Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[Si](C)(C)C.[CH2:6]([O:8][C:9]([C:11]1[CH:12]=[N:13][N:14]([C:16]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=2)=[N:17][C:18](OCC)=[O:19])[CH:15]=1)=[O:10])[CH3:7].CN(C=O)C>O>[CH2:6]([O:8][C:9]([C:11]1[CH:12]=[N:13][N:14]([C:16]2[NH:17][C:18](=[O:19])[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=2)[CH:15]=1)=[O:10])[CH3:7]
Reactant: CCOC(=O)N=C(Nc1ccc(OC)c(OC)c1)n1cc(C(=O)OCC)cn1
Agent: C[Si](C)(C)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2nc3cc(OC)c(OC)cc3c(=O)[nH]2)c1
Temperature: 80 °C

Procedure:
Chlorotrimethylsilane (1.26 mL, 10.0 mmol) was added to a solution of 1-[(3,4-dimethoxy-phenylamino)-ethoxycarbonylimino-methyl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.39 g, 1.0 mmol) and DMF (3 mL), and the resulting mixture was heated to 80° C. for 16 h in a sealed tube. The reaction mixture was cooled and water (2 mL) was added. The crude reaction mixture was concentrated under reduced pressure and the resulting aqueous mixture was adjusted to pH 7 using 2M aqueous NH4OH. The residue was triturated well and collected by vacuum filtration. The titled compound was purified by preparative reverse-phase HPLC (0.28 g, 81%). MS (ESI): mass calcd. for C16H16N4O5, 344.4; m/z found, 345.7 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 13.06-12.23 (br m, 1H), 8.97 (s, 1H), 8.28 (s, 1H), 7.47 (s, 1H), 7.21 (s, 1H), 4.29 (q, J=7.1 Hz, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 1.32 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([CH2:9][CH:10]1[CH2:14][CH2:13][O:12][C:11]1=[O:15])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C2CC(C(O)=O)CCC=2)C=CC=CC=1>CS(C)=O.O1CCCC1>[C:2]1([C:1]2[CH2:9][CH:10]([C:11]([OH:12])=[O:15])[CH2:14][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CC1CCOC1=O)c1ccccc1
Agent: Br
Agent: O=C(O)C1CCC=C(c2ccccc2)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: O=C(O)C1CC=C(c2ccccc2)C1
Temperature: 170 °C
Yield: 67.3 %

Procedure:
3-(Benzoylmethyl)-4,5-dihydro-2(3H)-furanone (5.00 g, Step A) and triphenylphosphine hydrobromide (8.41 g) are mixed and heated to 170° C. in an oil bath under nitrogen for 1 hour. The mixture is cooled and powdered. The powder is dissolved in dimethylsulfoxide (50 mL) and diluted with tetrahydrofuran (30 mL). The solution is stirred under nitrogen and cooled in an ice-bath. Dimsyl sodium (25 mL of 2M, see Example D, Step C) is added dropwise over 20 minutes keeping the internal temperature below 14° C. The mixture is stirred at 25° C. for 2 hours and the solvents evaporated. The residue is treated with water (80 mL) containing saturated aqueous sodium bicarbonate (10 mL) and extracted with dichloromethane (3×50 mL). The extracts are washed with dilute aqueous sodium bicarbonate. The aqueous layers are washed with dichloromethane (30 mL) and acidified with concentrated hydrochloric acid. The aqueous layers are extracted with dichloromethane (3×50 mL), the extracts dried over magnesium sulfate, filtered, and evaporated to a brown oil. The oil is washed through silica gel (30 g) with 2:1 chloroform:ethyl acetate to give 3.1 g of 3-phenyl-3-cyclopentenecarboxylic acid as a brown solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:6][NH:7][C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C1OCCOCCOCCOCCOC1.[F:41][C:42]1[CH:43]=[C:44]([S:48](Cl)(=[O:50])=[O:49])[CH:45]=[N:46][CH:47]=1>O1CCCC1.O>[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:6][N:7]([S:48]([C:44]2[CH:45]=[N:46][CH:47]=[C:42]([F:41])[CH:43]=2)(=[O:50])=[O:49])[C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1cncc(F)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cn(S(=O)(=O)c2cncc(F)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Yield: 92.7 %

Procedure:
To a suspension of sodium hydride (60% in oil, 20 mg) in tetrahydrofuran (2 mL) were added tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (162 mg), 15-crown-5 (132 mg) and a solution of 5-fluoropyridine-3-sulfonyl chloride (127 mg) in tetrahydrofuran (1 mL) at room temperature, and the mixture was stirred for 1 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→7:3) to give the title compound as a colorless oil (yield 224 mg, 93%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C@@H:19]1[CH2:23][C@H:22]([OH:24])[C@H:21]([CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[C@H:20]1[CH2:41][OH:42])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([O:18][C@@H:19]1[CH2:23][C:22](=[O:24])[C@H:21]([CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[C@H:20]1[CH:41]=[O:42])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(CCC/C=C\C[C@@H]1[C@@H](CO)[C@H](OCc2ccccc2)C[C@@H]1O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C[C@H]1[C@H](OCc2ccccc2)CC(=O)[C@@H]1C/C=C\CCCC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 98.9 %

Procedure:
To a solution of oxalyl chloride (68.4 mmoL) in dichloromethane (10 volumes) at −78° C. was added DMSO (114.0 mmoL). The solution was stirred at −78° C. for 30-60 minutes followed by drop-wise addition of (5Z)-benzyl 7-[(1R,2S,3R,5S)-3-benzyloxy-5-hydroxy-2-(hydroxymethyl)cyclopentyl]hept-5-enoate (16, R1 is phenyl, R2 and R3 are H and R7 is benzyl, 10 g, 22.8 mmoL) in dichloromethane (10 volumes). The reaction mixture was stirred at −78° C. for 30 minutes at which time triethylamine (105.9 mmoL) was charged. The mixture was stirred at −78 to −60° C. for 4-6 hours followed by quenching with saturated aqueous ammonium chloride (10 volumes). The mixture was warmed to 0° C. The layers were separated; the organic layer was washed with saturated aqueous sodium carbonate, dried over sodium sulfate, filtered through Celite® and concentrated to dryness. The residue was purified by column chromatography (50% ethyl acetate in heptanes) to yield (5Z)-benzyl 7-[(1R,2R,3R)-3-benzyloxy-2-formyl-5-oxocyclopentyl]hept-5-enoate (17, R1 is phenyl, R2 and R3 are H and R7 is benzyl) as an oil (9.8 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][C:5](=[O:7])[CH:6]=1.Br[CH2:9][CH2:10][C:11]([OH:13])=[O:12]>O1CCOCC1>[CH3:1][C:2]1[CH2:6][C:5](=[O:7])[N:4]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[N:3]=1
Reactant: CC1=CC(=O)N=N1
Reactant: O=C(O)CCBr
Solvent: C1COCCO1
Product: CC1=NN(CCC(=O)O)C(=O)C1
Yield: 22 %

Procedure:
To a solution of 3-methyl-pyrazol-5-one (5.7 g, 58.0 mmol) in anhydrous 1,4-dioxane was added 3-bromopropionic acid, and the resulting mixture was heated to reflux for 48 h.12 The reaction mixture was concentrated under reduced pressure, and the crude product was purified by column chromotography using 5-10% MeOH/DCM as an eluent to give 3j (22%) as a solid.13 mp: 210-215° C. (Lit. mp 178-180° C.); 1H NMR (400 MHz, CDCl3): δ 2.21 (s, 3H), 2.76 (m, 2H), 3.14 (s, 2H), 4.14 (m, 2H), 8.01 (brs, 1H); HRMS (m/z): [M−H]− calcd for C7H4N2O3, 169.0619; found, 169.0622.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:26](OC)(OC)(OC)[CH3:27].Cl.[NH+]1C=CC=CC=1>ClCCCl>[CH3:26][C:27]1[N:12]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: COC(C)(OC)OC
Reactant: CC(C)(C)OC(=O)NCCOCCNc1c(N)cnc2ccccc12
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCCl
Product: Cc1nc2cnc3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 83.5 %

Procedure:
A solution of tert-butyl 2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate (12.05 g, 34.8 mmol) in 200 mL of 1,2-dichloroethane was treated with trimethyl orthoacetate (5.50 mL, 43.2 mmol) and the reaction mixture was heated to reflux. A 100 mg portion of pyridinium hydrochloride was then added and refluxing was continued for 4 h. The reaction was then cooled and washed with water and brine. The organic portion was dried over Na2SO4 and concentrated to give an orange foam. The foam was triturated with ether and filtered to yield 10.76 g of tert-butyl 2-[2-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a tan solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([O:11][CH3:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:13]1(=[O:19])[O:18][C:16](=[O:17])[CH2:15][CH2:14]1.Cl>C(OCC)(=O)C.C(Cl)Cl>[CH3:12][O:11][C:5]1[CH:10]=[CH:9][C:8]([C:13](=[O:19])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:7][CH:6]=1
Reactant: COc1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methylene chloride (300 ml) was added to aluminum chloride (185.6 g) and anisole (100 ml) was added dropwise thereto at 0° C. Succinic anhydride (100 g) was added thereto in 5 portions and the resulting mixture was warmed up to room temperature and stirred for 3 hours. The reaction solution was added to a 4N aqueous hydrochloric acid solution (2 L) and ethyl acetate (1 L) under ice-cooling, and the crystals precipitated were collected by filtration and dried to obtain 4-(4-methoxyphenyl)-4-oxobutanoic acid (160 g) as a white solid.
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[N:13]=1)#[N:2].[C:20](Cl)(=[O:34])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>N1C=CC=CC=1>[C:1]([CH2:3][CH2:4][N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[N:13]=[C:14]([CH3:19])[CH:15]=[C:16]([CH3:18])[N:17]=1)[C:20](=[O:34])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])#[N:2]
Reactant: CCCCCCCCCCCCCC(=O)Cl
Reactant: Cc1cc(C)nc(NCCCCCNCCC#N)n1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCC(=O)N(CCC#N)CCCCCNc1nc(C)cc(C)n1

Procedure:
Crude XIII was dissolved in dry pyridine to which 1 eq of tetradecanoyl chloride was added with stirring. The run was followed by tlc and excess acid chloride was added to drive the reaction to completion. Ice was then added to quench the reaction followed by the addition of CHCl3. The mixture was first extracted with 10% NaHCO3 and then with 1M HOAc to remove the bulk of the pyridine. The remaining CHCl3 phase was evaporated to yield the crude product which was purified by chromatography on a 100 g silica gel (Brinkman 50-200μ) column developed with 30% acetone/chloroform. The product (1 g) was collected after only 150 ml of eluant had passed through the column and was only partially purified.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH:3]1[CH2:23][CH2:22][C:6]2[O:7][C:8]3[CH:13]=[CH:12][C:11]([NH:14][C:15](OC(C)(C)C)=[O:16])=[CH:10][C:9]=3[C:5]=2[CH2:4]1.FC(F)(F)C(O)=O.[F:32][C:33]1[CH:41]=[CH:40][C:36](C(Cl)=O)=[CH:35][CH:34]=1>>[CH3:1][N:2]([CH3:24])[CH:3]1[CH2:23][CH2:22][C:6]2[O:7][C:8]3[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:16])[C:36]4[CH:40]=[CH:41][C:33]([F:32])=[CH:34][CH:35]=4)=[CH:10][C:9]=3[C:5]=2[CH2:4]1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CN(C)C1CCc2oc3ccc(NC(=O)OC(C)(C)C)cc3c2C1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C1CCc2oc3ccc(NC(=O)c4ccc(F)cc4)cc3c2C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60.3 %

Procedure:
A mixture of 0.090 gm (0.273 mMol) of (+)-N,N-dimethyl-8-(tert-butoxycarbonyl)amino-1,2,3,4-tetrahydro-2-dibenzofuranamine and 1 mL of trifluoro-acetic acid was stirred at room temperature for 20 minutes. The excess trifluoroacetic acid was then removed under reduced pressure. The residue was dissolved in 5 mL of tetrahydrofuran and to this solution were added 1.5 mL of triethylamine followed by 0.05 mL (0.42 mMol) of 4-fluorobenzoyl chloride. After stirring for 1 hour the volatiles were removed under reduced pressure. The residue was taken up in 5 mL of dichloromethane and stirred with dilute aqueous sodium carbonate. After stirring for 16 hours the dichloromethane layer was separated and the aqueous layer extracted with fresh dichloromethane. The dichloromethane extracts were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 5% methanol (containing 5% ammonium hydroxide) in chloroform. Fractions containing product were combined and concentrated under reduced pressure. The resulting residue was crystallized from toluene/hexane to provide 0.058 gm (60%) of the title compound as a crystalline solid in two crops.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]([CH2:12][CH2:13][CH:14]3[CH2:18][CH2:17][CH2:16][N:15]3[CH3:19])[C:7](=O)[CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:19][N:15]1[CH2:16][CH2:17][CH2:18][CH:14]1[CH2:13][CH2:12][N:6]1[CH2:7][CH2:8][CH2:9][CH2:10][C:4]2[CH:3]=[C:2]([NH2:1])[CH:21]=[CH:20][C:5]1=2
Reactant: CN1CCCC1CCN1C(=O)CCCc2cc(N)ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCCC1CCN1CCCCc2cc(N)ccc21
Temperature: 25 °C
Reaction time: 23 h
Yield: 75.2 %

Procedure:
A solution of compound 3 (825 mg, 2.87 mmol) in anhydrous THF (15 mL) was cooled to 0° C. and treated drop wise with LiAlH4 (1.0 M in THF, 11.5 mL, 11.5 mmol). The reaction mixture was warmed to room temperature and stirred overnight (23 h). The reaction mixture was cooled to 0° C. and quenched with H2O (0.4 mL), 2 N NaOH (0.4 mL), and additional H2O (0.4 mL) and stirred for 30 minutes upon, which a white precipitate formed. The solid was filtered off and washed with CH2Cl2 (2×50 mL) and the filtrate concentrated. The crude product was purified by column chromatography (2N NH3 in MeOH:CH2Cl2, 5:95) to give compound 4 (590 mg, 75%) as a thick brown syrup.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7](O)=[O:8])([O-:3])=[O:2].O=S(Cl)[Cl:19].CC(=O)OCC>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([Cl:19])=[O:8])([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(Cl)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 20 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
A mixture of 3-nitro-5-(trifluoromethyl)benzoic acid (2 g, 8.51 mmol) in DCM (30 mL) was added SOCl2 (1.242 mL, 17.01 mmol) at 20° C. The mixture was stirred at 20° C. for 2 h. TLC (PE/EA=2:1, Rf=0.3) showed the reaction was finished. The mixture was concentrated to give 3-nitro-5-(trifluoromethyl)benzoyl chloride (1.8 g, 6.50 mmol, 76% yield).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[N:8]([CH3:17])[CH2:7][C:6]=12.[CH:18]#[C:19][CH3:20]>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:17][N:8]1[C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:5]2[CH:4]=[N:3][C:2]([C:18]#[C:19][CH3:20])=[C:6]2[CH2:7]1
Reactant: CN1Cc2c(I)ncn2-c2ccccc2C1=O
Reactant: C#CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: CC#Cc1ncn2c1CN(C)C(=O)c1ccccc1-2

Procedure:
6.78 g (20 mmol) of 4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was heated to 100° in a pressure tube overnight with 80 mg of bis-(triphenylphosphine)-palladium(II) dichloride, 30 mg of copper(I) iodide and about 2 ml of propyne in 60 ml of diethylamine. The reaction mixture was then evaporated and the residue was chromatographed on 300 g of silica gel while eluting with ethyl acetate. By recrystallization of the crude product from ethanol there was obtained 4,5-dihydro-5-methyl-3-(1-propynyl)-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 206°-207°.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.Br[CH2:14][CH2:15][C:16]([O:18]C)=[O:17]>CS(C)=O.O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:8]=[CH:7]2
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: COC(=O)CCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)CCn1ccc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
Under an N2 atmosphere, crushed KOH was added to a solution of 5-chloro-1H-indole (2.0 g, 13.2 mmol) in DMSO (19 mL, 0.7 M), and the mixture was stirred for 2 h at RT. Methyl 3-bromopropanoate (1.9 mL, 17.2 mmol) was added dropwise, and the reaction was continued to stir at RT overnight. After diluting with H2O, the reaction was cleared with a 4.5 N aqueous KOH solution and washed 3 times with CH2Cl2. The aqueous layer was acidified with a 2N HCl solution to pH 3 and extracted 3 times with CH2Cl2. The organic fractions were combined, dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0-8% MeOH in CH2Cl2 gave 3-(5-chloro-1H-indol-1-yl)propanoic acid (2 g, 68%). 1H NMR (400 MHz, DMSO-d6) δ 7.58 (d, J=2.0 Hz, 1H), 7.54 (d, J=8.7 Hz, 1H), 7.44 (d, J=3.1 Hz, 1H), 7.13 (dd, J=8.7, 2.1 Hz, 1H), 6.42 (dd, J=3.2, 0.7 Hz, 1H), 4.40 (t, J=6.8 Hz, 2H), 2.75 (t, J=6.8 Hz, 2H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=224.5; tR=2.74 min.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[N+:8]([C:4]1[CH:3]=[C:2]([N:15]2[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]2)[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: CN1CCNCC1
Product: CN1CCN(c2cccc([N+](=O)[O-])c2)CC1
Temperature: 120 °C

Procedure:
A mixture of 3-fluoronitrobenzene (20 ml; 0.19 mol) and 1-methylpiperazine (40 ml; 0.36 mol) was heated to 120° C. for a week. The cooled mixture was purified by column-chromatography on silica gel using a mixture of ethyl acetate and methanol (9:1 v/1) as the eluent. Yield: 33 g (79%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])[C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][N:3]=1.[C:16](O)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:16]([NH:9][NH:8][C:6](=[O:7])[C:5]1[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])=[CH:11][C:2]([Cl:1])=[N:3][CH:4]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)Nc1cc(Cl)ncc1C(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Nc1cc(Cl)ncc1C(=O)NNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
6-chloro-4-(isopropylamino)nicotinohydrazide (10) (500 mg, 2.1 mmol) and benzoic acid (2.1 mmol, 1 equiv.) were dissolved in DMF (10 mL). EDC.HCl (1.5 equiv.), DIPEA (3 equiv.) and HOBT (1.5 equiv.) were added to the reaction mixture and stirred at room temperature for 5 h. The reaction mass was concentrated under reduced pressure to remove excess of solvent present. Diluted the residue with EtOAc and washed water followed by brine solution. The organic layer was collected, dried over Na2SO4, filtered and concentrated to get N′-benzoyl-6-chloro-4-(isopropylamino)nicotinohydrazide.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]([CH3:10])=[CH:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[CH3:13][N:14]([CH3:16])[CH:15]=[CH:2][C:1]([C:4]1[CH:5]=[N:6][C:7]([CH3:10])=[CH:8][CH:9]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccc(C)nc1
Product: Cc1ccc(C(=O)C=CN(C)C)cn1

Procedure:
As for Example 1, 3-acetyl-6-methylpyridine is refluxed with N,N-dimethylformamide dimethylacetal to yield 3-dimethylamino-1-(6-methyl-3-pyridyl)-2-propen-1-one. The preceding compound is heated at reflux temperature for 6 hours with 3-amino-4-chloropyrazole in glacial acetic acid to give the product of the example.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:8]([CH2:14][N:15](C)[CH2:16][CH2:17][C:18]([N:20]1[CH2:26][CH2:25][C:24]3[CH:27]=[C:28](OC)[C:29]([O:31][CH3:32])=[CH:30][C:23]=3[CH2:22][CH2:21]1)=[O:19])[CH2:7]2.COC1C(OC)=CC2CC(=O)NC=CC=2C=1.COC1C=CC2C=CNC(=O)CC=2C=1.CN.COC1C=C2C(=CC=1OC)[C@@H](CN)C2>O1CCOCC1.C1COCC1>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C@@H:8]([CH2:14][NH:15][CH2:16][CH2:17][C:18]([N:20]1[CH2:26][CH2:25][C:24]3[CH:27]=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:23]=3[CH2:22][CH2:21]1)=[O:19])[CH2:7]2
Reactant: COc1cc2c(cc1OC)CCN(C(=O)CCN(C)CC1Cc3cc(OC)c(OC)cc31)CC2
Agent: CN
Agent: COc1cc2c(cc1OC)CC(=O)NC=C2
Agent: COc1cc2c(cc1OC)[C@@H](CN)C2
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COc1ccc2c(c1)CCN(C(=O)CCNC[C@H]1Cc3cc(OC)c(OC)cc31)CC2

Procedure:
Obtained in the same manner as the product of Example 1, but with replacement, in Step 1, of the 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one by 8-methoxy-1,3-dihydro-2H-3-benzazepin-2-one and, in Step 4, of the racemic (3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl]methylamine by {[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}amine and of the THF by dioxane.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([N:6]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH2:5].[NH:22]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]1>C(#N)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:21])[CH:4]([N:6]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][N:22]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]1
Reactant: C=C(C(=O)OC)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: OC1CCNCC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)C(CN1CCC(O)CC1)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
To a solution of 2-(di-tert-butoxycarbonylamino)-acrylic acid methyl ester (1.0 g, 3.0 mmol) in acetonitrile (10 mL) was added piperidin-4-ol (0.33 g, 1.1 equiv). A gentle stream of nitrogen was placed over the reaction while it stirred overnight. The crude oil which resulted was dissolved in ethyl acetate, washed with water, then brine, dried over magnesium sulfate, and concentrated to give 1.38 g (quant.) as an oil which was used without purification. Mass spec.: 403.42 (MH)+.