Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([CH2:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][CH2:14][S:15]([OH:18])(=[O:17])=[O:16])([OH:4])(=[O:3])=[O:2].[OH2:19].[OH-].[Na+:21].[C:22](Cl)(=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>CC(C)=O>[C:22]([N:8]([CH2:9][CH2:10][N:11]([C:22](=[O:19])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:12][CH2:13][CH2:14][S:15]([O-:18])(=[O:16])=[O:17])[CH2:7][CH2:6][CH2:5][S:1]([O-:4])(=[O:2])=[O:3])(=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].[Na+:21].[Na+:21]
Reactant: CCCCCCCC(=O)Cl
Reactant: O
Reactant: O=S(=O)(O)CCCNCCNCCCS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCCCCCCC(=O)N(CCCS(=O)(=O)[O-])CCN(CCCS(=O)(=O)[O-])C(=O)CCCCCCC
Temperature: 10 °C
Reaction time: 1 h

Procedure:
Subsequently, N,N'-bis(3-sulfopropyl)ethylenediamine (5 g, 0.016 mol), water (30 g), and acetone (13 g) were placed in a four-necked flask. The pH of the contents was adjusted to 8.5 with an aqueous 4N NaOH solution. The flask was cooled to 10° C., and caprylic chloride (5.3 g, 0.033 mol) was added dropwise. Since pH falls as the reaction proceeds, an aqueous 4N NaOH solution was added if necessary to maintain the pH between 9 and 10. When the caprylic chloride had been completely added, the mixture was stirred for 1 hour. Water was removed using an evaporator while the mixture underwent azeotropic distillation with ethanol. Thereafter, water (250 g) was added and the mixture was filtered to remove insoluble matter. The residue was desalted by electrodialysis and then freeze-dried to obtain 3.0 g of disodium 4,7-dioctanoyl-4,7-diazadecane-1, 10-disulfonate (separation yield: 31 wt %). Mass analysis (FAB ionization method) m/z: 601(M+H+), m=C24H46S2O8N2 Na2.
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([CH3:27])[N:5]([P:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:29][O:30][K].Cl>>[OH:30][NH:29][C:3](=[O:2])[C@H:4]([N:5]([P:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:27]
Reactant: COC(=O)[C@@H](C)N(Cc1ccccc1)P(=O)(c1ccccc1)c1ccccc1
Reactant: NO[K]
Agent: Cl
Product: C[C@H](C(=O)NO)N(Cc1ccccc1)P(=O)(c1ccccc1)c1ccccc1
Reaction time: 16 h

Procedure:
To N-(diphenylphosphinyl)-N-benzyl-D-alanine methyl ester (100 mg, 0.25 mmol) is added a solution of NH2OK (0.88 mL, 1.76M in methanol) prepared as described in Fieser and Fieser, Vol. 1, p. 478. The reaction is stirred for 16 hours at which time TLC indicates completion. The reaction mixture is neutralized with 1M aqueous HCl and the volatiles are removed. The product is purified by silica gel flash chromatography (100% ethyl acetate) to give N-hydroxy-2(R)-[[diphenylphosphinyl]benzylamino]-propionamide as an oil: MS-IS m/z 395 [M+H]+, 417 [M+Na]+. (R1 =benzyl, R2 =methyl, R3 =phenyl, R4 =phenyl).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-])=O.C(O[C:17](=[S:19])[S-:18])C.[K+]>>[SH:19][C:17]1[S:18][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[N:11]=1
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCOC(=S)[S-]
Agent: [K+]
Product: O=C(O)c1ccc2sc(S)nc2c1
Yield: 66 %

Procedure:
2-Mercapto-benzothiazol-5-carboxylic acid (240) (3.5 g, 66%) was synthesized from 4-chloro-3-nitro-benzoic acid, obtained from Fluka, and potassium dithiocarbonate O-ethyl ester, obtained from Lancaster, according to the procedure of Chaudhuri, N. Synth. Commun. 1996, 26, 20, 3783.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([NH:14][C:15]1[CH:23]=[C:22]2[C:18]([CH:19]=[CH:20][NH:21]2)=[CH:17][C:16]=1[C:24](O)=[O:25])=[O:13].[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>CC#N>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([NH:14][C:15]1[CH:23]=[C:22]2[C:18]([CH:19]=[CH:20][NH:21]2)=[CH:17][C:16]=1[C:24]([N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:25])=[O:13]
Reactant: C1CCNCC1
Reactant: O=C(O)c1cc2cc[nH]c2cc1NC(=O)c1c[nH]c2ccccc2c1=O
Solvent: CC#N
Product: O=C(Nc1cc2[nH]ccc2cc1C(=O)N1CCCCC1)c1c[nH]c2ccccc2c1=O

Procedure:
4-Oxo-N-[5-(1-piperidylcarbonyl)-1H-indol-6-yl]-1H-quinoline-3-carboxamide (148) was synthesized following the general scheme above, coupling the acid (188-I) with piperidine. Overall yield (12%). HPLC ret. time 2.79 min, 10-99% CH3CN, 5 min run; ESI-MS 415.5 m/z (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[CH3:21][C:17]1[C:15]2[N:16]=[C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[S:13][C:14]=2[CH:20]=[CH:19][CH:18]=1.[S:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=[CH:12]1
Reactant: C#CCCc1nc2c(C)cccc2s1
Reactant: Brc1ccccn1
Product: Cc1cccc2sc(CCC#Cc3ccccn3)nc12
Product: c1ccc2scnc2c1

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (193 mg, 1.22 mmol) and 2-but-3-ynyl-4-methyl-benzo[d]thiazole (246 mg, 1.22 mmol). The crude residue was purified by flash chromatography DCM/MeOH 99:1 to 98:2) to yield 86 mg (0.31 mmol, 25%) of 4-methyl-2-(4-pyridin-2-yl)but-3-ynyl)benzo[d]thiazole as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][N:9]=[C:10]([C:13]#[N:14])[C:11]#[N:12])[CH:5]=[CH:6][CH:7]=1.ClC1C=C(C=CC=1)N.C(#N)CC#N.O.[NH2:29][NH2:30]>>[NH2:14][C:13]1[C:10](=[N:9][NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:11]([NH2:12])=[N:30][N:29]=1
Reactant: N#CC(C#N)=NNc1cccc(Cl)c1
Reactant: NN
Solvent: O
Solvent: N#CCC#N
Solvent: Nc1cccc(Cl)c1
Product: NC1=NN=C(N)C1=NNc1cccc(Cl)c1
Yield: 14 %

Procedure:
This compound was prepared using 102 mg (0.5 mmol) of 2-[(3-chlorophenyl)-hydrazono]malononitrile, which was derived from 3-chloroaniline (106 μL, 1.0 mmol) and malononitrile (1.5 mmol) as, described in Example 8, and hydrazine hydrate. Precipitate formed in the reaction tube approximately 5 min after the addition of hydrazine hydrate. The resulting solid was isolated by filtration, precipitated from an ethyl acetate solution by the addition of hexanes, and dried to yield 17 mg (14%) of the title compound as a yellow solid. 1H NMR (ppm, DMSO-d6): 5.98 (br, s, 2H), 6.38 (br, s, 2H), 7.18 (d, 1H), 7.40 (t, 1H), 7.60 (d, 1H), 7.69 (s, 1H), 10.78 (s,1H).
Reaction SMILES: C([Mg]Br)C.C1COCC1.[CH2:10]([O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[C:11]#[CH:12].[CH2:20]([O:22][CH:23](OCC)[O:24][CH2:25][CH3:26])[CH3:21]>C1(C)C=CC=CC=1>[CH2:20]([O:22][CH:23]([O:24][CH2:25][CH3:26])[C:12]#[C:11][CH2:10][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[CH3:21]
Reactant: C#CCOC1CCCCO1
Reactant: CCOC(OCC)OCC
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(C#CCOC1CCCCO1)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
A 1M solution of ethylmagnesium bromide in THF (200 ml, 0.2 mol) was treated with 29 ml (0.2 mol) of a solution of 3,4,5,6-tetrahydro-2-(2-propynyloxy)-2H-pyran in toluene, while maintaining ambient temperature through use of a cool water bath. The resulting solution was stirred for 4 h arid treated with 47 ml (0.28 mol) of a solution of triethylorthoformate in toluene, while maintaining ambient temperature with a cool water bath. The resulting solution was heated to 85° C. for 8 h, allowing the removal of THF by distillation. After being allowed to cool, the resulting solution was poured into 500 ml of ice-water containing 29 g of NH4OAc, extracted with two portions of ether, dried over K2CO3, and concentrated in vacuo. The residue was distilled at ca. 0.5 mm Hg pressure (b.p. 103°-108° C.) to provide 39.5 g (79%) of the desired compound. 1H NMR (CDCl3) δ1.24 (t, J=7 Hz, 6H), 1.5-1.9 (m, 6H), 3.5-3.65 (m, 3H), 3.7-3.9 (m, 3H), 4.32 (AA', 2H), 4.81 (m, 1H), 5.31 (m, 1H). Mass spectrum: (M+NH4)+ =260.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].C[O:23][CH:24]1[CH:28]([CH:29]=O)[CH2:27][CH:26](OC)O1>C(O)(=O)C.C(OCC)(=O)C>[CH:24]([C:28]1[CH:27]=[CH:26][N:1]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:18])=[O:19])[C:5]3=[O:21])[CH:29]=1)=[O:23]
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(N)cc2c1=O
Reactant: COC1CC(C=O)C(OC)O1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(-n3ccc(C=O)c3)cc2c1=O

Procedure:
A solution of N-(6-amino-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (470 mg, 1.49 mmol) and 2,5-dimethoxytetrahydrofuran-3-aldehyde (796 mg, 4.47 mmol) in acetic acid (0.5 ml) is refluxed for five hours. The solvent is removed by rotavapor evaporation to give a brown oil which is dissolved in ethyl acetate and washed three times with water. The organic layer is dried over magnesium sulfate, filtered and the solvent removed by rotavapor evaporation to give the title compound nearly pure as a brown solid, m.p. 230-245° C. (decomp).
Reaction SMILES: [O:1]=[C:2]([CH3:14])[CH2:3][C:4](ON1C(=O)CCC1=O)=[O:5].[CH3:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][NH:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=1.C(N(CC)CC)C.[Cl-].[Na+]>ClCCl>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][N:22]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:4](=[O:5])[CH2:3][C:2](=[O:1])[CH3:14])=[CH:29][CH:30]=1
Reactant: COC(=O)CCNCc1ccc(OC)cc1
Reactant: CC(=O)CC(=O)ON1C(=O)CCC1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCN(Cc1ccc(OC)cc1)C(=O)CC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A flask with stirbar was charged with 2,5-dioxopyrrolidin-1-yl 3-oxobutanoate (6.47 g, 32.5 mmol), methyl 3-(4-methoxybenzylamino)propanoate (prepared as described in Bew, S. et al, Chem Commun. 2006 (41), 4338-40, 7.7 g, 34.5 mmol) and triethylamine (5 mL, 35.9 mmol) in dichloromethane (125 mL). The solution was stirred overnight at ambient temperature, then shaken in a separatory funnel with saturated aqueous sodium chloride. The organics were then washed with saturated aqueous sodium chloride containing 0.1M HCl and dried over anhydrous sodium sulfate. Filtration and solvent removal provided the title compound.
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([S:15](Cl)(=[O:17])=[O:16])[CH:6]=1)(=[O:3])[CH3:2].[CH:19]12[CH2:27][CH2:26][CH:23]([CH2:24][CH2:25]1)[CH2:22][NH:21][CH2:20]2>C(Cl)(Cl)Cl.N1C=CC=CC=1>[C:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([S:15]([N:21]2[CH2:22][CH:23]3[CH2:26][CH2:27][CH:19]([CH2:25][CH2:24]3)[CH2:20]2)(=[O:17])=[O:16])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: C1CC2CCC1CNC2
Reactant: CC(=O)Oc1cc(S(=O)(=O)Cl)cc2ccccc12
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1cc(S(=O)(=O)N2CC3CCC(CC3)C2)cc2ccccc12
Yield: 63.1 %

Procedure:
4-Acetoxy-2-naphthalenesulfonyl chloride (861 mg, 3.02 mmol) and 3-azabicyclo[3.2.2]nonane (379 mg, 3.02 mmol) were combined in CHCl3 (20 ml) and pyridine (20 ml), and the mixture was stirred at room temperature for 15 hours. At this time, the solvent was evaporated under reduced pressure and the residue was partitioned between EtOAc and 1N aqueous HCl. The EtOAc was then washed with saturated aqueous NaHCO3, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography using 1% acetone in CHCl3 to provide 712 mg of the pure white product as a white foam: 1H NMR (CDCl3) δ 1.52-1.84 (9H, m, 4×CH2), 2.02-2.13 (2.H, br s, 2×CH) 2.46 (3H, s, CH3CO), 3.31 (4H, d, J=4.2 Hz, 2×CH2), 7.56-7.71 (3H, m, ArH), 7.92-8.02 (2H, m ArH).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=[O:2].[CH:13]([O-])([O-])[O:14]C.[CH3:18][O-].[Na+]>CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:9][O:8][C:6]([O:14][CH3:13])([O:7][CH3:18])[C:5]1[CH:10]=[CH:11][CH:12]=[C:3]([CH:1]=[O:2])[CH:4]=1
Reactant: C[O-]
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: COC([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CO
Product: COC(OC)(OC)c1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Methyl 3-formylbenzoate (0.67 g) was dissolved in 10 ml of methanol, and 0.74 g of methyl orthoformate and 8 mg of p-toluenesulfonic acid were added. The mixture was stirred at room temperature for 10 hours. Sodium methoxide was added to the reaction mixture to make it basic, and then the solvent was evaporated. The residue was dissolved in ethyl acetate, and washed with a 5% aqueous solution of sodium hydrogen carbonate. The solvent was then evaporated to give 0.75 g of methyl 3-formylbenzoate dimethyl acetal.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].[OH2:19].Cl[CH2:21]Cl>>[O:19]=[C:21]1[N:8]([CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1]1
Reactant: O
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)NCCNc1ccccc1N
Product: CC(C)(C)OC(=O)NCCn1c(=O)[nH]c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
1,1-carbonyldiimidazole (0.36 g, 2.23 mmol) was added to a solution of tert-butyl 2-(2-aminophenylamino)ethylcarbamate (0.56 g, 2.23mmol) in dichloromethane (15 mL) and stirred at rt overnight. Water (50 mL) was added and the mixture was extracted with dichloromethane (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and filtered. The solvent was removed and the product was purified by column chromatography eluting with ethyl acetate/hexane (1:3) to give the title compound (230 mg, 37%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C@@H:5]1[NH:10][CH2:9][CH2:8][N:7]([C:11]2[C:20]3[N:19]=[C:18]([C:21]([F:24])([F:23])[F:22])[S:17][C:16]=3[NH:15][C:14]3[CH:25]=[CH:26][CH:27]=[CH:28][C:13]=3[N:12]=2)[CH2:6]1.[CH:29](=O)[CH3:30]>>[CH2:29]([N:10]1[CH2:9][CH2:8][N:7]([C:11]2[C:20]3[N:19]=[C:18]([C:21]([F:23])([F:24])[F:22])[S:17][C:16]=3[NH:15][C:14]3[CH:25]=[CH:26][CH:27]=[CH:28][C:13]=3[N:12]=2)[CH2:6][C@@H:5]1[CH2:4][CH2:3][O:2][CH3:1])[CH3:30]
Reactant: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C(F)(F)F)nc32)CCN1
Reactant: CC=O
Product: CCN1CCN(C2=Nc3ccccc3Nc3sc(C(F)(F)F)nc32)C[C@@H]1CCOC

Procedure:
Using the method of Example 346 using (5)-10-[3-(2-methoxy-ethyl)-piperazin-1-yl]-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene and acetaldehyde at ambient temperature, and purification by flash chromatography, eluting with a gradient of a 5% solution of 2M ammonia in methanol, in dichloromethane, (0-50% over 25 minutes, 50% for 10 minutes, 50-100% over 23 minutes, 100% for 5 minutes) gives the title compound: mass spectrum (APCI, m/e): 440 (M+1); NMR (1H, 300 MHz, DMSO-d6), δ (ppm): δ 8.47 (s, 1H), 6.96-6.81 (m, 3H), 6.71 (m, 1H), 3.50 (br. m, 3H), 3.35-3.21 (m, 2H), 3.21-3.07 (m, 4H), 2.76-2.51 (m, 3H), 2.37 (m, 2H), 1.67 (m, 2H), 0.96 (t, 3H, J=6.9 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)=[O:7])=[C:4]([Cl:25])[CH:3]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(Cl)(Cl)Cl>[C:26]([NH:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)=[O:7])=[C:4]([Cl:25])[CH:3]=1)(=[O:28])[CH3:27]
Reactant: Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)c(Cl)c1
Reaction time: 0.25 h

Procedure:
3 g of 1-(4-amino-2-chlorobenzoyl)-4-[2-(4-chlorophenyl)ethyl]-piperazine are stirred for 1 hour at room temperature in 30 ml of chloroform with 10 ml of acetic anhydride. The solution is concentrated by evaporation and water, 2N sodium hydroxide solution and 20 ml of ethyl acetate are added to the residue and the whole is stirred for 15 minutes. Filtering with suction and recrystallisation from ethanol/petroleum ether yield 1-[4-(N-acetylamino)-2-chlorobenzoyl]-4-[2-(4-chlorophenyl)ethyl]-piperazine having a melting point of 158°-160°.
Reaction SMILES: CS(O)(=O)=O.CS(O)(=O)=O.[NH2:11][C@H:12]1[C:26](=[O:27])[N:25]([CH2:28][C:29]([F:32])([F:31])[F:30])[CH2:24][C:15]2[C:16]3[CH:17]=[N:18][NH:19][C:20]=3[C:21]([Cl:23])=[CH:22][C:14]=2[CH2:13]1.[O:33]=[C:34]1[NH:42][C:37]2=[N:38][CH:39]=[CH:40][CH:41]=[C:36]2[C:35]21[CH2:50][C:49]1[C:44](=[CH:45][CH:46]=[C:47]([C:51](O)=[O:52])[CH:48]=1)[CH2:43]2.C(N(CC)C(C)C)(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Cl:23][C:21]1[C:20]2[NH:19][N:18]=[CH:17][C:16]=2[C:15]2[CH2:24][N:25]([CH2:28][C:29]([F:31])([F:30])[F:32])[C:26](=[O:27])[C@H:12]([NH:11][C:51]([C:47]3[CH:48]=[C:49]4[C:44](=[CH:45][CH:46]=3)[CH2:43][C:35]3([C:36]5[C:37](=[N:38][CH:39]=[CH:40][CH:41]=5)[NH:42][C:34]3=[O:33])[CH2:50]4)=[O:52])[CH2:13][C:14]=2[CH:22]=1
Reactant: N[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(CC(F)(F)F)C1=O
Reactant: O=C(O)c1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Agent: CS(=O)(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(CC(F)(F)F)C1=O)c1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (7R)-7-amino-4-chloro-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one bis-methanesulfonate from Step B (20 mg, 0.038 mmol), (±)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridine]-5-carboxylic acid (11 mg, 0.038 mmol) [Bell et al. WO 2006/031606], N,N-diisopropylethylamine (25 mg, 33 uL, 0.19 mmol), HOBT (7.0 mg, 0.046 mmol), and EDC (8.8 mg, 0.046 mmol) in DMF (0.5 mL) was stirred at ambient temperature for 2 h. The reaction mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H-90:10:0.1 to 5:95:0.1. The pure, product-containing fractions were concentrated in vacuo to provide the title compound. MS: m/z=595.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.[Br:12]Br>O>[BrH:12].[Br:12][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[CH2:11][CH:3]([NH2:2])[CH2:4]2
Reactant: NC1Cc2ccccc2C1
Reactant: BrBr
Agent: Cl
Solvent: O
Product: Br
Product: NC1Cc2ccc(Br)cc2C1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of 118.8 g of 2-aminoindane hydrochloride in 594 mL of water is heated to a temperature of 58-60° C. and 120.0 g of bromine is added over a period of 50 minutes while maintaining an internal temperature at 58 to 62° C. The mixture is stirred at 60-62° C. for 1 hour and 107 mL of hydrobromic (48%) is added over a period of 5 minutes while maintaining the internal temperature of 60-62° C. The mixture is stirred for an additional 10 minutes. The reaction mixture is cooled to an internal temperature of 20-23° C. over a period of 1 hour. The resulting solid is collected by filtration, washed with 3×133 mL of 2-propanol and dried at 58-60° C. under vacuum (10-30 torr) to obtain crude (±)-5-bromo-2-aminoindan hydrobromide. A suspension of 156.0 g of crude (±)-5-bromo-2-aminoindane hydrobromide in 390 mL of deionized water is heated to a temperature at 95-100° C. to obtain a clear solution. The solution is cooled to an internal temperature at 20-23° C. over a period of 2.5 hours and stirred at 20-23° C. for an additional 30 minutes. The resulting solid is collected by filtration and washed with 3×20 mL of water (precooled to 0-5° C.), and dried at 60-65° C. under vacuum (10-30 torr) with nitrogen bleeding to obtain (±)-5-bromo-2-aminoindane hydrobromide. A mixture of 130.0 g of (±)-5-bromo-2-aminoindane hydrobromide and 1500 mL of isopropyl acetate is stirred at 20-25° C. under nitrogen. A solution (precooled to 20-25° C.) of 26.62 g of sodium hydroxide and 186.35 g of sodium chloride in 750 mL of water is added over a period of 5 minutes while maintaining an internal temperature at 20-25° C. The suspension is stirred efficiently until all the solid dissolves (30 minutes). The organic layer is separated and the aqueous layer is extracted with 750 mL of isopropyl acetate. The organic layers are combined to afford ˜2330 mL of a solution of (±)-5-bromo-2-aminoindane free base.
Reaction SMILES: Cl[C:2](Cl)([O:4][C:5](=[O:11])[O:6][C:7](Cl)(Cl)Cl)Cl.[Br:13][C:14]1[CH:23]=[C:22]([Br:24])[C:21]([CH2:25]CO)=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2>O1CCOCC1>[Br:13][C:14]1[CH:23]=[C:22]([Br:24])[C:21]([CH2:25][CH2:2][O:4][C:5]([O:6][CH3:7])=[O:11])=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCCc1c(Br)cc(Br)c2cccnc12
Solvent: C1COCCO1
Product: COC(=O)OCCc1c(Br)cc(Br)c2cccnc12
Reaction time: 8 h

Procedure:
Triphosgene, 740 mg (2.5 mmol) was dissolved in 5 mL of anhydrous dioxane and stirred at ambient temperature while 5,7-dibromo-8-(2-hydroxyethyl)quinoline was added in several portions. The mixture was stirred overnight and capped to protect from atmospheric moisture. The solvent and excess reagent were removed under a stream of dry argon. Residue was redissolved in 10 mL of methanol, stirring for 1 hr., and the solvent was removed. The residue was recrystallized from methanol/water. Melting point: 102.5104.5° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[C:3]=1[O:12][CH3:13].C([Li])CCC.[Cl:19][CH:20]1[C:29](=O)[C:28]2[C:23](=[CH:24][C:25]([N:31]([CH3:33])[CH3:32])=[CH:26][CH:27]=2)[O:22][CH2:21]1>C1COCC1>[Cl:19][C:20]1[CH2:21][O:22][C:23]2[C:28]([C:29]=1[C:7]1[CH:6]=[C:5]([O:8][CH3:9])[C:4]([O:10][CH3:11])=[C:3]([O:12][CH3:13])[CH:2]=1)=[CH:27][CH:26]=[C:25]([N:31]([CH3:33])[CH3:32])[CH:24]=2
Reactant: COc1ccc(I)c(OC)c1OC
Reactant: CN(C)c1ccc2c(c1)OCC(Cl)C2=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C2=C(Cl)COc3cc(N(C)C)ccc32)cc(OC)c1OC
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Iodotrimethoxybenzene (40 mg, 0.133 mmol) was dissolved into 1 mL of dry THF and cooled to −78° C. The butyl lithium solution 1.16 M (126 μL, 0.146 mmol, 1.1 eq.) was added dropwise and the mixture was stirred at −78° C. for 15 min. 3-Chloro-7-dimethylamino-chroman-4-one (30 mg, 0.133 mmol) in 1 mL of dry THF was added and the mixture was allowed to warn to room temperature. After 3 h, the mixture was quenched with a saturated aqueous solution of NH4Cl (10 mL) and extracted with EtOAc (2×10 mL). Combined organic extracts were dried with Na2SO4 and concentrated. The residue was diluted in a mixture of 2 mL of ethanol and 0.75 mL of concentrated hydrochloric acid, and stirred overnight at room temperature. A saturated solution of sodium bicarbonate was added until neutralization and the resulting solution was extracted with EtOAc (2×25 mL).