Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH2:23][C:24]1[CH2:29][N:28]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26][CH:25]=1)=[N+]=[N-]>C1COCC1.O>[NH2:20][CH2:23][C:24]1[CH2:29][N:28]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)NN1CCC=C(CN=[N+]=[N-])C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NN1CCC=C(CN)C1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
Triphenylphosphine on polystyrene (5.24 g) was added to a solution of tert-butyl 5-azidomethyl-3,6-dihydro-2H-pyridine-1-carbamate (1 g, 4.2 mmol) in THF (25 ml) and water (0.250 ml). The reaction mixture was shaken at room temperature for 36 hours. The polymer was filtered off and then washed with THF. The filtrate was concentrated.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[CH2:31]([O:33][C:34]([C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)=[O:35])[CH3:32].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:31]([O:33][C:34](=[O:35])[C:36]1[CH:37]=[CH:38][CH:39]=[C:40]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:30])[CH2:3][CH2:4]2)=[O:9])[CH:41]=1)[CH3:32]
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc32)c1
Yield: 29 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), 3-ethoxycarbonylphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light yellow foam (29%).
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:17]([NH2:19])[CH3:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][N:25]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[CH:1]1([N:7]2[C:11]3[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:17]([NH:19][C:21]2[N:29]=[CH:28][N:27]=[C:26]3[C:22]=2[N:23]=[CH:24][NH:25]3)[CH3:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1C1CCCCC1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1C1CCCCC1
Temperature: 100 °C

Procedure:
(S)-1-(1-Cyclohexyl-6-fluoro-1H-benzoimidazol-2-yl)ethylamine (0.41 g, 1.56 mmol) was dissolved in n-butanol (5 mL) and 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (0.374 g, 1.56 mmol) and DIPEA (1.38 mL, 7.82 mmol) added. The reaction mixture was heated to 100° C. overnight. The resultant mixture was allowed to cool to RT and was concentrated in vacuo. The residue was passed down an Isolute® SCX-2 cartridge, eluting with DCM, MeOH and 2M NH3 in MeOH to afford crude product. This was purified by column chromatography (silica gel, gradient 0-10% MeOH in DCM) to afford 201 as a pale yellow gum, which solidified on standing (204 mg, 35%). LCMS (Method K): RT 3.31 min [M+H]+ 380.1 1H NMR (DMSO-d6, 400 MHz): δ 8.30 (1H, s), 8.15 (1H, s), 8.04 (1H, s), 7.66-7.54 (2H, m), 7.02 (1H, td, J=9.29, 2.34 Hz), 6.00 (1H, s), 4.51-4.37 (1H, m), 2.27-2.13 (1H, m), 2.07-1.95 (1H, m), 1.88-1.75 (2H, m), 1.70 (3H, d, J=6.70 Hz), 1.64-1.44 (3H, m), 1.39-1.26 (2H, m), 0.75-0.57 (1H, m)
Reaction SMILES: [C:1]([C:3](=[N:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:4]([NH:6][CH2:7][CH2:8][CH3:9])=[O:5])#[N:2].[Cl-].[Al+3].[Cl-].[Cl-].C(OCC)(=O)C>C1(C)C=CC=CC=1>[NH2:2][C:1]1[C:17]2[C:12](=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]=[CH:15][CH:16]=2)[N:11]=[N:10][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH3:9])=[O:5]
Reactant: CCCNC(=O)C(C#N)=NNc1ccccc1-c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCNC(=O)c1nnc2c(-c3ccccc3)cccc2c1N
Temperature: 25 °C
Yield: 93.9 %

Procedure:
To a suspension of the product of Example A (9.50 g) in dry toluene (150 ml) was added aluminum chloride (14.44 g). The mixture was stirred under nitrogen at reflux (110°) for three hours. The reaction mixture was then cooled to room temperature, and the toluene was decanted from the dark, oily layer into a flask. The oily layer was chilled to 0°, and aqueous sodium hydroxide (1 Liter of 20% w/v solution) was slowly added with stirring to produce a yellow suspension which was stirred with the previously decanted toluene and ethyl acetate (1 Liter) until the precipitate dissolved. The organic layer was separated and the aqueous layer was extracted two times with ethyl acetate (500 ml each time). The extracts were combined, washed with water (1 Liter) and saturated NaCl (500 ml), dried, and evaportated in vacuo to provide 8.92 g (94% yield) of a yellow solid. The solid was purified by flash chromatography over silica gel. Elution with dichloromethane/acetonitrile (95:5) provided the title compound as 7.70 g (81% yield) of an off white solid. Recrystallization from toluene/hexane provided 6.43 g (68% yield) of white crystals m.p. 153°-155°. A second recrystallization from toluene/hexane provided the title compound as white crystals, m.p. 153°-155°. 1H NMR (CHCl3 -d, characteristic peaks only): 1.00 (t, 3H), 1.66 (sextet, 2H), 3.46 (q, 2H), 7.43-7.54 (m, 3H), 7.69-7.88 (m, 5H), 8.60 (br.t, exchangeable, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]2=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=C1CCCc2c1[nH]c1ccc(Cl)cc21
Reactant: Nc1ccccc1
Product: Clc1ccc2[nH]c3c(c2c1)CCCC3Nc1ccccc1

Procedure:
6-Chloro-N-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-one and aniline in a similar manner as described in Example 13 to give 200 mg (74% yield) of a yellow solid. 1H-NMR (CDCl3): δ 8.04 (s, 1H), 7.46 (d, 1H), 7.27-7.20 (m, 2H), 7.17 (dd, 1H), 7.10 (dd, 1H), 6.79 (m, 1H), 6.74 (m, 2H), 4.81 (m, 1H), 3.85 (s, 1H), 2.70 (m, 2H), 2.25 (m, 1H), 2.03 (m, 1H), 1.93-1.78 (m, 2H); MS m/z 295 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[C:5]2[OH:13].[N+:14]([O-])([OH:16])=[O:15]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([N+:14]([O-:16])=[O:15])=[C:5]2[OH:13]
Reactant: O=[N+]([O-])O
Reactant: O=c1cc(O)c2cc(Br)ccc2[nH]1
Solvent: CC(=O)O
Product: O=c1[nH]c2ccc(Br)cc2c(O)c1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
A suspension of 6-bromo-4-hydroxycarbostyril (2.23g, 0.0093 mole) in glacial acetic acid (15 ml) was swirled during the addition of concentrated nitric acid (2.5 ml, d, 1.42). On heating at 100° C for several minutes a thick yellow solid separated. After cooling, ethanol (40 ml) was added and the mixture filtered and the solid washed free of nitric acid with ethanol. Drying in vacuo over P2O5 gave the title compound, m.p. 231°-4° C (d). (Found; C, 37.83; H, 1.74; N, 9.77; Br, 28.33; C9H5N2BrO4 requires; C, 37.92; H, 1.77; N, 9.83; Br, 28.03%).
Reaction SMILES: CC(C)([O-])C.[K+].[Si:7]([O:14][CH2:15][CH2:16][OH:17])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[Cl:18][C:19]1[CH:20]=[C:21]([N+:26]([O-:28])=[O:27])[CH:22]=[CH:23][C:24]=1F>C1COCC1>[C:10]([Si:7]([O:14][CH2:15][CH2:16][O:17][C:24]1[CH:23]=[CH:22][C:21]([N+:26]([O-:28])=[O:27])=[CH:20][C:19]=1[Cl:18])([CH3:9])[CH3:8])([CH3:12])([CH3:13])[CH3:11]
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)OCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc([N+](=O)[O-])cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 102.2 %

Procedure:
Potassium tert-butoxide (354 mg, 3.2 mmol) was added in one portion to a stirred solution of 2-((tert-butyldimethylsilyl)oxy)ethan-1-ol (506 mg, 2.9 mmol) in THF (3 mL) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 30 min then 3-chloro-4-fluoronitrobenzene (251 mg, 1.4 mmol) was added in one portion (reaction turned dark color). The mixture was stirred at 0° C. for 10 min then the ice-bath removed, the reaction was allowed to warm to room temperature (10 min) and stirred for 1 hr. The solvent was removed under vacuum and the residue partitioned between EtOAc (50 mL) and H2O (50 mL). The aqueous layer was extracted with EtOAc (2×50 mL) and the combined organic layers dried (Na2SO4), filtered and the solvent removed under vacuum to leave the product as an oil (yield assumed quantitative=475 mg). The product was used in the next step without further purification.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][C@@H:6](O)[CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])#[N:2].C(N(S(F)(F)[F:22])CC)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[C:1]([C@@H:3]1[CH2:7][C@H:6]([F:22])[CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])#[N:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C#N
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C#N
Temperature: -30 °C

Procedure:
(2S,4R)-tert-Butyl 2-cyano-4-hydroxypyrrolidine-1-carboxylate 13d (49.7 g, 0.2344 mol) was dissolved in 1130 mL of dichloromethane with stirring under argon atmosphere. The mixture was cooled to −30° C. followed by addition of diethylaminosulfur trifluoride (56.7 g, 0.3516 mol). After stirred for 45 minutes, the reaction mixture was warmed up to −5° C. Then the mixture was reacted overnight at room temperature. The reaction was monitored by TLC until the disappearance of the starting materials. The reaction mixture was neutralized with saturated aqueous sodium carbonate solution to pH >7 at such a rate that the reaction temperature was kept below 20° C. Then ice water and 500 mL of dichloromethane were added. The separated organic phase was washed with 500 mL of saturated aqueous sodium hydrogen sulfate and 500 mL of saturated brine successively, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure in which the concentration temperature was kept below 38° C. to obtain the title compound (2S,4S)-tent-butyl 2-cyano-4-fluoropyrrolidine-1-carboxylate 13e (50 g, yield 100%) as a light yellow solid.
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[C:10]1(=[O:14])[CH2:13][CH2:12][CH2:11]1>>[Cl:9][C:3]1[CH:4]=[C:5]([Cl:8])[N:6]=[CH:7][C:2]=1[C:10]1([OH:14])[CH2:13][CH2:12][CH2:11]1
Reactant: Clc1cc(Cl)c(Br)cn1
Reactant: O=C1CCC1
Product: OC1(c2cnc(Cl)cc2Cl)CCC1

Procedure:
The title compound was synthesized in analogy to Example 123a, using 5-bromo-2,4-dichloropyridine (CAN 849937-96-8) and cyclobutanone (CAN 1191-95-3) as starting materials and isolated (5.1 g, 76%); MS (ESI, m/z): 218.4 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH:12]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][CH:14]=2)[N:7]=1>C1COCC1.CO.[Pt]>[CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH:12]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][CH:14]=2)[N:7]=1
Reactant: COC(=O)/C=C/c1cc(C)n(C(OCc2ccc(Cl)cc2)c2cccc(Cl)c2)n1
Agent: [Pt]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CCc1cc(C)n(C(OCc2ccc(Cl)cc2)c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of unsaturated ester 6 (0.31 g, 0.65 mmol) and 5 Pt/C (0.01 g) in THF (6 mL) and MeOH (12 mL), previously purged with nitrogen, was stirred under a hydrogen atmosphere (balloon) at RT overnight. The platinum was removed by filtration through Hyflo and the filtrate was evaporated to dryness to afford the saturated ester 7, 0.31 g (99%).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5](Cl)(=[O:7])[CH3:6].[O:9]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][CH:11]=[C:10]1[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(=S)=S>[C:5]([C:17]1[CH:16]=[CH:15][C:14]2[O:9][C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11][O:12][C:13]=2[CH:18]=1)(=[O:7])[CH3:6]
Reactant: CCOC(=O)C1=COc2ccccc2O1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCOC(=O)C1=COc2cc(C(C)=O)ccc2O1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
12.5 g of aluminum trichloride are added to a mixture of 4.27 g of acetyl chloride and 7.5 g of ethyl 1,4-benzodioxin-2-carboxylate in 150 ml of carbon disulfide at 0° C. The reaction mixture is stirred at room temperature for 14 hours. After acid hydrolysis with 50 ml of hydrochloric acid (2N) and extraction of the aqueous phase with dichloromethane, the organic phase is washed with saturated sodium hydrogen carbonate solution and then dried over magnesium sulfate. The acylated product is purified by chromatography on silica gel (eluent: petroleum ether/ethyl acetate, 7:3).
Reaction SMILES: Br.[C:2]([N:5]1[CH2:10][CH2:9][C:8](=O)[CH:7](Br)[CH2:6]1)(=[O:4])[CH3:3].C(N(CC)CC)C.[C:20]([NH2:23])(=[S:22])[CH3:21]>CC(C)=O>[C:2]([N:5]1[CH2:10][CH2:9][C:8]2[N:23]=[C:20]([CH3:21])[S:22][C:7]=2[CH2:6]1)(=[O:4])[CH3:3]
Reactant: CC(N)=S
Reactant: CC(=O)N1CCC(=O)C(Br)C1
Agent: Br
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2nc(C)sc2C1

Procedure:
N-Acetyl-3-bromo-4-piperidone hydrobromide (5.0 g, 16.6 mmol) in acetone (160 ml) was heated to 60° and treated with triethylamine (2.31 ml, 33.1 mmol) and thioacetamide (1.24 g, 16.6 mmol). The reaction mixture was heated to reflux for 24 hours, then cooled and filtered, to provide a yellow solid which was purified by column chromatography (eluant:89:10:1 chloroform: methanol: concentrated aqueous ammonium hydroxide). The title product was obtained as a yellow oil (995 mg, 5.1 mmol, 31% yield).
Reaction SMILES: [CH3:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:14][CH:13]=2)[C:10](=[O:25])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:26](I)[CH3:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:26]([N:22]1[CH2:23][CH2:24][CH:19]([O:18][C:15]2[CH:14]=[CH:13][C:12]([N:11]3[C:10](=[O:25])[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[C:2]3[CH3:1])=[CH:17][CH:16]=2)[CH2:20][CH2:21]1)[CH3:27]
Reactant: Cc1nc2ccccc2c(=O)n1-c1ccc(OC2CCNCC2)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCC(Oc2ccc(-n3c(C)nc4ccccc4c3=O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.9 %

Procedure:
2-methyl-3-[4-(4-piperidinyloxy)phenyl}-4(3H)-quinazolinone (50 mg, 0.15 mmol), ethyl iodide (23 mg, 0.15 mmol) and potassium carbonate (0.30 mmol) were mixed in dimethylformamide (1 mL), and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, ethyl acetate and 1N sodium hydroxide aqueous solution was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with distilled water, dried with anhydrous sodium sulfate, and the product was purified by silica gel column chromatography (chloroform/methanol=30/1) to obtain the title compound (25 mg, 46%) as a colorless solid.
Reaction SMILES: [C:1]1([PH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.Cl.Cl[CH2:21][N:22]1[CH:26]=[CH:25][CH:24]=[N:23]1>O1CCCC1>[C:8]1([P:7]([CH2:21][N:22]2[CH:26]=[CH:25][CH:24]=[N:23]2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: ClCn1cccn1
Reactant: c1ccc(Pc2ccccc2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: c1ccc(P(Cn2cccn2)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
Diphenylphosphine (2.642 g, 14.2 mmol) is placed into a Schlenk flask with degassed tetrahydrofuran (50 ml). The solution is cooled to −78° C. and n-butyllithium (8.4 ml, 1.6 M in hexanes, 15.0 mmol) is added dropwise. The red solution is stirred at −78° C. for an additional 1 hour then the cooling bath is removed and the solution is stirred for 3 hours. The red solution is cooled to 0° C. and 1-(chloromethyl)pyrazole hydrochloride (0.698 g, 4.56 mmol) is added at once. The ice bath is removed and the reaction is stirred for 11 hours before adding degassed methanol (25 ml) and water (20 ml). The organic phase is separated and the aqueous phase is extracted with diethyl ether (3×10 ml). The organic phase is dried over magnesium sulfate, filtered and concentrated. The crude material is purified by chromatography (SiO2, 10% ethyl acetate/petroleum ether) to give 1-(diphenylphosphinomethyl)pyrazole as a white solid in 47% yield (0.574 g, 2.16 mmol). This material is characterized as follows: 1H NMR (CDCl3, 500 MHz) δ 7.49 (dd. J=2.0, 0.5 Hz, 1 H), 7.45-7.40 (m, 4 H), 7.40-7.35 (m, 6 H), 7.25 (dd, J=2.5, 0.5 Hz, 1 H), 6.19 (dd, J=2.5, 2.0 Hz, 1 H), 4,91 (d, J=4.5 Hz, 2 R); 13C{1H} NMR (CDCl3, 125 MHz) δ 139.50, 136.04 (d, J=13.4 Hz), 133.18 (d, J=19.3 Hz), 129.34, 129.49, 128.95 (d, J=6.4 Hz), 106.11, 53.01 (d, J=16.0 Hz); 13P{1H} NMR (CDCl3, 80 MHz) δ−14.98.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:23]([OH:31])(=[O:30])[C:24]([CH2:26][C:27](O)=[O:28])=[CH2:25]>>[O:28]=[C:27]1[N:1]([C:2]2[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[C:4]([NH:12][C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH:3]=2)[CH2:25][CH:24]([C:23]([OH:31])=[O:30])[CH2:26]1
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: Nc1cc(NC(=O)NCc2ccccc2)cc(C(F)(F)F)c1
Product: O=C(NCc1ccccc1)Nc1cc(N2CC(C(=O)O)CC2=O)cc(C(F)(F)F)c1
Reaction time: 10 h

Procedure:
A mixture of N-(3-amino-5-(trifluoromethyl)phenyl)(benzylamino)carboxamide and itaconic acid was fused at 110° C. for 10 hours. The resulted solid was washed with methanol and then dried at 50° C. for 12 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[O:30]([CH2:37][CH2:38]O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl>>[ClH:1].[O:17]([CH2:18][CH2:20][O:24][C:23]([C:18]1([C:20]([O:22][CH2:38][CH2:37][O:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:21])[O:17][C:16]2[CH:26]=[CH:27][C:13]([CH2:12][CH:11]([NH:10][CH2:9][CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[OH:29])[CH3:28])=[CH:14][C:15]=2[O:19]1)=[O:25])[C:16]1[CH:26]=[CH:27][CH:13]=[CH:14][CH:15]=1
Reactant: OCCOc1ccccc1
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Agent: Cl
Product: CC(Cc1ccc2c(c1)OC(C(=O)OCCOc1ccccc1)(C(=O)OCCOc1ccccc1)O2)NCC(O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 2-phenoxyethanol according to the procedure of Example 1 as an off-white gummy solid; 1H NMR (300 MHz, CDCl3): δ 1.23-1.40 (brs, 3H), 2.70-2.90 (brm, 1H), 3.05-3.30 (brm, 2H), 3.31-3.52 (brm, 2H), 4.12 (t, J=4.4 Hz, 4H), 4.57 (t, J=4.8 Hz, 4H), 5.38-5.60 (brs, 2H), 6.70-7.0 (complexm, 10H), 7.15-7.47 (complex m, 7H), 8.60-8.80 (brs, 1H), 9.90-10.20 (brs, 1H).; MS (ES) m/z (relative intensity): 662 (M+ -HCl, (100), 594 (20), 498 (35).
Reaction SMILES: S(Cl)([Cl:3])=O.Cl.[NH2:6][CH2:7][C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12]>CN(C)C=O>[ClH:3].[NH2:6][CH2:7][C:8](=[O:14])[CH2:9][CH2:10][C:11]([O:13][CH2:10][CH2:9][CH:8]=[CH2:7])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: NCC(=O)CCC(=O)O
Agent: Cl
Solvent: CN(C)C=O
Product: C=CCCOC(=O)CCC(=O)CN
Yield: 77 %

Procedure:
To 1 ml of thionyl chloride (SOCl2) were added 3 drops of N,N-dimethylformamide (DMF) with stirring. Following the addition of 5-aminolevulinic acid hydrochloride (ALA.HCl, 200 mg, 1.19 mmol), the solution was stirred for 12 hours at room temperature. Concentration in a vacuum was conducted before the addition of 3-butenol. Then, the reaction mixture was stirred for 1.5 hours at room temperature, followed by purification by silica gel chromatography to afford 3-butenyl 5-aminolevulinate hydrochloride at a yield of 77%.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:15]=[N:16][C:17]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[C:18]([CH3:20])[CH:19]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.C[Si](C)(C)CCOC[N:33]1[CH:37]=[CH:36][C:35]([C:38]([NH2:40])=[O:39])=[N:34]1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:20][C:18]1[CH:19]=[C:14]([CH:12]([N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:40][C:38]([C:35]4[CH:36]=[CH:37][NH:33][N:34]=4)=[O:39])[C:7]=3[CH2:8]2)[CH3:13])[CH:15]=[N:16][C:17]=1[O:21][CH2:22][C:23]([F:26])([F:25])[F:24]
Reactant: C[Si](C)(C)CCOCn1ccc(C(N)=O)n1
Reactant: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1OCC(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C(C)N2Cc3c(ccnc3NC(=O)c3cc[nH]n3)C2=O)cnc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.5 %

Procedure:
The reaction is carried out in a similar manner to Example-1 (Method-A) using 4-chloro-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (50 mg, 0.13 mmol, Intermediate-2, single enantiomer) and 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxamide (63 mg, 0.26 mmol). The obtained crude is diluted with DCM/TFA (1:1, 2 mL), and the mixture is stirred at rt for 1 h. Then, the solvent is removed in vacuo, and the residue is purified by preparative LC-MS to give 6.3 mg (11% yield) of the title compound.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([N+:8]([O-])=O)[CH:6]([CH3:11])[CH2:5][CH:4]=[CH:3]1.[H][H]>[Pd]>[CH3:11][CH:6]1[CH2:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH:7]1[NH2:8]
Reactant: CC1C=CCC(C)C1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Product: CC1CCCC(C)C1N

Procedure:
contacting said 3,5-dimethyl-4-nitro-cyclohexene with hydrogen at a temperature of about 0° C. to about 200° C. and a pressure of about 0 psig to about 1500 psig in the presence of a palladium catalyst to form 2,6-dimethylcyclohexyl amine; and