Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Na+].[Cl:4][C:5]1[C:9]([Cl:10])=[C:8]([CH3:11])[NH:7][C:6]=1[C:12]([NH:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[C:23]([C:31]([O:33]C)=[O:32])[N:22]=2)[CH2:17][CH2:16]1)=[O:13].Cl>C1COCC1.CCOC(C)=O>[Cl:4][C:5]1[C:9]([Cl:10])=[C:8]([CH3:11])[NH:7][C:6]=1[C:12]([NH:14][CH:15]1[CH2:16][CH2:17][N:18]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[C:23]([C:31]([OH:33])=[O:32])[N:22]=2)[CH2:19][CH2:20]1)=[O:13]
Reactant: COC(=O)c1cc2ccccc2c(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1[nH]c(C(=O)NC2CCN(c3nc(C(=O)O)cc4ccccc34)CC2)c(Cl)c1Cl
Temperature: 80 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
In a mixture of 20 ml THF, 5 ml H2O, and 1 ml 50 wt % NaOH (aq) was dissolved methyl 1-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)isoquinoline-3-carboxylate (Example 301; 70 mg). The solution was stirred at 80° C. for 1 hr. The solution was cooled to room temperature, diluted with EtOAc and acidified with dilute HCl (aq). The EtOAc fraction was isolated, at which time a white solid precipitated from solution. The solid was collected by filtration and washed with acetonitrile to yield 50 mg white solid product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(O)(=O)(=O)C.[Cl:12][CH2:13][CH2:14][CH2:15][O:16][C:17]12[CH:26]=[CH:25][CH:24]=[CH:23][CH:18]1[CH2:19][CH:20]2[CH2:21]O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:12][CH2:13][CH2:14][CH2:15][O:16][C:17]12[CH:26]=[CH:25][CH:24]=[CH:23][CH:18]1[CH2:19][CH:20]2[CH2:21][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCC1CC2C=CC=CC21OCCCCl
Reactant: C1CCNCC1
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: ClCCCOC12C=CC=CC1CC2CN1CCCCC1

Procedure:
Piperidine (3.19 ml) is added to a solution of 3-(3-chloropropoxy)-1-hydroxymethylbenzocyclobutene mesylate (2.45 g) in toluene (32 ml) and the reaction mixture refluxed under nitrogen for about 12 hours. The reaction mixture is diluted with ethyl acetate and extracted with saturated NaHCO3 followed by saturated NaCl. The organic extract is dried, filtered and concentrated yielding the crude product used in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]#[N:8])=[N:4][O:5][N:6]=1.[CH2:9]([NH2:13])[CH:10]([CH3:12])[CH3:11].[Al+3].[Cl-].[Cl-].[Cl-]>ClC(Cl)C>[NH2:1][C:2]1[C:3]([C:7]([NH:13][CH2:9][CH:10]([CH3:12])[CH3:11])=[NH:8])=[N:4][O:5][N:6]=1
Reactant: N#Cc1nonc1N
Reactant: CC(C)CN
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(C)CNC(=N)c1nonc1N
Reaction time: 0.33 h

Procedure:
To a solution of 4-amino-1,2,5-oxadiazole-3-carbonitrile (220 mg, 2 mmol) and isobutylamine (0.2 mL, 2 mmol) in dichloroethane (1 mL) was added AlCl3 (293 mg, 2.2 mmol). The reaction mixture is stirred for 20 min and then quenched with ice cold water (5 mL). The mixture is extracted with diethyl ether (3×20 mL). Combined extracts was dried over anhydrous Na2SO4 and concentrated under vacuum to afford the title compound as a white solid. MS 184 M+1. The crude product was carried to next step without further purification.
Reaction SMILES: N[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5].[I:14]CI.N(OC(C)(C)C)=O>C(#N)C.CCOCC>[I:14][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(C(F)(F)F)ccc1N
Reactant: ICI
Agent: CC(C)(C)ON=O
Solvent: CC#N
Solvent: CCOCC
Product: N#Cc1cc(C(F)(F)F)ccc1I
Temperature: 35 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-amino-5-(trifluoromethyl)benzonitrile (Intermediate 7, 15.1 g) and diiodomethane (24 mL) in acetonitrile (150 mL) at 35° C. was added t-butyl nitrite (21 mL) dropwise. The reaction was maintained at approximately 35° C. during the addition. The reaction was aged for 30 min and then heated to 60° C. for 30 minutes. The reaction mixture was cooled, diluted with ether and washed twice with water, twice with aqueous sodium bisulfite, water and then brine. The solution was dried over anhydrous MgSO4, filtered through a silica gel plug and then concentrated giving afford a red oil. The product was purified by silica gel chromatography eluting sequentially with hexanes, 3:1 hexanes/CH2Cl2 and 1:1 hexanes/CH2Cl2 to afford 2-iodo-5-(trifluoromethyl)benzonitrile. 1H NMR (CDCl3, 500 MHz) δ 8.10 (d, J=8.5 Hz, 1H), 7.85 (d, J=1.8 Hz, 1H), 7.52 (dd, J=8.5, 1.8 Hz, 1H).
Reaction SMILES: O=C1CCC(=O)N1[O:8][C:9](=O)[CH2:10][CH2:11][C@H:12]([NH:20][C:21](=[O:45])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[NH2:47][C@H:48]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:49][CH2:50][C:51](=[O:53])[OH:52].CCN(C(C)C)C(C)C.Cl>C(#N)C.O>[C:57]([O:56][C:54](=[O:55])[C@@H:48]([NH:47][C:9](=[O:8])[CH2:10][CH2:11][C@@H:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[NH:20][C:21](=[O:45])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:39])[CH2:49][CH2:50][C:51]([OH:52])=[O:53])([CH3:60])([CH3:59])[CH3:58]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCC(=O)O
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(S)-2-(17-tert-Butoxycarbonylheptadecanoylamino)pentanedioic acid 1-tert-butyl ester 5-(2,5-dioxopyrrolidin-1-yl) ester (0.5 g, 0.766 mmol) was dissolved in acetonitrile (20 mL). This solution was added to a solution of H-Glu-OtBu (0.171 g, 0.84 mmol) in water (30 mL) pH was adjusted to 10 with DIPEA. The mixture was stirred at RT for 15 min, then acidified to pH 7 with HCl (2M) and evaporated in vacuo. The residue was partitioned between ethyl acetate and HCl (0.1 M). The organic layer was dried (MgSO4), filtered, and evaporated in vacuo to dryness. This afforded (S)-2-[(S)-4-tert-butoxycarbonyl-4-(17-tert-butoxycarbonylheptadecanoylamino)butyrylamino]pentanedioic acid 1-tert-butyl ester as an oil. LC-MS (electrospray): m/z=741 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C@H:3]1[NH2:12].O.[C:14](=S)=[S:15]>C(O)C>[NH:1]1[C@@H:2]2[C:11]3[C:6]([CH2:5][CH2:4][C@H:3]2[NH:12][C:14]1=[S:15])=[CH:7][CH:8]=[CH:9][CH:10]=3
Reactant: S=C=S
Reactant: N[C@@H]1CCc2ccccc2[C@H]1N
Solvent: O
Solvent: CCO
Product: S=C1N[C@@H]2c3ccccc3CC[C@H]2N1
Temperature: 25 °C
Yield: 60 %

Procedure:
Trans-1,2-diamino-1,2,3,4-tetrahydronaphthalene (461 mg, 2.84 m mol) was dissolved in ethanol (8 ml), water (4 ml) was added to the solution, then carbon disulfide (190 μl, 3.17 m mol) was added thereto under stirring at room temperature. The mixture was heated under reflux for 4 hours and cooled in an ice-water bath. The crystals precipitating out were separated by filtration, washed with ether and dried in vacuum to give trans-3a,4,5,9b-tetrahydronaphth[1,2-d]imidazoline-2-thione (350 mg, 1.71 m mol) in 60% yield. The data spectroscopy and elemental analysis were as follows:
Reaction SMILES: [OH-].[Na+].[CH2:3]([SH:6])[CH:4]=[CH2:5].C(O[CH:11]1[NH:14][C:13](=[O:15])[CH2:12]1)(=O)C>O>[CH2:3]([S:6][CH:11]1[NH:14][C:13](=[O:15])[CH2:12]1)[CH:4]=[CH2:5]
Reactant: C=CCS
Reactant: CC(=O)OC1CC(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCSC1CC(=O)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 42.9 g of sodium hydroxide in 500 ml of water was made up under nitrogen and cooled to room temperature, 108 ml of allyl mercaptan were added and the mixture stirred under nitrogen for 30 minutes. 138.7 g of 4-acetoxyazetidin-2-one were added to the mixture over 10 minutes under nitrogen and the reaction mixture was stirred overnight. The reaction was checked for completion by T.L.C. (hexane-ethyl acetate) and extracted into dichloromethane (6×250 ml). The organic layer was washed with water (2×250 ml), dried over magnesium sulphate and evaporated in vacuo to dryness. Purification, over silica gel and elution with hexane-ethyl acetate afforded the above product as a yellow oil. (112.1 g, 73% of the theoretical yield). νmax=1769, 1778 (sh) cm-1.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[CH2:12]([C:14]1[CH:28]=[C:17]2[C:18]([C:23](=[O:27])[CH:24](Br)[CH3:25])=[CH:19][C:20]([F:22])=[CH:21][N:16]2[N:15]=1)[CH3:13]>CN(C=O)C>[CH2:12]([C:14]1[CH:28]=[C:17]2[C:18]([C:23](=[O:27])[CH:24]([CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])[CH3:25])=[CH:19][C:20]([F:22])=[CH:21][N:16]2[N:15]=1)[CH3:13]
Reactant: COC(=O)CC(=O)OC
Reactant: CCc1cc2c(C(=O)C(C)Br)cc(F)cn2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cc2c(C(=O)C(C)C(C(=O)OC)C(=O)OC)cc(F)cn2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Dimethyl malonate (327 μL) was added to DMF (4.6 mL) in an argon atmosphere. While the solution was kept at 0° C., 60% sodium hydride (105 mg) was added and the mixture was stirred at room temperature for 30 min. Subsequently, the compound of Example 188 (655 mg) in DMF (10 mL) was added at 0° C. and the mixture was stirred at room temperature for 4 hours. The reaction was terminated by adding a saturated aqueous solution of ammonium chloride and the mixture was extracted three times with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. Evaporation of the solvent under reduced pressure and purification by silica gel column chromatography (hexane:ethyl acetate=6:1) afforded the title compound as a yellow oil (680 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH2:6](O)[CH2:7]O.[C:10]([O:14][CH2:15][CH2:16][OH:17])(=[O:13])C=C>O1CCCC1>[CH:5]12[S:1][CH:2]([CH:6]=[CH:7]1)[CH2:3][CH:4]2[C:10]([O:14][CH2:15][CH2:16][OH:17])=[O:13]
Reactant: OCCO
Reactant: c1ccsc1
Reactant: C=CC(=O)OCCO
Solvent: C1CCOC1
Product: O=C(OCCO)C1CC2C=CC1S2
Temperature: 70 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
Tetrahydrofuran solvent (500 g), thiophene (1.0 mole), represented by Chemical Formula 2a below, ethylene glycol (0.22 mole) and 2-hydroxyethyl acrylate (1.2 mole), represented by Chemical Formula 3a, are introduced into a 2-liter flask, and the mixture is stirred at 70° C. for 24 hours. After the reaction is completed, the solvent and excess 2-hydroxyethyl acrylate are removed by using a rotary evaporator, and the residue is distilled in vacuo to obtain pure 2-hydroxyethyl 7-thiabicyclo[2.2.1]hept-5-ene-2-carboxylate represented by Chemical Formula 101 below (yield: 80%).
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:34]([N:37]([CH3:45])[CH2:38][CH2:39][N:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1.C(Cl)(Cl)Cl>CO.C(OCC)(=O)C.[C].[Pd]>[OH:8][C:9]1[CH:36]=[CH:35][C:34]([N:37]([CH3:45])[CH2:38][CH2:39][N:40]2[CH2:41][CH2:42][CH2:43][CH2:44]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12]
Reactant: CN(CCN1CCCC1)c1ccc(OCc2ccccc2)c(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)OC(C)(C)C)c1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(CCN1CCCC1)c1ccc(O)c(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.1 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-5-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)benzamido)-4-phenylbenzoate (0.097 g) in methanol (1.5 mL) and ethyl acetate (1.5 mL), 10% palladium-carbon (0.097 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours. Chloroform was added to the reaction mixture, and the insoluble substance was removed by filtration. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-95% chloroform/methanol] to obtain 0.048 g of tert-butyl 2-(2-hydroxy-5-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)benzamido)-4-phenylbenzoate.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:8][C@H:9]1[CH2:13][N:12]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][C@@H:10]1[NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:7].[H-].[Na+]>C1COCC1.CN(C=O)C>[CH2:14]([N:12]1[CH2:13][C@H:9]([N:8]2[CH2:2][CH2:3][CH2:4][CH2:5][C:6]2=[O:7])[C@@H:10]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:11]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(Cc2ccccc2)C[C@@H]1NC(=O)CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CN(Cc2ccccc2)C[C@@H]1N1CCCCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To a solution of the product of Step 7 (6.3 g, 13.9 mmol) in THF (60 mL) and DMF (30 mL) was added sodium hydride (611 mg, 60% in oil, 15.29 mmol). After stirring the reaction mixture overnight at RT, it was quenched with water and extracted with EtOAc (3×100 mL). The combined extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to furnish the crude product. The residue was purified by column chromatography on silica gel (90:10 petroleum ether/EtOAc) to obtain desired product (4.53 g, 87.4%). 1H NMR (300 MHz, CDCl3) δ 5.38 (1H, s), 4.60 (1H, m), 4.18 (1H, s), 3.50-3.20 (6H, m), 3.00 (1H, m), 2.80 (1H, m), 2.40 (4H, m), 1.80 (4H, m), 1.40 (9H, m). MS m/z 374 (MH+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[NH2:6].C(N(CC)CC)C.Cl.[C:24](Cl)(=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>O.ClCCl>[OH:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][C@H:5]([NH:6][C:24](=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:4]([O:3][CH3:2])=[O:15])=[CH:13][CH:12]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: CCCCCCCC(=O)Cl
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OC
Reaction time: 3.5 h
Yield: 93.6 %

Procedure:
200 ml of dichloro methane (DCM) was added to (L)-tyrosine methyl ester HCl salt (23.16 g, 0.1 mol), and 28 ml of triethyl amine (TEA, 0.2 mol) was added thereto, thereby dissolving HCl salt. The reactor was temperature-lowered to 0° C. by using an ice bath, and 16.6 ml of octanoyl chloride (0.1 mol) was slowly added, following by stirring for 3-4 hours. 200 ml of water was added to the reacted material, followed by extraction with 400 ml of ethyl acetate. Drying over sodium sulfate followed by filtering was carried out. The solvent was removed from the filtrate by rotary evaporation, followed by separation by column chromatograph using hexane and ethyl acetate (Hex:EA=2:1), thereby obtaining a white solid (30.1 g, 93.3% yield).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH2:11][C:12]#[N:13])=[N:7][C:6]=2[CH:14]=1.[ClH:15].[OH:16][NH2:17].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[Cl:15][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH2:11][C:12](=[NH:13])[NH:17][OH:16])=[N:7][C:6]=2[CH:14]=1
Reactant: NO
Reactant: N#CCSc1nc2cc(Cl)ccc2s1
Reactant: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N=C(CSc1nc2cc(Cl)ccc2s1)NO
Yield: 34 %

Procedure:
14.4 g (0.6 m) (5-chloro-2-benzothiazolylthio)acetonitrile, prepared according to Example 1, 4.17 g (0.06 m) hydroxyamine hydrochloride and 4.14 g (0.03 m) potassium carbonate are dissolved in a mixture of 180 ml ethanol and 2 ml water. The mixture is heated overnight and then cooled. The solid which is collected is washed with water. The crude material is recrystallized from ethanol. The recrystallized product weighs 5.6 g (34% yield) and melts at 155°-7° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=O)[CH:7]=[N:6]2.COC1C=C2C(N=CC(=O)N2)=CC=1.O=P(Cl)(Cl)[Cl:29]>>[Cl:29][C:7]1[CH:8]=[N:9][C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[N:6]=1
Reactant: COc1ccc2[nH]c(=O)cnc2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: COc1ccc2ncc(=O)[nH]c2c1
Product: COc1ccc2ncc(Cl)nc2c1
Yield: 44.6 %

Procedure:
A solution of 6-methoxyquinoxalin-2(1H)-one & 7-methoxyquinoxalin-2(1H)-one (3 g, 18.28 mmol) in POCl3 (20 ml) was refluxed for 3 h. The solvent was evaporated under reduced pressure and the residue was diluted with cold water. The aqueous solution was basified by solid sodium carbonate and extracted with ethyl acetate. The combine organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (20% ethyl acetate in pet ether) to afford mixture of regioisomers (3.7 g). 2 g of the above mixture was separated by SFC purification to afford 2-chloro-7-methoxyquinoxaline (0.7 g, 34.7%) and 2-chloro-7-methoxyquinoxaline (0.9 g, 44.6%) as off white solid.
Reaction SMILES: [CH2:1]=[CH:2][CH3:3].[CH3:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]>>[CH3:1][C:2]([CH:5]([CH3:6])[CH3:4])=[CH2:3].[CH3:1][C:8]([CH2:7][CH2:6][CH3:5])=[CH2:9]
Reactant: C=CC
Reactant: CCCCCC
Product: C=C(C)C(C)C
Product: C=C(C)CCC
Temperature: 32 °C

Procedure:
Ta(C5Me5)(propylene)Cl2 (0.11 g, 0.25 mmol) was dissolved in 2.5 ml of hexane in a 20 ml glass pressure bottle containing a small teflon-coated magnetic stir bar. A pressure head equipped with a rubber system for sampling the mixture was clamped to the glass vessel and the vessel was pressurized to 40 psi with propylene and immersed in a stirred bath maintained at 32° C. Samples were withdrawn by syringe at regular intervals, quenched with gaseous oxygen, and analyzed by gas chromatography. 2,3-dimethyl-1-butene and 2-methyl-1-pentene formed steadily in a 98:2 ratio at a rate of 0.0014 M min-1 or k1 =0.014 min-1 since the catalyst concentration is 0.1 M. At 40° k1 =0.039 min-1 which amounts to about 1 turnover per hour per Ta. The rate increases markedly at higher temperatures (ΔH++ =19±1 kcal mol-1, ΔS ++ =14±3 eu).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][N:5]([CH3:19])[C:6]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]1.[C-:20]#[N:21].[K+].Cl>O.CO>[CH3:1][N:2]([CH3:3])[C:9]1([C:20]#[N:21])[CH2:10][CH2:11][C:6]([N:5]([CH3:19])[CH3:4])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH2:8]1
Reactant: [C-]#N
Reactant: CNC
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: CN(C)C1(C#N)CCC(c2ccccc2)(N(C)C)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
40% aqueous dimethylamine solution (14 mL, 110.5 mmol), 4-dimethylamino-4-phenylcyclohexanone (5.00 g, 23.04 mmol) and potassium cyanide (3.60 g, 55.3 mmol) were added to a mixture of 4N hydrochloric acid (14 mL) and methanol (5 mL) with ice cooling. The mixture was stirred for 2 d at room temperature and then after adding water (200 mL) was extracted with ether (4×150 mL). After the solution was concentrated to low volume, the residue was taken up in dichloromethane (200 mL) and dried with magnesium sulphate overnight, filtered and the solvent removed in a vacuum. The nitrile was obtained as an oil which was crystallised through.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[Br:11][CH2:12][C:13](Br)=[O:14].C(N(CC)CC)C.O>C(Cl)Cl>[Br:11][CH2:12][C:13]([NH:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:14]
Reactant: COc1ccc(CN)cc1
Reactant: O=C(Br)CBr
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CNC(=O)CBr)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.8 %

Procedure:
7.42 g of 4-methoxybenzylamine was dissolved in 70 mL of methylene chloride, and a solution (10 mL) of 23.2 g of bromoacetyl bromide in methylene chloride was added thereto at −10° C. To the reaction liquid was added dropwise a solution (10 mL) of 8.0 mL of triethylamine in methylene chloride at 0° C., followed by stirring at room temperature for 30 minutes. To the reaction liquid was added water under ice-cooling, followed by extraction with methylene chloride. The organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10 to 0:100) to obtain a product, which was recrystallized from ethyl acetate to obtain 6.11 g of 2-bromo-N-(4-methoxybenzyl)acetamide.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[O:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:6]=2[N:7]=1.[NH:21]1[C:29]2[CH:28]=[CH:27][CH:26]=[C:25](B3OC(C)(C)C(C)(C)O3)[C:24]=2[CH:23]=[CH:22]1>COCCOC.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>[NH:21]1[C:29]2[C:24](=[C:25]([C:2]3[N:3]=[C:4]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:5]4[O:10][C:9]5[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=5[C:6]=4[N:7]=3)[CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22]1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)c2oc3ccccc3c2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: c1cc(-c2nc(N3CCOCC3)c3oc4ccccc4c3n2)c2cc[nH]c2c1
Temperature: 90 °C
Yield: 87.1 %

Procedure:
Argon gas was bubbled through a mixture of 2-chloro-4-morpholinobenzofuro[3,2-d]pyrimidine (ASA75) (80 mg, 0.276 mmol, 1.0 eq) and Indole-4-boronic acid pinacol ester (MW 243) (267 mg, 1.10 mmol, 4.0 eq) in 1,2 dimethoxyethan and 2 M Na2CO3 (3:1) (6 mL) for 5 min. dichloro 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (MW 732) (5.05 mg, 0.00690 mmol, 0.025 eq) was added and the reaction mixture was heated to reflux (90° C.) for 15 h 30 min, cooled and diluted with EtOAc (20 mL). The organic solution was washed with a mixture of H2O:Na2CO3:NH4OH (conc. 32% in water)=5:4:1 (9 mL), then NH4Cl (sat.) and brine (2×), dried over Na2CO3, filtered and concentrated. Purification by silica gel chromatography (gradient from 100% hexane in EtOAc to 50% hexane) gave a yellowish solid (89.0 mg, 87%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.[Br:21]N1C(=O)CCC1=O.C(OCC)(=O)C>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][C:3]=1[Br:21]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(N)cc2)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(N)c(Br)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
In a 100 mL round-bottomed flask, (R)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate (4.3 g, 15.4 mmol) was dissolved in dimethylformamide (30 ml). N-Bromosuccinimide (2.75 g, 15.4 mmol) was added and the mixture was stirred at room temperature for 1 h. The reaction mixture was poured into ethyl acetate and extracted with saturated sodium chloride solution. The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 100 g, gradient 0-50% ethyl acetate in heptane) to yield a white solid (5.2 g, 94%), MS (ISP): 301.3 ([{79Br}M-tBu+H]+), 303.4 ([{81Br}M-tBu+H]+).