Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])[CH:16]=2)[CH:4]=1)[CH3:2]
Reactant: C1CCNC1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Product: CCc1cc(-c2cncc(C(=O)N3CCCC3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and pyrrolidine to afford the title compound. MS: m/e=312 (M+H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.CC(O)=O.CN.Cl.[BH3-][C:20]#[N:21].[Na+]>CO>[CH3:20][NH:21][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1
Reactant: [BH3-]C#N
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNC1CCC2(CC1)OCCO2
Reaction time: 2 h
Yield: 54 %

Procedure:
1,4-Dioxaspiro[4.5]decan-8-one (10.0 g, 64.10 mmol, 1.0 eq.) was dissolved in MeOH (100 ml); AcOH (0.1 ml) and CH3NH2.HCl (8.65 g, 128.21 mmol, 2.0 eq.) were added and stirring was carried out for 2 hours at RT. NaCNBH3 (10.0 g, 160.256 mmol, 2.5 eq.) was added in portions at 0° C. and the mixture was then stirred for 16 hours at RT. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (Alox, 5% MeOH in DCM). Yield: 54% (6.0 g, 35.08 mmol)
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:11]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:12]=1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:16]([C:15]1[C:11]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:12][N:13]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:14]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1cn(-c2cccnc2)nc1Cl
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=[N+]([O-])c1cn(-c2cccnc2)nc1-c1ccccc1
Temperature: 110 °C
Yield: 125.6 %

Procedure:
To a suspension of phenylboronic acid (0.546 g, 4.47 mmol) in toluene (6.63 ml) was added 3-(3-chloro-4-nitro-1H-pyrazol-1-yl)pyridine (0.335 g, 1.492 mmol) followed by ethanol (3.31 ml) and 2 M aqueous potassium carbonate (1.492 ml, 2.98 mmol). The solution was degassed by applying vacuum and then purging with nitrogen (3 times). To the reaction mixture was added palladium tetrakis (0.086 g, 0.075 mmol) and the flask was heated at 110° C. under nitrogen for 16 hours. The aqueous layer was removed and the organic layer was concentrated. The crude product was purified via silica gel chromatography (0-100% ethyl acetate/hexanes) to give 3-(4-nitro-3-phenyl-1H-pyrazol-1-yl)pyridine (499 mg, 1.874 mmol, 80%) as a yellow solid: mp 144.0-146.0° C.; 1H NMR (400 MHz, CDCl3) δ 9.09 (d, J=2.3 Hz, 1H), 8.82 (s, 1H), 8.71 (dd, J=4.8, 1.4 Hz, 1H), 8.16 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.82-7.74 (m, 2H), 7.55-7.48 (m, 4H); EIMS m/z 266.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[C:20]([N:10]1[CH2:11][CH2:12][CH2:13][CH:9]1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cccc(C2CCCN2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cccc(C2CCCN2C(=O)c2ccccc2)c1
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of 2-(3-methoxyphenyl)pyrrolidine (1.0 g) in dry acetonitrile (50 ml) was added milled potassium carbonate (2.0 g) followed by benzoyl chloride (0.73 ml) at ambient temperature, under nitrogen. The reaction mixture was stirred for 2 hrs, filtered through a pad of celite, and the filter cake was washed with ethyl acetate. The combined filtrates were concentrated, and the residue was purified by flash column chromatography (silica gel, 0-25% ethyl acetate/dichloromethane). The appropriate fractions were collected and concentrated to give 1.2 g (75%) of 1-benzoyl-2-(3-methoxyphenyl)pyrrolidine.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.O>CN(C)C=O>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([O:1][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: COc1cc(O)ccc1C=O
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OCc2ccccn2)ccc1C=O
Temperature: 50 °C
Reaction time: 4 h
Yield: 89.9 %

Procedure:
In 53 mL of N,N-dimethylformamide were dissolved 8.00 g (52.6 mmol) of 4-hydroxy-2-methoxybenzaldehyde, 14.5 g (105 mmol) of potassium carbonate, and 9.06 g (55.2 mmol) of 2-chloromethylpyridine hydrochloride and the solution was stirred at 50° C. for 4 hours. To the reaction mixture, 260 mL of water was added at room temperature and the precipitated crystal was separated by filtration. The crystal was washed with water and dried under reduced pressure to give 11.5 g (82% yield) of the title compound as a pale grey-brown powder with the following properties.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:3]=1[NH2:4].C(O[CH:16]=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C.C1(C)C=CC=CC=1>CCCCCC>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:10])([F:11])[F:12])=[CH:5][C:3]=1[NH:4][CH:16]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCOC(=O)C(=CNc1cc(C(F)(F)F)ccc1Cl)C(=O)OCC
Temperature: 140 °C

Procedure:
2-Chloro-5-(trifluoromethyl)aniline (2) (200 g, 1.023 mol), diethyl 2-(ethoxymethylene)malonate (3) (276 g, 1.3 mol) and toluene (100 mL) were combined under a nitrogen atmosphere in a 3-neck, 1-L round bottom flask equipped with Dean-Stark condenser. The solution was heated with stirring to 140° C. and the temperature was maintained for 4 hours (h). The reaction mixture was cooled to 70° C. and hexane (600 mL) was slowly added. The resulting slurry was stirred and allowed to warm to room temperature. The solid was collected by filtration, washed with 10% ethyl acetate in hexane (2×400 mL) and then dried under vacuum to provide the product, diethyl 2-((2-chloro-5-(trifluoromethyl)phenylamino)methylene)malonate (4), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.28 (d, J=13.0 Hz, 1H), 8.63 (d, J=13.0 Hz, 1H), 8.10 (s, 1H), 7.80 (d, J=8.3 Hz, 1H), 7.50 (dd, J=1.5, 8.4 Hz, 1H), 4.24 (q, J=7.1 Hz, 2H), 4.17 (q, J=7.1 Hz,2 H), 1.27 (m, 6H).
Reaction SMILES: [C:1]([NH:4][C:5]([NH2:7])=[S:6])(=[NH:3])[NH2:2].Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O>CC(C)=O>[C:12]1([C:10]2[N:7]=[C:5]([NH:4][C:1]([NH2:2])=[NH:3])[S:6][CH:9]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N=C(N)NC(N)=S
Reactant: O=C(CBr)c1ccccc1
Solvent: CC(C)=O
Product: N=C(N)Nc1nc(-c2ccccc2)cs1
Temperature: 25 °C
Yield: 86.7 %

Procedure:
A mixture of amidinothiourea (2.0 g, 16.9 mmol), 2-bromoacetophenone (3.4 g, 16.9 mmol) was heated at reflux in acetone (12 mL) for 4 h. The mixture was cooled to room temperature and removed half of the solvent. The precipitate was filtered, washed with acetone, and dried to give N-(4-phenyl-1,3-thiazol-2-yl)guanidine (3.2 g, 87%).
Reaction SMILES: [CH2:1]([O:5][N:6]=[C:7]([C:13](=O)[CH2:14]Cl)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]([CH3:4])[CH3:3].[NH2:17][C:18]([NH2:20])=[S:19].C(O)C>O>[NH2:20][C:18]1[S:19][CH:14]=[C:13]([C:7](=[N:6][O:5][CH2:1][CH:2]([CH3:4])[CH3:3])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:17]=1
Reactant: CCOC(=O)C(=NOCC(C)C)C(=O)CCl
Reactant: NC(N)=S
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(=NOCC(C)C)c1csc(N)n1
Yield: 50.8 %

Procedure:
Ethyl 2-iso-butoxyimino-4-chloro-3-oxobutyrate (syn isomer, 31.9 g.), thiourea (9.72 g.), sodium acetate 3-hydrate (17.4 g.), ethanol (120 ml.) and water (80 ml.) were treated in a similar manner to that of Example F-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-iso-butoxyiminoacetate (syn isomer, 17.6 g.), mp 122° to 124° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[N+](=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N-]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][O:14][C@H:11]1[CH2:10][CH2:9][C@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:15])[CH2:13][CH2:12]1)[CH3:23]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)CO[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of trans (4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester (1.03 g, 4.80 mmol) in dry toluene (38 mL) under an nitrogen atmosphere was treated with rhodium acetate (110 mg, 200 μmol) and heated at reflux. A solution of ethyl diazoacetate (600 μL, 5.70 mmol) in dry toluene (9 mL) was added dropwise over 1.5 hours. The mixture was then stirred at reflux for a further 30 minutes and allowed to cool to ambient temperature overnight. The reaction was treated with a further portion of rhodium acetate (50 mg) and re-heated to reflux. Further ethyl diazoacetate (300 μL) in dry toluene (5 mL) was added dropwise over 1 hour. Heating was continued for 30 minutes and then the cooled mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel (gradient: 0-35% ethyl acetate in cyclohexane) to afford 720 mg (50%) of trans (4-tert-butoxycarbonylamino-cyclohexyloxy)-acetic acid ethyl ester as a white solid. LCMS (Method Q, ESI): RT=3.63 min, m+H=324.0; 1H NMR (400 MHz, CDCl3) δ: 4.35 (br s, 1H), 4.21 (q, 2H), 4.09 (s, 2H), 3.44 (br s, 1H), 3.32 (m, 1H), 2.04 (m, 4H), 1.44 (m, 11H), 1.28 (t, 3H), 1.13 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH:20]1[C:32]2[CH:31]([CH2:33][O:34][C:35](Cl)=[O:36])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1.O1CCOCC1>O>[CH:20]1[C:32]2[CH:31]([CH2:33][O:34][C:35]([NH:1][C:2]3[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=3)=[O:36])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: Nc1ccc(C(=O)O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1ccc(C(=O)O)c([N+](=O)[O-])c1)OCC1c2ccccc2-c2ccccc21
Reaction time: 20 h
Yield: 67.2 %

Procedure:
To a solution of 11.4 g 4-amino-2-nitro-benzoic acid in 228 ml of water containing 6.63 g of sodium carbonate were added 17.0 g of 9-fluorenylmethyl-chloroformate and dropwise 20 ml of dioxane. After stirring for 20 hours under nitrogen, the mixture was filtered and the filtrate was washed five times with methyl-tert.-butylether. Residual methyl-tert.-butylether was removed from the aqueous phase by evaporation under vacuum. To the aqueous phase were added 456 g of 0° C. cold water. The mixture was adjusted to pH=3 by addition of 31 ml of 2M aqueous hydrochloric acid. The precipitate was sucked off, washed with 513 ml of water, dried at 40° C. in vacuum to give 17.0 g of 4-(((9H-fluorene-9-yl)methoxy)carbonylamino)-2-nitrobenzoic acid as off-white crystals.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:11][CH:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=2)=[CH:5][CH:4]=[N:3]1.[NH2:15][CH:16]([C:29]([CH3:37])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30])[CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[O:28]=[C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26](=[O:27])[N:18]1[CH2:17][CH:16]([NH:15][C:12]([C:9]1[CH:8]=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[S:11][CH:10]=1)=[O:14])[C:29]([CH3:30])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:37]
Reactant: CC(C)(c1ccccc1)C(N)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1nccc1-c1cc(C(=O)O)cs1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1-c1cc(C(=O)NC(CN2C(=O)c3ccccc3C2=O)C(C)(C)c2ccccc2)cs1
Reaction time: 16 h
Yield: 29.6 %

Procedure:
To a heterogeneous mixture of 5-(1-methyl-1H-pyrazol-5-yl)-3-thiophenecarboxylic acid (155 mg, 0.74 mmol), 2-(2-amino-3-methyl-3-phenylbutyl)-1H-isoindole-1,3(2H)-dione (200 mg, 0.65 mmol)[from Preparation 4] and PyBrOP (426 mg, 0.91 mmol) in CHCl3 (10 mL) at 25° C. was added diisopropylethyl amine (0.5 mL, 2.9 mmol) dropwise. After 16 h, the mixture was adsorbed onto silica and the mixture purified via column chromatography (silica, 35-50% EtOAc/Hex) affording the title compound (96 mg, 26%) as a white solid: LC-MS (ES) m/z=499 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]2[CH:11]=[C:10]([CH3:12])[C:9](N)=[CH:8][CH:7]=2)=[CH:4][CH:3]=1.C(#N)C.N(OCCCC)=O.[BrH:26]>[Cu]Br>[Br:26][C:9]1[CH:8]=[CH:7][C:6]([C:5]2[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:11][C:10]=1[CH3:12]
Reactant: Br
Reactant: Cc1cc(-c2ccc(Cl)cc2)ccc1N
Agent: [Cu]Br
Agent: CCCCON=O
Solvent: CC#N
Product: Cc1cc(-c2ccc(Cl)cc2)ccc1Br
Temperature: 25 °C

Procedure:
4′-Chloro-3-methylbiphen-4-ylamine (16.5 g, 0.077 mol) is added to acetonitrile (140 ml) and stirred at room temperature until dissolution is complete. The reaction mixture is cooled to between −5° C. and 0° C., tent-butyl nitrite (90%, 12.4 ml, 0.093 mol) is added dropwise and the reaction mixture is maintained at between −5 and 0° C. for 30-40 minutes. The mixture is added slowly to the preheated (50° C.) suspension of copper (I) bromide (5.8 g, 0.04 mol) in hydrobromic acid (5.8 ml) and stirred at 50° C. for 10-15 minutes. The reaction mixture is cooled to room temperature, then poured into ice-cold water and extracted with ethyl acetate (3×300 ml). The organic extracts are washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to yield 4-bromo-4′-chloro-3-methylbiphenyl (11.5 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[C:13](O)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O>[N:38]1([C:13](=[O:14])[CH:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:9])=[O:10])[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:22])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: Cc1ccc(S(=O)(=O)NC(CCCCNC(=O)OCc2ccccc2)C(=O)O)cc1
Reactant: C1CCNCC1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)NC(CCCCNC(=O)OCc2ccccc2)C(=O)N2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.6 %

Procedure:
To a cold (0° C.), nitrogen-blanketed mixture of 2-[[(4-methylphenyl]sulfonyl]amino]6-[[(phenylmethoxy)carbonyl]amino]hexanoic acid (18.00g, 44.43 mmol), triethylamine (5.80 mL, 41.43 mmol) and piperidine (4.10 mL, 41.43 mmol) in anhydrous dimethylformamide (80 mL) was added dropwise diphenylphosphoryl azide (8.90 mL, 41.43 mmol). The mixture was stirred at about 0° C. for about 1 hour and at ambient temperature for about 2 hours before it was partitioned between ethyl acetate and water. The organic phase was separated and the aqueous phase was extracted three additional times with ethyl acetate. The combined extracts were then washed with saturated sodium bicarbonate solution, 1N hydrochloric acid and brine prior to drying and solvent concentration. There was isolated in sufficiently pure state 20.90g (100%) of the title compound of as pale yellow oil; 1H NMR (CDCl3) δ 7.62 (d, J=8.2 Hz, 2H), 7.30-7.22 (m, 5H), 7.19 (d, J=8.1 Hz, 2H), 5.94 (d, J=8.9 Hz, 1H), 5.09-5.07 (m, 1H), 5.03 (s, 2H), 3.90-3.88 (m, 1H), 3.43-3.36 (m, 1H), 3.09-2.91 (m, 5H), 2.32 (s, 3H), 1.43-1.23 (m, 10H), 1.09-0.97 (m, 2H); 13C NMR (CDCl3) ppm 168.28, 156.09, 142.87, 136.43, 136.30, 128.98, 127.95, 127.43, 126.96, 65.81, 52.08, 45.70, 42.67, 40.14, 32.58, 28.72, 25.49, 24.65, 23.64, 21.71, 20.93; IR (KBr, cm-1) 3316, 2938, 2860, 1718, 1634, 1526, 1452, 1416, 1340, 1246, 1162, 1092; MS m/z (MH+) calcd 502.2376, obsd 502.2363.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N:10]=[C:11]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:13]=[CH:12]2)[CH:9]=1)[C:5]#[N:6].Cl.Cl[CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.CCN(C(C)C)C(C)C>CC(CC)CO>[Cl:21][C:17]1[CH:16]=[C:15]2[C:20]([C:11](=[N:10][C:8]3[CH:7]=[C:4]([CH:3]=[C:2]([NH:1][CH2:32][CH2:33][N:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)[CH:9]=3)[C:5]#[N:6])[CH:12]=[CH:13][N:14]2[CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:19][CH:18]=1
Reactant: ClCCN1CCCCC1
Reactant: N#Cc1cc(N)cc(N=c2ccn(CCN3CCCCC3)c3cc(Cl)ccc23)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC(C)CO
Product: N#Cc1cc(N=c2ccn(CCN3CCCCC3)c3cc(Cl)ccc23)cc(NCCN2CCCCC2)c1
Yield: 16.9 %

Procedure:
3-amino-5-({7-chloro-1-[2-(piperidin-1-yl)ethyl]-1,4-dihydroquinolin-4-ylidene}amino)benzonitrile prepared from example 21 (132 mg, 0.32 mmol), 1-(2-chloroethyl)piperidine hydrochloride (182 mg, 3 eq) and DIEA (0.51 mL, 9.3 eq) were refluxed in 15 mL of 2-methylbutan-1-ol for 10 h. The reaction mixture was then evaporated and the residue and was purified by preparative thin-layer chromatography (DCM/MeOH/NH4OH//95/5/1) to yield expected compound as a yellow oil (28 mg, 17% yield). m/z (ESI) 517.5 [M+H]+.
Reaction SMILES: [CH:1]1([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:20]=[C:19]([CH:21]=[N:22][C:23]3[C:28]([CH:29]([CH3:31])[CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=3[CH:32]([CH3:34])[CH3:33])[CH:18]=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[Li])([CH3:37])[CH3:36].O>CCOCC>[CH:1]1([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:20]=[C:19]([CH:21]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[CH:35]([CH3:37])[CH3:36])[NH:22][C:23]3[C:24]([CH:32]([CH3:34])[CH3:33])=[CH:25][CH:26]=[CH:27][C:28]=3[CH:29]([CH3:30])[CH3:31])[CH:18]=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [Li]c1ccccc1C(C)C
Reactant: CC(C)c1cccc(C(C)C)c1N=Cc1cccc(-c2ccccc2CNC2CCCCC2)n1
Solvent: O
Solvent: CCOCC
Product: CC(C)c1ccccc1C(Nc1c(C(C)C)cccc1C(C)C)c1cccc(-c2ccccc2CNC2CCCCC2)n1
Temperature: 25 °C

Procedure:
Et2O (10 mL) was added to compound 9 (0.189 g, 0.417 mmol) to form a clear pale yellow solution. At −80° C., an Et2O (5 mL) solution of 2-isopropylphenyllithium (0.136 g, 1.08 mmol) was added dropwise to form a red-purple solution. The mixture was allowed to slowly warm to ambient temperature overnight. Water (50 mL) was then added followed by Et2O (50 mL). The organics were separated, dried with brine and then MgSO4. Evaporation of the volatiles afforded compound 10, which did not require any purification. Yield: 0.224 g, 76.2%. 1H NMR (CD2Cl2): δ 7.67 (t, 2H), 7.1-7.53 (m, 10H), 7.00 (m, 3H), 5.44 (d, 1H), 4.40 (d, 1H), 3.69 (s, 2H), 3.11 (sept, 1H), 2.91 (sept, 2H), 2.24 (m, 1H), 1.5-1.7 (m, 6H), 1.25 (d, 3H), 1.1-1.2 (m, 4H), 0.97 (d, 12H), 0.93 (d, 6H).
Reaction SMILES: C(OC1C=C[C:15]2[C:11](=[C:12]([C:31]3[CH:36]=[CH:35][C:34]([O:37]C)=CC=3)[C:13]([C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)(C(OC)=O)[CH:14]=2)C=1)C1C=CC=CC=1.C[CH2:40][O:41][C:42]([CH3:44])=O>CCO.[Pd]>[OH:37][C:34]1[CH:35]=[C:36]2[C:14](=[CH:15][CH:11]=1)[CH:13]([C:22]1[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=1)[CH:12]([C:29]([O:28][CH3:25])=[O:30])[CH:31]2[C:11]1[CH:15]=[CH:44][C:42]([O:41][CH3:40])=[CH:13][CH:12]=1
Reactant: COC(=O)C1(c2ccc3c(c2)OCO3)C=c2ccc(OCc3ccccc3)cc2=C1c1ccc(OC)cc1
Reactant: CCOC(C)=O
Agent: [Pd]
Solvent: CCO
Product: COC(=O)C1C(c2ccc3c(c2)OCO3)c2ccc(O)cc2C1c1ccc(OC)cc1
Reaction time: 20 h
Yield: 89 %

Procedure:
To a degassed solution of methyl(RS)-5-benzyloxy-3-(4-methoxyphenyl)-2-(3,4-methylenedioxyphenyl)indene-2-carboxylate (6.60 g, 13.0 mmol) in EtOAc (25 ml) and EtOH (175 ml) was added 5% palladium on activated carbon (0.6 g). The resulting suspension was shaken on a Parr hydrogenator at 60 psi H2 for 20 h, at which time NMR analysis of the reaction mixture indicated that the reaction was incomplete. The catalyst was removed by filtration through a pad of Celite, and fresh 5% palladium on activated carbon (0.6 g) was added. The mixture was shaken on a Parr hydrogenator at 60 psi H2 for an additional 48 h. The catalyst was removed by filtration through a pad of Gelite, and the filtrate was concentrated under reduced pressure. The residue was crystallized from EtOAc/hexanes to afford the title compound (4.83 g, 89%); m.p. 187°-188° C.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][CH:4](I)[CH3:5].[N-:9]=[N+:10]=[N-:11].[Na+]>C(O)C>[N:9]([CH:4]([CH3:5])[CH2:3][C:2]([F:8])([F:7])[F:1])=[N+:10]=[N-:11]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(I)CC(F)(F)F
Agent: [Na+]
Solvent: CCO
Product: CC(CC(F)(F)F)N=[N+]=[N-]

Procedure:
1,1,1-Trifluoro-3-iodobutane (20.00 g, 0.084 mol) was added slowly to a stirred solution of sodium azide (13.00 g, 0.200 mol) in aqueous ethanol (60% ethanol, 200 ml) contained in a 500 ml flask (3-necked) with an argon lute, then refluxed for 11 h. The solution was extracted with ether (250 ml), which was washed and dried, and shown by g.l.c. analysis (2 m D.N.P. at 60°) to contain one major product, 3-azido-1,1,1-trifluorobutane, [approximately 9 g (estimated from g.l.c. analysis), 0.059 mol, 70%] which was not isolated because of the explosive hazard.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][C:21]=3[CH2:23][OH:24])[CH:16]=[CH:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:27][O:28][CH2:29]Cl.C(OCC)(=O)C>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][C:21]=3[CH2:23][O:24][CH2:27][O:28][CH3:29])[CH:16]=[CH:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCl
Reactant: CC(C)(C)OC(=O)N1CCC(n2ccc3cccc(CO)c32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCOCc1cccc2ccn(C3CCN(C(=O)OC(C)(C)C)CC3)c12
Reaction time: 0.67 h
Yield: 80.8 %

Procedure:
Dissolve 4-(7-hydroxymethylindol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (0.25 g, 0.76 mmol) in 5 mL of tetrahydrofuran and add sodium hydride (36 mg, 1.5 mmol) at room temperature. After 40 minutes, add methoxymethyl chloride (0.11 mL, 1.5 mmol) and stir the mixture for 4 hours. Concentrate the reaction and subject it to flash chromatography using 5:1 hexanes:ethyl acetate to give 0.23 g product. FAB MS 374.