Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13](Cl)=[O:14].[CH2:16]=[CH2:17]>C(Cl)Cl>[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:7]=1[CH2:12][C:13](=[O:14])[CH2:17][CH2:16]2
Reactant: O=C(Cl)Cc1ccccc1Br
Reactant: C=C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1CCc2cccc(Br)c2C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
83.5 g of aluminum chloride (0.63 mmol) were introduced into 1.8 liters of methylene chloride at 0°-+5° C. 105 g (0.49 mole) of 2-bromophenyl-acetyl chloride (dissolved in 200 ml of methylene chloride) were added dropwise at 0°-+5° C. over 30 minutes. After stirring for 30 minutes at 0°-+5° C., 50 g of ethylene were passed in at such a rate that the reaction temperature did not exceed +10° C. The mixture was stirred for a further 2 hours at 20°-+25° C. The aluminum complex was decomposed by careful addition of 500 ml of ice water, the phases were separated, and the aqueous phase was extracted with 250 ml of methylene chloride. The title compound was obtained from the dried methylene chloride phase in a yield of 109 g as a yellow oil (content according to GC 97%) and employed without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:24]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:25]([O:27]CC)=[O:26])[CH:6]=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:8]=1[O:9][CH2:10][CH:11]1[CH2:13][CH2:12]1)#[N:2].CO.O.O[Li].O>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:24]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:25]([OH:27])=[O:26])[CH:6]=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:16][CH:15]=2)[C:8]=1[O:9][CH2:10][CH:11]1[CH2:12][CH2:13]1)#[N:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(C#N)c(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CC(C(=O)O)c1cc(C#N)c(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.6 %

Procedure:
To a stirred solution of ethyl 2-(5-cyano-6-(cyclopropylmethoxy)-4′-(trifluoromethyl) biphenyl-3-yl)-4-methylpentanoate (0.125 g, 0.272 mmol) in a mixture of THF (5 mL), methanol (5 mL) and water (2 mL) was added LiOH.H2O (34 mg, 0.816 mmol) at room temperature and the mixture was stirred at RT for 2 h. After complete consumption of starting material as monitored by TLC, the reaction mixture was diluted with water (10 mL) and acidified using 1 N HCl at 0° C. The aqueous layer was extracted with EtOAc (2×20 mL); combined organic extracts were washed with water (10 mL), brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude material was purified by column chromatography to afford 2-(5-cyano-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid (50 mg) as an off white solid. 1HNMR (500 MHz) (CDCl3): δ (ppm) 7.70 (m, 4H), 7.61 (s, 1H), 7.51 (s, 1H), 3.71 (t, 1H), 3.55 (m, 2H), 2.00 (m, 1H), 1.67 (m, 1H), 1.51 (m, 1H), 1.02 (m, 1H), 0.91 (d, 6H), 0.45 (m, 2H), 0.05 (m, 2H).
Reaction SMILES: [CH2:1]1[C@@H:5]2[C@@H:6]3[C:11](=[O:12])[O:10][C:8](=[O:9])[C@@H:7]3[C@H:2]1[CH:3]=[CH:4]2.C1(C)C=CC=CC=1.COC1C=CC2N=CC=C([C@H](O)[C@@H]3N4C[C@H](C=C)C(CC4)C3)C=2C=1.[CH3:44][OH:45]>C(Cl)(Cl)(Cl)Cl>[CH3:44][O:45][C:11]([C@H:6]1[C@H:5]2[CH2:1][C@H:2]([CH:3]=[CH:4]2)[C@H:7]1[C:8]([OH:10])=[O:9])=[O:12]
Reactant: CO
Reactant: O=C1OC(=O)[C@H]2[C@@H]1[C@@H]1C=C[C@H]2C1
Agent: C=C[C@H]1CN2CCC1C[C@@H]2[C@@H](O)c1ccnc2ccc(OC)cc12
Solvent: Cc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)[C@@H]1[C@H](C(=O)O)[C@H]2C=C[C@@H]1C2
Temperature: -55 °C
Reaction time: 0.17 h
Yield: 99.2 %

Procedure:
The starting material (a) was prepared as described in J. Org. Chem. 2000, 65, 6984-6991. cis-5-Norbornene-exo-2,3-dicarboxylic anhydride (5 g, 30.45 mmol) was suspended in a 1:1 mixture of toluene and carbon tetrachloride (150 mL). The mixture was stirred for 10 min. Quinidine (10.9 g, 33.5 mmol) was added and the flask was degassed and backfilled with nitrogen. The solution was cooled to −55° C. While stirring, methanol (3.7 mL, 91.35 mmol) was added. The mixture was stirred at −55° C. for 16 h. Upon warming to 25° C., the mixture was concentrated in vacuo to a foam. The foam was dissolved in a mixture of ethyl acetate (400 mL) and 1.0 M aqueous hydrochloric acid solution (400 mL). The layers were separated and the organic layer was further washed with 1.0 M aqueous hydrochloric acid solution (2×100 mL), saturated aqueous brine solution (100 mL) and dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the desired product, (1R,2R,3S,4S)-3-(methoxycarbonyl)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (5.92 g, 30.2 mmol, 99%), as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ: 1.29 (1H, d, J=10.2 Hz), 1.96 (1H, d, J=8.6 Hz), 2.47-2.49 (2H, m), 2.93-2.94 (2H, m), 3.51 (3H, s), 6.15-6.20 (2H, m), 12.15 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([OH:10])=[O:9].O[CH2:26][C:27]1[O:28][C:29]2[CH:35]=[C:34]([CH2:36][C:37]3[NH:38][CH:39]=[CH:40][N:41]=3)[CH:33]=[CH:32][C:30]=2[N:31]=1.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([O:10][CH2:26][C:27]1[O:28][C:29]2[CH:35]=[C:34]([CH2:36][C:37]3[NH:41][CH:40]=[CH:39][N:38]=3)[CH:33]=[CH:32][C:30]=2[N:31]=1)=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Reactant: OCc1nc2ccc(Cc3ncc[nH]3)cc2o1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCc2nc3ccc(Cc4ncc[nH]4)cc3o2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
332 mg (1 mM) of 1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid together with 229 mg (1 mM) of 2-hydroxymethyl-6-(1-imidazolylmethyl)benzoxazole 248 mg (1.2 mM) of dicyclohexylcarbodiimide and 134 mg (1.1 mM) of 4-N,N-dimethylaminopyridine were dissolved in 5 ml of toluene, while heating, and refluxed for six hours. The solution was cooled to room temperature, and the crystals produced were filtered off. The filtrate was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by chromatography on a silica gel column, whereby the captioned compound was obtained. The yield was 542 mg (99.9%).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1)=[NH:4].[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[O:25][CH:26]([CH3:28])[CH3:27])[C:19](Cl)=O.C(N(CC)CC)C>CN(C)C=O>[Cl:15][C:16]1[CH:17]=[C:18]([C:19]2[O:1][N:2]=[C:3]([C:5]3[CH:14]=[CH:13][CH:12]=[C:11]4[C:6]=3[CH:7]=[CH:8][N:9]=[CH:10]4)[N:4]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH:26]([CH3:27])[CH3:28]
Reactant: CC(C)Oc1ccc(C(=O)Cl)cc1Cl
Reactant: N=C(NO)c1cccc2cnccc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4cnccc34)no2)cc1Cl
Temperature: 25 °C
Yield: 87.2 %

Procedure:
N-hydroxy-5-isoquinolinecarboximidamide (D1; 1.18 g, 6.30 mmol) was added to a solution of 3-chloro-4-[(1-methylethyl)oxy]benzoyl chloride (D4; 1.54 g, 6.62 mmol), triethylamine (0.966 ml, 6.93 mmol) and N,N-dimethylformamide (DMF) (10 ml) at 0° C. under a blanket of nitrogen. The mixture was allowed to warm to room temperature over 1 h and then heated at 120° C. under nitrogen overnight. The mixture was allowed to cool and then filtered. An off-white solid was collected and washed with acetonitrile to give the title compound (2.01 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[Br-].[CH2:12]([Zn+])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1.C(OCC)(=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH2:12]([C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[CH:7][C:6]=2[CH:10]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Brc1ccc2sccc2c1
Reactant: [Zn+]Cc1ccccc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: c1ccc(Cc2ccc3sccc3c2)cc1
Temperature: 100 °C
Yield: 65 %

Procedure:
5-Bromobenzothiophene (2.13 g, 10 mmol) was dissolved in a THF solution of benzyl zinc(II) bromide (0.5M, 10 mL, 20 mmol) in a microwave reaction tube. Pd(PtBu3)2 (255 mg, 0.5 mmol) was added to this solution. The mixture was purged with N2 gas for 3-5 minutes and heated at 100° C. for 30 minutes under microwave irradiation. Upon completion of the reaction, the reaction mixture was diluted with ethyl acetate (150 mL), washed with 1N HCl aqueous solution, brine, filtered through Celite. The filtrate was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (ISCO system, 5% EtOAc in hexanes) to give the desired product (65% yield): 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J=8.4 Hz, 1H), 7.63 (s, 1H), 7.40 (d, J=5.6 Hz, 1H), 7.18-7.30 (m, 7H), 4.10 (s, 2H).
Reaction SMILES: C[O:2][C:3]1[C:8]([NH:9][C:10]2[C:15]([CH3:16])=[C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:13]=[C:12]([NH:23][C@@H:24]3[CH2:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]3)[N:11]=2)=[CH:7][CH:6]=[CH:5][N:4]=1.Cl>O1CCOCC1>[CH3:16][C:15]1[C:10]([NH:9][C:8]2[C:3](=[O:2])[NH:4][CH:5]=[CH:6][CH:7]=2)=[N:11][C:12]([NH:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]2)=[N:13][C:14]=1[N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: COc1ncccc1Nc1nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)nc(N2CCOCC2)c1C
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(Nc2ccc[nH]c2=O)nc(N[C@@H]2CCCNC2)nc1N1CCOCC1
Yield: 27.2 %

Procedure:
A mixture of (R)-tert-butyl 3-(4-(2-methoxypyridin-3-ylamino)-5-methyl-6-morpholino pyrimidin-2-ylamino)piperidine-1-carboxylate (Preparation 27a, 0.523 g, 1.05 mmol) and a 4N solution of hydrogen chloride in 1,4-dioxane (10 mL) was stirred at ambient temperature for 3 days. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. Solid potassium carbonate was added to the aqueous phase until a basic pH was reached and the aqueous solution was extracted with methylene chloride (×3). The combined organic extracts were dried (Na2SO4) and the solvent was evaporated under reduced pressure to give the title compound (0.110 g, 23%) as a yellow solid that was used in the next synthetic step without further purification.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[CH:11][CH:12]=2)[CH2:7]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1.C(OCC)C>[CH3:17][O:16][C:10]1[CH:9]=[C:8]2[C:13]([CH2:14][CH2:15][CH:6]([CH2:4][OH:3])[CH2:7]2)=[CH:12][CH:11]=1
Reactant: CCOC(=O)C1CCc2ccc(OC)cc2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc2c(c1)CC(CO)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 23.43 g (100 mmol) of 7-methoxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid ethyl ester in 160 ml of absolute tetrahydrofuran is added dropwise, over a period of 30 minutes, while stirring at room temperature, to a suspension of 3.79 g (100 mmol) of lithium aluminium hydride in 160 ml of absolute diethyl ether. After stirring at room temperature for 1 hour, 3.8 ml of water, 3.8 ml of sodium hydroxide solution (15%) and 11.4 ml of water are added to the reaction mixture. The resulting precipitate is filtered off with suction and the filtrate is concentrated to dryness by evaporation in vacuo. The oily residue is dissolved in diethyl ether, washed with water, dried with sodium sulphate and concentrated to dryness by evaporation. 7-methoxy-1,2,3,4-tetrahydro-naphthalene-2-methanol is obtained in the form of a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:10])=[C:7]([CH:9]=1)[NH2:8].C(N(CC)CC)C.[Cl:18][CH2:19][C:20](Cl)=[O:21].Cl>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:10])=[C:7]([NH:8][C:20](=[O:21])[CH2:19][Cl:18])[CH:9]=1
Reactant: COc1ccc(C)c(N)c1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C)c(NC(=O)CCl)c1
Reaction time: 0.75 h

Procedure:
To a solution of 5-methoxy-2-methylaniline (7.62 g) and triethylamine (15.5 ml) in dichloromethane (150 ml) at 0-5° C. was added chloroacetyl chloride (5.0 ml) dropwise and the ice bath removed. The resulting reaction mixture was stirred for 45 min before being poured into dil HCl and extracted with dichloromethane. Organic extracts were combined, washed with water, dried (Na2SO4) and concentrated to give a brown solid that was triturated with diethyl ether to leave the sub-title compound as a beige solid (5.7 g).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18]C)=[O:17])=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([OH:18])=[O:17])=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2c(ccn2Cc2ccc(Br)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2c(ccn2Cc2ccc(Br)cc2)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
To a solution of methyl 1-(4-bromobenzyl)-1H-indole-5-carboxylate (1.09 g, 3.2 mmol, 1 equiv) in methanol (30 mL) was added a 5 N NaOH solution (6.3 mL, 32 mmol, 10 equiv). The reaction mixture was stirred 2 h at 40° C. The mixture was then acidified and extracted with DCM. After concentration in vacuo, the title compound was precipitated in Et2O to afford a white powder (1.03 g, 3.1 mmol, 99%). ESI-MS (m/z): 330/332 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:23])[C:5]2[CH:11]=[C:10]([C:12]#[C:13][Si](C)(C)C)[C:9](=[O:18])[N:8]([CH:19]3[CH2:22][CH2:21][CH2:20]3)[C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+]>CO>[NH2:1][C:2]1[N:3]=[C:4]([CH3:23])[C:5]2[CH:11]=[C:10]([C:12]#[CH:13])[C:9](=[O:18])[N:8]([CH:19]3[CH2:22][CH2:21][CH2:20]3)[C:6]=2[N:7]=1
Reactant: Cc1nc(N)nc2c1cc(C#C[Si](C)(C)C)c(=O)n2C1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cc2c(C)nc(N)nc2n(C2CCC2)c1=O
Reaction time: 5 h
Yield: 98.9 %

Procedure:
To a stirred solution of 2-amino-8-cyclobutyl-4-methyl-6-(2-(trimethylsilyl)ethynyl)pyrido[2,3-d]pyrimidin-7(8H)-one (105 mg, 0.322 mmol) in MeOH (7 mL) was added K2CO3 (50 mg, 0.36 mmol) and the mixture was stirred for 5 h. LC-MS indicated complete conversion. Solvent was evaporated and the residue was purified by flash chromatography, using CHCl3, to give the title compound (81 mg, 99%).
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[CH:6]([C:9]1[S:13][CH2:12][N:11]([CH3:14])[CH:10]=1)[O:7][CH3:8].CN(C)C=O.[CH3:24][CH:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[H-].[Na+]>CCOCC>[CH3:8][O:7][CH:6]([C:9]1[S:13][CH2:12][N:11]([CH3:14])[CH:10]=1)[C:5]1[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=1[CH:3]=[N:2][O:1][CH:25]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:24]
Reactant: CC(Br)c1ccccc1
Reactant: COC(C1=CN(C)CS1)c1ccccc1C=NO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(C1=CN(C)CS1)c1ccccc1C=NOC(C)c1ccccc1
Reaction time: 3 h
Yield: 86.8 %

Procedure:
To a mixture of 0.25 g (1 mmol) of 5-(2-hydroxyiminomethyl-α-methoxybenzyl)-3-methylthiazole, 3 ml of N,N-dimethylformamide and 0.24 g (1.3 mmol) of α-methylbenzyl bromide was added 0.05 g (1.3 mmol) of 60% sodium hydride under ice-cooling and stirred at the same temperature for 3 hours. After completion of the reaction, 100 ml of ether was added and washed twice with 80 ml of brine. The ether layer was dried over anhydrous magnesium and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give 5-[α-methoxy-2-(4-phenyl-2-aza-3-oxa-1-pentenyl)benzyl]-3-methylthiazole (0.32 g, 91.3%) as colorless oil.
Reaction SMILES: C[Al](C)C.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.CO>[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][CH:8]=1)=[NH:17]
Reactant: N#Cc1ccccc1Cl
Reactant: Nc1ccc(Cl)cc1
Agent: C[Al](C)C
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: N=C(Nc1ccc(Cl)cc1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Trimethylaluminum (2M in hexanes, 100 ml, 200 mmol) was added dropwise to a solution of 4-chloro-phenylamine (18.2 g, 143 mmol) in toluene (550 ml) under a N2 atmosphere at 0° C. The reaction mixture was warmed to room temperature and stirred for 3.5 hours. A solution of 2-chlorobenzonitrile (23.6 g, 171 mmol) in toluene (140 ml) was added and the reaction mixture was heated at 80° C. for 17 hours, during which time it became homogeneous. The reaction mixture was then cooled to room temperature and poured over a slurry of silica gel in CHCl3/methanol (2:1). After filtration, the filter cake was washed with a mixture of CH2Cl2/MeOH (2:1). The combined filtrates were concentrated in vacuo, and the solid yellow residue was triturated with hexanes/ether (2:1). The product I-5a (25.1 g, 66%) was used in the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6].[CH2:11]([O:13][C:14]([C@@H:16]1[CH2:18][C@H:17]1[C:19](O)=O)=[O:15])[CH3:12].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:5]([C:4]1[CH:7]=[CH:8][C:9]2[NH:10][C:19]([CH:17]3[CH2:18][CH:16]3[C:14]([O:13][CH2:11][CH3:12])=[O:15])=[N:1][C:2]=2[CH:3]=1)#[N:6]
Reactant: CCOC(=O)[C@@H]1C[C@H]1C(=O)O
Reactant: N#Cc1ccc(N)c(N)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CC1c1nc2cc(C#N)ccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.3 %

Procedure:
To a mixture of 3,4-diaminobenzonitrile (326 mg, 2.45 mmol), trans-2-(ethoxycarbonyl)cyclopropanecarboxylic acid (323 mg, 2.04 mmol), and triethylamine (1.44 mL, 10.2 mmol) in DMF (10 mL) was added HBTU (1.01 g, 2.66 mmol). After stirring at room temperature for 3 h, the mixture was poured into water, and the aqueous phase was extracted with EtOAc twice. The combined organic layer was dried over sodium sulfate and concentrated in vacuo. To the residue was added acetic acid (10 mL), and the mixture was stirred at 90° C. for 12 h. After cooling to room temperature, the solvent was removed in vacuo. The residue was poured into saturated sodium bicarbonate aqueous solution, and the aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate to give 210 mg (40%) of the title compound as a white amorphous:
Reaction SMILES: O[CH2:2][N:3]1[C:8](=[O:9])[N:7]2[CH:10]=[N:11][C:12]([C:13]([NH2:15])=[O:14])=[C:6]2[N:5]=[N:4]1.Br[CH2:17][C:18]#[C:19]C.C1CCN2C(=NCCC2)CC1.Cl>C(#N)C>[CH2:2]([N:3]1[C:8](=[O:9])[N:7]2[CH:10]=[N:11][C:12]([C:13]([NH2:15])=[O:14])=[C:6]2[N:5]=[N:4]1)[C:17]#[C:18][CH3:19]
Reactant: NC(=O)c1ncn2c(=O)n(CO)nnc12
Reactant: CC#CCBr
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC#CCn1nnc2c(C(N)=O)ncn2c1=O
Reaction time: 0.5 h

Procedure:
To a cooled solution of 3-(Hydroxymethyl)-4-oxo-3,4-dihydroimidazo[5,1-][1,2,3,5]tetrazine-8-carboxamide (MM-001) (1 equiv) in acetonitrile (0.17 M concentration substrate in solvent) was added the 1-bromo-2-butyne (4 equivs) and DBU (1.4 equivs). The mixture was stirred at this temperature for 30 minutes whereupon it was acidified with 1 N HCl. The mixture was extracted with EtOAc (3×1 reaction volume). The combined organic extracts were combined, dried (MgSO4), filtered and concentrated in vacuo to give an oily residue which was then precipitated from Et2O and washed with further Et2O to give the title compound. 1H NMR (400 MHz, d6-DMSO) δ ppm: 8.84 (1H, s), 7.82 (1H, s), 7.70 (1H, s), 5.08 (2H, q, J=2.4 Hz), 1.84 (3H, t, J=2.4 Hz).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].N.[NH2:10][C@H:11]([C:16]([OH:18])=[O:17])[CH2:12][C:13]([OH:15])=[O:14].[OH-].[Na+].Cl>O>[NH:10]([CH:11]([CH2:12][C:13]([OH:15])=[O:14])[C:16]([OH:18])=[O:17])[CH:3]([CH2:2][C:1]([OH:8])=[O:7])[C:4]([OH:6])=[O:5]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: O=C(O)/C=C\C(=O)O
Agent: Cl
Agent: N
Agent: [Na+]
Solvent: O
Product: O=C(O)CC(NC(CC(=O)O)C(=O)O)C(=O)O
Temperature: 95 °C
Reaction time: 20 h

Procedure:
A mixture of 12.77 g (110 mmol) maleic acid, 19.2 g (300 mmol) of 28% aqueous ammonia, and 13.3 g (100 mmol) aspartic acid in 75 ml water was heated to 95° C. with stirring. The solution was adjusted to a pH of 9 with 10% aqueous sodium hydroxide, then stored at 95° C. for 20 hours. The resulting clear solution was cooled to room temperature and 11.95 g (300 mmol) concentrated hydrochloric acid was added. The resulting precipitate of maleic and fumeric acid was removed by filtration, and the supernatant was concentrated under pressure to yield the product as a white solid.
Reaction SMILES: [CH2:1]([N:8]=[N+:9]=[N-:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]1([C:17]#[CH:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C[C-]1C(C)=C(C)C(C)=C1C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ru+].C1C=CC=CC=1>[CH2:1]([N:8]1[C:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:18][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: C#Cc1ccccc1
Agent: Cl[Ru+]
Agent: Cc1c(C)c(C)[c-](C)c1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: c1ccc(Cn2nncc2-c2ccccc2)cc1

Procedure:
Benzyl azide (0.100 g, 0.751 mmol), phenylacetylene (0.150 mL, 1.37 mmol), Cp*RuCl(PPh3)2 (30 mg, 0.038 mmol). Solvent, benzene; reaction temperature, r.t.; reaction time, 24 hours; yield, 0.13 g (75%). EI-MS: m/z 236 [M+1].
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([C:25]1[C:34]([OH:35])=[CH:33][C:28]3[O:29][CH2:30][CH2:31][O:32][C:27]=3[CH:26]=1)[C:5](=[O:24])[N:6]2[CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:36]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:25]3[C:34](=[CH:33][C:28]4[O:29][CH2:30][CH2:31][O:32][C:27]=4[CH:26]=3)[O:35][CH2:36]1)[C:5](=[O:24])[N:6]2[CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: O=C1C(c2cc3c(cc2O)OCCO3)c2c(Br)cccc2N1C(c1ccccc1)c1ccccc1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Br)c2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 4-bromo-1-(diphenylmethyl)-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 4′-bromo-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (66%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ7.47-7.16 (m, 12H), 6.85 (s, 1H), 6.82-6.76 (m, 1H), 6.57 (s, 1H), 5.92 (s, 1H), 5.66 (ABq, 2H), 4.22-4.14 (m, 4H).