([F:22])[F:21]
Reactant: CO
Reactant: [OH-]
Reactant: N#Cc1c(C(F)(F)F)c(C(F)(F)C(F)(F)F)nn1-c1ncccc1Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)c1[nH]nc(C(F)(F)C(F)(F)F)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 168 h

Procedure:
4.9 g (12.5 mmol) of 3-chloro-2-[5-cyano-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazol-1-yl]pyridine are dissolved in 24 ml of methanol and admixed with 32.6 ml (494 mmol) of 50% strength sodium hydroxide solution (494 mmol). The reaction mixture is stirred for 7 days at room temperature. The reaction mixture is diluted with 10 ml of water and then concentrated to half the volume by evaporation. The mixture is then dripped onto concentrated hydrochloric acid with ice. The colourless solid which precipitates out is filtered off and dried in vacuo. This gives 2.95 g of 3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (79%) as a colourless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:29][CH3:30])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([OH:24])=O)[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CCOC(C)=O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:29][CH3:30])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:39][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:24])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: NCc1ccccc1
Reactant: CSc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CSc1nc(-c2cc(C(=O)NCc3ccccc3)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C

Procedure:
3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (0.15 g, 0.342 mmol) was dissolved in CH2Cl2 (10 mL) and stirred under argon at room temperature. N-Benzylamine (0.11 g, 1.03 mmol) was added followed by EDC (0.082 g, 0.41 mmol) and HOBT (0.055 g, 0.41 mmol). The reaction was stirred overnight. The solvents were pumped off in vacuo, and the residue taken up in EtOAc and washed twice with H2O, once with brine, dried over anhydrous Na2SO4 filtered and evaporated. The residue was flash chromatographed on silica gel (20 g) eluted with 0-1.5% MeOH/CH2Cl2 to give the title compound. mp (dec) 124-130° C. LC-MS m/z 529 (M+H)+, 2.36 min (ret time).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[C:11]1([C:17]([CH:19]([Br:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1C=CC=CC=1>[Br-:26].[C:11]1([C:17]([CH:19]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][NH+:2]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:18])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(c1ccccc1)C(Br)c1ccccc1
Reactant: c1ccc2cnccc2c1
Solvent: c1ccccc1
Product: O=C(c1ccccc1)C(c1ccccc1)c1[nH+]ccc2ccccc12
Product: [Br-]
Reaction time: 8 h

Procedure:
A solution of isoquinoline(10 g) and desylbromide (10 g) in dry benzene (50 ml) was stirred at 40° for seven hours. The suspension was allowed to stand overnight, and the benzene solution decanted off. The solid was ground to a powder, washed well with ether, and dried. Yield 12.3 g (85%), m.p. 239°-241° (Found C 68.3; H 4.6; N 3.4, Required C 68.3; H 4.5; N 3.5).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:14][N:15]([CH3:17])[CH3:16])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].ClC(Cl)(O[C:22](=[O:28])OC(Cl)(Cl)Cl)Cl.[CH2:30]([NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>>[CH3:17][N:15]([CH3:16])[CH2:14][C@H:2]([NH:1][C:22]([N:42]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:28])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: CCCCCCCCCCCCNc1ccccc1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: CCCCCCCCCCCCN(C(=O)N[C@H](CC(=O)OCc1ccccc1)CN(C)C)c1ccccc1

Procedure:
According to the method described in example S40a, (R)-benzyl 3-amino-4-(dimethylamino)butanoate is reacted with of triphosgene and N-dodecylaniline to yield (R)-benzyl 4-(dimethylamino)-3-(3-dodecyl-3-phenylureido)butanoate. According to the methods described in example S40b,c the preceding benzyl ester is converted to the title compound.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)C(=O)[C:3]=1[C:24](=O)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1.O.[NH2:38][NH2:39].[C:40](=[O:43])([O-])O.[Na+]>CN(C=O)C>[F:20][C:19]([F:22])([F:21])[O:18][C:14]1[CH:13]=[C:12]([N:5]2[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]3[NH:38][N:39]=[C:24]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:33])[F:35])[CH:27]=4)[C:3]=3[C:40]2=[O:43])[CH:17]=[CH:16][CH:15]=1
Reactant: O=C([O-])O
Reactant: NN
Reactant: O=C(Cc1cccc(C(F)(F)F)c1)c1c(O)c2cccnc2n(-c2cccc(OC(F)(F)F)c2)c1=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cc3cccc(C(F)(F)F)c3)n[nH]c2c2cccnc2n1-c1cccc(OC(F)(F)F)c1
Temperature: 105 °C
Reaction time: 1 h
Yield: 4.8 %

Procedure:
To a suspension of 4-hydroxy-1-(3-trifluoromethoxyphenyl)-3-(3-trifluoromethylphenylacetyl)-1,8-naphthyridin-2(1H)-one (254 mg, 0.50 mmol) produced in Synthesis Example 21 in DMF (5 mL) was added hydrazine monohydrate (purity of 80%, 97 μL), and the mixture was stirred at 100 to 110° C. for 1 hour. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, recrystallized from ethanol, and dried to give 5-(3-trifluoromethoxyphenyl)-3-(3-trifluoromethylbenzyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one (12 mg, yield 4.8%).
Reaction SMILES: N1[CH:5]=[CH:4]N=C1.[CH2:6]([Si:8](Cl)([CH2:11][CH3:12])[CH2:9][CH3:10])[CH3:7].[OH2:14]>CN(C)C=O>[CH2:6]([Si:8]([O:14][Si:8]([CH2:4][CH3:5])([CH2:9][CH3:10])[CH2:6][CH3:7])([CH2:11][CH3:12])[CH2:9][CH3:10])[CH3:7]
Reactant: O
Reactant: CC[Si](Cl)(CC)CC
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)O[Si](CC)(CC)CC
Reaction time: 12 h

Procedure:
A solution of 205 (15 mmol) in dimethylformamide (30 mL) is cooled to 0° C. and treated with imidazole (30 mmol) and triethylsilyl chloride (20 mmol). The resultant solution is warmed to room temperature. After 12 h, the reaction mixture is poured into 300 mL of water and extracted with ether (3×40 mL). The ethereal extracts are washed with water (2×25 mL) and saturated aqueous brine (25 mL), dried over magnesium sulfate and concentrated in vacuo. The residue is purified by flash chromatography to afford 206.
Reaction SMILES: [C:1]([O:8]C)(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-])=[O:5].[NH:10]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([O-:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[NH2:11].C(=O)([O-])[O-].[Na+].[Na+].Cl>O>[C:1]([CH:2]1[CH2:3][C:4](=[O:5])[N:10]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([OH:21])(=[O:19])=[O:20])=[CH:14][CH:13]=2)[NH:11]1)([OH:8])=[O:7]
Reactant: COC(=O)/C=C\C(=O)[O-]
Reactant: NNc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C1CC(=O)N(c2ccc(S(=O)(=O)O)cc2)N1
Temperature: 100 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
110 parts of monomethyl maleate are added with stirring to 800 parts of water containing 152 parts of p-hydrazinobenzene sulphonate and 88 parts of sodium carbonate. The mixture is warmed until all reactants are in solution and the pH is adjusted by addition of sodium carbonate to 7.0. The resulting solution is heated at 100° C for 9 hours during which period the pH is adjusted to 7.0 after 6 hours. On completion of heating, the pH is adjusted to 3.8 by addition of hydrochloric acid and the 3-carboxy-1-(4'-sulphophenyl)-5-pyrazolidone thus formed is filtered off and dried between 50°-100° C. The actual weight yield is 266 parts of strength 77% (determined by N.M.R.) which represents a yield of 85% theory.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[N+:8]([C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1)([O-:10])=[O:9].Cl[C:19]1[CH:20]=[CH:21][N:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[C:24]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:23]2=[O:34]>O.C(OCC)(=O)C>[N+:8]([C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[O:17][C:19]1[CH:20]=[CH:21][N:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[C:24]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:23]2=[O:34])([O-:10])=[O:9]
Reactant: CCOC(=O)c1ccc2cc(Cl)ccn2c1=O
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc2cc(Oc3cccc([N+](=O)[O-])c3)ccn2c1=O
Reaction time: 2 h
Yield: 67 %

Procedure:
An oven-dried 50 ml three-necked round-bottom flask was purged with argon and charged with sodium hydride (200 mg, 60% suspension in oil, 5 mmol and washed with hexane) and 10 ml dry DMF. To this suspension, m-nitrophenol (626 mg, 4.5 mmol) was added in one portion. After gas evolution had ceased, ethyl 8-chloro-4-oxo-4H-quinolizine-3-carboxylate (2) (1.00 g, 4 mmol) was added in one portion and stirring was continued at room temperature for 2 h. When the reaction was complete as indicated by thin layer chromatography (ethyl acetate), the reaction mixture was poured into 250 ml of water. The aqueous layer was extracted three times with 200 ml dichloromethane, and the combined organic layers were washed three times with 200 ml water. The organic solvent was evaporated and the crude product was stirred overnight with 30 ml ether. Filtration gave a bright yellow solid (950 mg, 67%). M.p. 161-163° C. 1H NMR (δ, CDCl3): 1.42 (t, J=7 Hz, 3H), 4.41 (q, J=7 Hz, 2H), 6.39 (d, J=8 Hz, 1H), 6.70 (d, J=2 Hz, 1H), 6.99 (dd, J=0.5 Hz, J=7 Hz, 1H), 7.55 (d, J=7 Hz, 1H), 7.72 (dd, J=8 Hz, J=8 Hz, 1H), 8.07 (s, 1H), 8.24 (d, J=8 Hz, 1H), 8.32 (d, J=8 Hz, 1H), 9.43 (d, J=7 Hz, 1H). MS: m/z 354.0850; required for C18H14N2O6: 354.0852.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][N:11]=[C:12]2[Cl:17].CN([CH:21]=[O:22])C>>[Cl:17][C:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[C:7]([CH:21]=[O:22])[C:8]=2[CH:9]=[CH:10][N:11]=1
Reactant: CN(C)C=O
Reactant: Clc1nccc2c(Br)cccc12
Agent: [Li]CCCC
Product: O=Cc1cccc2c(Cl)nccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 39.1 %

Procedure:
A solution of n-BuLi (1.76 mL, 2.5 M in hexanes, 4.4 mmol) was added to a stirred solution of 5-bromo-1-chloroisoquinoline (Braye, E.; Eloy, F.; Hoogzand, C.; Lenaers, R. Eur. J. Med. Chem., Chim. Therap. 1974, 9, 197) (1.0 g, 4.12 mmol) in THF-ether (36 mL, 1:1) at −78° C. under N2. After 20 minutes, DMF (0.66 mL, 8.5 mmol) was added and after an additional 30 minutes at −78° C. the reaction was quenched with EtOH (3 mL) and warmed to room temperature. The mixture was diluted with ether (150 mL), washed with saturated NH4Cl (50 mL), brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by column chromatography upon silica gel using hexanes-EtOAc (95:5 to 50:50) as eluant to give 1-chloro-5-isoquinolinecarboxaldehyde (308 mg, 1.61 mmol) as a white solid.
Reaction SMILES: [SH2:1].[NH2:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][N:6]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:4]=1.O>N1C=CC=CC=1>[NH2:2][C:3]1[C:8]([C:9](=[S:1])[NH2:10])=[CH:7][N:6]=[C:5]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:4]=1
Reactant: S
Reactant: N#Cc1cnc(-c2ccccc2)nc1N
Solvent: O
Solvent: c1ccncc1
Product: NC(=S)c1cnc(-c2ccccc2)nc1N
Reaction time: 8 h

Procedure:
Hydrogen sulfide is passed through a solution of 4-amino-2-phenyl-5-pyrimidinecarbonitrile (9.811 g., 0.050 mole) in dry pyridine (125 ml.) for one hour. The emerald green solution is stored overnight at 5° C. The solution is poured into water (500 ml.) with stirring. After stirring for one hour at ambient temperature, the pale yellow solid which separated is collected by filtration, dried at 110° C./0.1 mm. The yield of product melting at 197° C. dec. (uncorr.) was 10.481 g. (91.0%). The initial product is recrystallized from toluene (Darco G-60) affording yellow needles melting at 198° C. dec. (uncorr.) in a yield of 7.733 g. (67.1%).