Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]=[C:6]2[S:20][CH:19]=[C:18]([CH3:21])[N:7]2[C:8](=[O:17])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)[CH3:3].Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[NH:25][CH:26]=[N:27]2.C(N(CC)C(C)C)(C)C.C(Cl)Cl>C(O)CCC>[N:31]1[C:23]([NH:1][C@H:2]([C:4]2[N:5]=[C:6]3[S:20][CH:19]=[C:18]([CH3:21])[N:7]3[C:8](=[O:17])[C:9]=2[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH3:3])=[C:24]2[C:28]([NH:27][CH:26]=[N:25]2)=[N:29][CH:30]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: Cc1csc2nc([C@H](C)N)c(-c3cccc(F)c3)c(=O)n12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1csc2nc([C@H](C)Nc3ncnc4[nH]cnc34)c(-c3cccc(F)c3)c(=O)n12
Temperature: 105 °C

Procedure:
A mixture of (S)-7-(1-aminoethyl)-6-(3-fluorophenyl)-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one (108.2 g, 357 mmol), 6-chloropurine (71.73 g, 464.1 mmol), and N,N-diisopropylethylamine (74.6 mL, 428.4 mmol) in 1-butanol (952 mL) was degassed with nitrogen bubbling for 5 minutes. The reaction mixture was heated at 105° C. under nitrogen for 15 hours, at which point HPLC indicated amine was consumed. The reaction mixture was cooled down to room temperature before being treated with water (200 mL) at room temperature. The resulting mixture was concentrated under reduced pressure to give an oily residue and the residue was treated with CH2Cl2 (1000 mL) to give a brownish clear solution. The resulting solution was washed with 2.5% aqueous sodium carbonate solution (Na2CO3, 250 mL×2) and the organic layer was concentrated under reduced pressure to afford the crude desired product as a brownish solid. The solution of the crude desired product in CH2Cl2 was absorbed onto silica gel (300 g) and the dried silica gel was loaded onto a flash column. The flash column was eluted with pure CH2Cl2 and a mixture of CH2Cl2, MeOH and aqueous NH4OH (2000:10:5) to afford pure desired product. The fractions containing pure desired product were combined and concentrated under reduced pressure. The resulting yellowish solid (90.3 g) was dissolved in a mixture of CH2Cl2 and methanol (500:50 mL). The resulting solution was treated with ethyl acetate (900 mL) and the resulting mixture was distilled until the internal solution temperature reached 68° C. The mixture was then cooled to room temperature and subsequently to 0-5° C. for 1 hour. The solids were collected by filtration, washed with cold ethyl acetate (100 mL), and dried overnight on the filter under vacuum to afford (S)-7-(1-(9H-purin-6-ylamino)ethyl)-6-(3-fluorophenyl)-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one (89.5 g, 59.4% yield, 99.4% ee) as a light yellowish solid. LCMS calculated for C20H17FN7OS (M+H)+ for the free base: m/z 422.1. Found: 422.0; 1H NMR (500 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.99 (br s, 1H), 7.45 (m, 1H), 7.21-7.12 (m, 3H), 6.8 (m, 1H), 6.42 (s, 1H), 5.52 (br s, 1H), 2.79 (d, J=1.3 Hz, 3H), 1.43 (d, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[O:9])[C:5]([OH:11])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][C:18]=1[F:25]>>[F:25][C:18]1[CH:19]=[C:20](/[CH:21]=[CH:10]/[C:8]([C:6]2[CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]=2[OH:11])=[O:9])[CH:23]=[CH:24][C:17]=1[O:16][CH3:15]
Reactant: CC(=O)c1cc(C)cc([N+](=O)[O-])c1O
Reactant: COc1ccc(C=O)cc1F
Product: COc1ccc(/C=C/C(=O)c2cc(C)cc([N+](=O)[O-])c2O)cc1F
Yield: 75.2 %

Procedure:
2-Hydroxy-5-methyl-3-nitroacetophenone (100 mg, 0.51 mmol) and 4-methoxy-3-fluorobenzaldehyde (95 mg, 0.61 mmol) were reacted according to the same procedure as Preparation 1 to give 127 mg (Yield 74%) of the title compound.
Reaction SMILES: [CH2:1]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@H:9]1[CH2:18][C:17]2[C:16](B(O)O)=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:30]1[CH:35]=[CH:34][N:33]=[N:32][CH:31]=1>>[CH2:1]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@@H:9]1[CH2:10][CH2:11][C:12]2[C:17](=[C:16]([C:30]3[CH:35]=[CH:34][N:33]=[N:32][CH:31]=3)[CH:15]=[CH:14][CH:13]=2)[CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccnnc1
Reactant: OB(O)c1cccc2c1C[C@H](N(Cc1ccccc1)Cc1ccccc1)CC2
Product: c1ccc(CN(Cc2ccccc2)[C@@H]2CCc3cccc(-c4ccnnc4)c3C2)cc1
Yield: 45 %

Procedure:
The title compound was synthesized as described for Intermediate example I-48 in 45% yield starting from [(7R)-7-(dibenzylamino)-5,6,7,8-tetrahydronaphthalen-1-yl]boronic acid and 4-bromopyridazine (1 equiv): 1H NMR (400 MHz, CDCl3) δ ppm 9.24 (dd, 1 H), 9.17 (dd, 1 H), 7.31-7.36 (m, 5 H), 7.25-7.30 (m, 4 H), 7.15-7.24 (m, 4 H), 7.00 (dd, 1 H), 3.59-3.70 (m, 4 H), 2.92-3.08 (m, 2 H), 2.69-2.89 (m, 2 H), 2.51-2.62 (m, 1 H), 2.13-2.25 (m, 1 H), 1.71-1.86 (m, 1 H); MS (ESI) m/z 406[M+H+].
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][C:10]2=[O:13])=[CH:5][CH:4]=1)=[CH2:2].[H-].[Na+].I[CH3:17].O>C1(C)C=CC=CC=1.O1CCCC1>[CH:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([CH3:17])[C:10]2=[O:13])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: CI
Reactant: C=Cc1ccc2c(c1)C(=O)NCC2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=Cc1ccc2c(c1)C(=O)N(C)CC2
Temperature: 25 °C
Yield: 74.6 %

Procedure:
To a solution of 7-ethenyl-3,4-dihydro-1(2H)-isoquinolinone (224 mg, 1.295 mmol) in toluene (2 ml) and tetrahydrofuran (2 ml) at 0° C. was added sodium hydride (60% in oil, 37 mg, 1.554 mmol). The reaction mixture was warmed to room temperature and stirred for 0.5 h before addition of iodomethane (242 μl, 3.885 mmol). The reaction mixture was stirred at room temperature for 1 h before addition of additional iodomethane (242 μl, 3.885 mmol). The reaction mixture was then stirred at room temperature for a further 1 h before addition of water (20 ml). The mixture was extracted with 10% methanol/dichloromethane (3×100 ml), the organic layers were dried with magnesium sulphate and evaporated. Chromatography on silica, eluting with 0-100% ethyl acetate/hexane, gave the product (181 mg, 75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH:49]1[CH2:53][CH2:52][CH2:51][CH:50]1[CH2:54][CH2:55][C:56]1[CH:57]=[C:58]([CH:61]=[CH:62][CH:63]=1)[C:59]#[N:60]>CCOC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:13]([N:49]3[CH2:53][CH2:52][CH2:51][CH:50]3[CH2:54][CH2:55][C:56]3[CH:57]=[C:58]([CH:61]=[CH:62][CH:63]=3)[C:59]#[N:60])=[O:15])=[CH:16][CH:17]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2)cn1
Reactant: N#Cc1cccc(CCC2CCCN2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccc(C(=O)N3CCCC3CCc3cccc(C#N)c3)cc2)cn1
Yield: 44 %

Procedure:
A flask containing 4-(6-Methoxy-pyridin-3-yl)-benzoic acid (0.114 g, 0.5 mmol) and DMF (3 mL) is stirred. To this is added Diisopropylethylamine (87 uL, 0.5 mmol) followed by TBTU (0.16 g, 0.5 mmol) and stirred 2 minutes. A solution of 3-(2-Pyrrolidin-2-(R,S)-ylethyl)-benzonitrile (0.10 g, 0.5 mmol) and DMF (1 mL) is added and the reaction stirred for 24 h. The reaction mixture is diluted with EtOAc (100 mL) and washed with saturated sodium bicarbonate (4×20 mL), brine (25 mL), dried over MgSO4 and concentrated. Purification by flash chromatography (1:1/EtOAc:Hexanes) gives the title compound as a clear oil (0.09 g, 0.22 mmol). 1H NMR (CDCl3, 300 MHz) 8.38(s, 1H), 7.81(d, 1H), 7.65-7.35(m, 8H), 6.83(d, 1H), 4.40-4.25(m, 1H), 3.97(s, 3H), 3.58-3.45(m, 2H), 2.82-2.68(m, 2H), 2.45-2.30(m, 1H), 2.25-2.10(m, 1H), 2.02-1.86(m, 1H), 1.85-1.65(m, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1C(=O)[C:9](=[O:12])[C:8]2([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[N:7]=1.[NH2:18][C@H:19]([CH2:23][OH:24])[CH:20]([CH3:22])[CH3:21].C(OCC)(=[O:27])C>>[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:7][C:8]1([C:9]([NH:18][C@H:19]([CH2:23][OH:24])[CH:20]([CH3:22])[CH3:21])=[O:12])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)=[O:27]
Reactant: O=C1C(=O)C2(CCCCC2)N=C1c1ccc[nH]1
Reactant: CC(C)[C@H](N)CO
Reactant: CCOC(C)=O
Product: CC(C)[C@@H](CO)NC(=O)C1(NC(=O)c2ccc[nH]2)CCCCC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 76.4 %

Procedure:
220 mg (1.01 mmol) of 2-(1H-pyrrol-2-yl)-3-oxo-1-azaspiro[4.5]dec-1-en-4-one was added to a solution of 252 mg (2.45 mmol) of L-valinol in 5 ml of ethyl acetate, and the mixture was stirred at room temperature for 4 days. The reaction solution was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain 247 mg (76.4%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:15][C:16]1[CH:24]=[C:23]2[C:19]([CH2:20][CH2:21][NH:22]2)=[CH:18][CH:17]=1>C(O)(C)C>[ClH:1].[Cl:15][C:16]1[CH:24]=[C:23]2[C:19]([CH2:20][CH2:21][N:22]2[C:2]2[C:11]3[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1ccc2c(Cl)ncnc2c1
Reactant: Clc1ccc2c(c1)NCC2
Solvent: CC(C)O
Product: Cl
Product: O=[N+]([O-])c1ccc2c(N3CCc4ccc(Cl)cc43)ncnc2c1
Temperature: 25 °C

Procedure:
4-Chloro-7-nitroquinazoline (11.22 g, 53.5 mmol) was slurried into 35 ml isopropanol, treated with 6-chloroindoline (8.25 g, 53.7 mmol), refluxed for three hours, then cooled slowly to room temperature. Product was filtered and air dried overnight to afford bright yellow powder; 13.18 g (68%): M.P. 230° C. (dec); LC-MS: 327 (MH+), 329 ((M+2)H+); Calc. C16H11ClN4O2.HCl: C,52.91; H,3.3; N,15.43; Cl,19.52; Found: C,52.77; H,3.61; N,14.78; Cl,19.62.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:24])=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:31][CH3:32].[NH2:33][CH2:34][CH2:35][OH:36].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[OH:36][CH2:35][CH2:34][NH:33][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:24])=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:31][CH3:32]
Reactant: NCCO
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCNCCO
Temperature: 80 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
(2-{[7-(2-Chloroethoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (compound 123) (50 mg), 2-aminoethanol (20 mg), and potassium carbonate (76 mg) were suspended in N,N-dimethylformamide (3 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (23 mg, yield 44%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:46]=[CH:45][CH:44]=[CH:43][C:9]=2[C:10]([NH:12][C:13]2[CH:42]=[CH:41][C:16]([C:17]([N:19]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]([CH2:30][C:31]([N:33]4[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]4)=[O:32])[C:22](=[O:40])[CH2:21][CH2:20]3)=[O:18])=[CH:15][CH:14]=2)=[O:11])=[CH:4][CH:3]=1.[CH3:47][I:48]>ClCCl>[I-:48].[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:46]=[CH:45][CH:44]=[CH:43][C:9]=2[C:10]([NH:12][C:13]2[CH:42]=[CH:41][C:16]([C:17]([N:19]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]([CH2:30][C:31]([N:33]4[CH2:34][CH2:35][N+:36]([CH3:47])([CH3:39])[CH2:37][CH2:38]4)=[O:32])[C:22](=[O:40])[CH2:21][CH2:20]3)=[O:18])=[CH:15][CH:14]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N3CCC(=O)N(CC(=O)N4CCN(C)CC4)c4ccccc43)cc2)cc1
Reactant: CI
Solvent: ClCCl
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N3CCC(=O)N(CC(=O)N4CC[N+](C)(C)CC4)c4ccccc43)cc2)cc1
Product: [I-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
A mixture of 5-{4-[2-(4-methylphenyl)benzoylamino]benzoyl}-1-(4-methyl-1-piperazinylcarbonyl)methyl-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (110 mg) and methyl iodide (76.1 mg) in dichloromethane (10 ml) was stirred at ambient temperature overnight and a precipitate was filtered to give 4-{5-{4-[2-(4-methylphenyl)benzoylamino]benzoyl}-2-oxo-1,3,4 ,5-tetrahydro-2H-1,5-benzodiazepin-1-yl) acetyl-1,1-dimethylpiperazinium iodide (118 mg).
Reaction SMILES: [I:1][C:2]1[C:7]2[C:8](=[O:19])[C:9]3[CH:16]=[CH:15][CH:14]=[C:13](C=O)[C:10]=3[CH2:11][CH2:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[O-].[Na+].[CH3:23]I.[C:25](=[O:28])([O-])[O-:26].[K+].[K+]>CN(C)C=O.O>[I:1][C:2]1[C:7]2[C:8](=[O:19])[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[CH2:11][CH2:12][C:6]=2[C:5]([C:25]([O:26][CH3:23])=[O:28])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cccc2c1CCc1cccc(I)c1C2=O
Reactant: CI
Agent: [K+]
Agent: [Na+]
Agent: [O-]Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(I)c2c1CCc1ccccc1C2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
120 mg of the mixture of 6-iodo-5-oxo-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-1-carboxaldehyde and its 4-iodo form prepared in Example 6-b was oxidized by the procedure of Example 4 using sodium hypochlorite. The resulting carboxylic acids were dissolved in 10 ml of N,N-dimethylformamide, and 0.03 ml of methyl iodide and 70 mg of potassium carbonate were added, followed by stirring at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:10), to give 110 mg of a mixture of the title compounds as a colorless oil.
Reaction SMILES: CC(O)(C)[C:3]#[C:4][C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])=[CH:7][CH:6]=1.C1(C)C=CC=CC=1.[OH-].[Na+].Cl>C(OCC)(=O)C.O>[C:4]([C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])=[CH:7][CH:6]=1)#[CH:3]
Reactant: CC(C)(O)C#Cc1ccc(OCCCCCO)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C#Cc1ccc(OCCCCCO)cc1
Yield: 98.1 %

Procedure:
A flask equipped with a stirrer and a thermometer was charged with 5.41 g (20.6 mmol) of 5-[4-(3-methyl-3-hydroxybutyne-1-yl)phenoxy]pentanol and 70 ml of toluene under a nitrogen atmosphere. To the flask, 1.65 g (41.2 mmol) of sodium hydroxide was added, and stirred under reflux for 4 hours. After the completion of the reaction, water, 1N hydrochloric acid, and ethyl acetate were added to the reactant to adjust the pH to an acidity and effect ethyl acetate extraction. The resulting organic phase was washed with NaCl saturated water, dried over anhydrous sodium sulfate, filtered, and concentrated to thereby obtain 4.13 g of 5-(4-ethynylphenoxy)pentanol in the form of a brown oil in a 98% yield.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[NH:6][N:5]=1)(=O)[CH3:2].BrBr.BrC(Br)C(C1C=C(C(OC)=O)NN=1)=O.[C:29]([NH2:32])(=[S:31])[CH3:30]>C(Cl)(Cl)Cl.CO>[CH3:30][C:29]1[S:31][CH:2]=[C:1]([C:4]2[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[NH:6][N:5]=2)[N:32]=1
Reactant: CC(N)=S
Reactant: COC(=O)c1cc(C(C)=O)n[nH]1
Agent: BrBr
Agent: COC(=O)c1cc(C(=O)C(Br)Br)n[nH]1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)c1cc(-c2csc(C)n2)n[nH]1
Yield: 101.7 %

Procedure:
Methyl 3-acetyl-1H-pyrazole-5-carboxylate (100 mg, 0.595 mmol) was refluxed with bromine (143 mg, 0.892 mmol) in chloroform. Solvent was evaporated and thus obtained methyl 3-(2,2-dibromoacetyl)-1H-pyrazole-5-carboxylate (191 mg, 0.586 mmol) was treated with thioacetamide (44 mg, 0.586 mmol) in refluxing methanol. Solvent was evaporated and the residue was dissolved in DCM and washed with water. Organic phase was dried over Na2SO4, filtered and evaporated to give 133 mg (102%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 2.71 (s, 3H), 3.83 (s, 3H), 7.10 (s, 1H), 7.90 (s, 1H) 14.0 (broad s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][O:11][C:12]([O:21][CH3:22])([CH3:20])[C:13](=[O:19])[CH2:14][C:15]([O:17][CH3:18])=[O:16].N1CCCCC1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[C:14]([C:13](=[O:19])[C:12]([O:11][CH3:10])([O:21][CH3:22])[CH3:20])[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)CC(=O)C(C)(OC)OC
Reactant: O=Cc1ccccc1Cl
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: COC(=O)C(=Cc1ccccc1Cl)C(=O)C(C)(OC)OC
Yield: 112.6 %

Procedure:
A mixture of 2-chlorobenzaldehyde (2.81 g), methyl 4,4-dimethoxy-3-oxovalerate (3.81 g) and piperidine (0.2 ml) in benzene (20 ml) was refluxed under azeotropic dehydration for 7.5 hours. A small amount of benzene was added to the reaction mixture and the resultant solution was washed with water and dried over magnesium sulfate. The solvent was removed from the solution to give a reddish oil (7.04 g) of methyl 2-(2-chlorobenzylidene)-4,4-dimethoxy-3-oxovalerate. The mixture of the oily product (6.39 g) obtained above and methyl 3-aminocrotonate (2.33 g) was heated at 132° C. for 3.5 hours, allowed to stand and then dissolved in ethyl acetate. The resultant solution was washed with water and an aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was removed from the solution under reduced pressure to give a viscous and brown oil (8.28 g). This oil was subjected to column chromatography on silica gel with an eluent (a mixture of 20 parts of benzene and one part of ethyl acetate by volume) to give an oily substance (5.26 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:18]=[CH:17][C:11]([CH:12]=[CH:13][C:14]([OH:16])=O)=[CH:10][CH:9]=1.[NH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.C(P(C#N)(CC)=O)C.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(N(CC)CC)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11](/[CH:12]=[CH:13]/[C:14]([NH:19][CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[O:16])=[CH:17][CH:18]=1
Reactant: COCCOCOc1ccc(C=CC(=O)O)cc1
Reactant: NCc1cccnc1
Agent: CCP(=O)(C#N)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCOCOc1ccc(/C=C/C(=O)NCc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
3.74 g of 4-[(2-methoxyethoxy)methoxy]cinnamic acid and 1.68 g of 3-(aminomethyl)pyridine were dissolved in 30 ml dimethylformamide, and stirred with 2.7 ml diethylphosphoryl cyanide and subsequently with 2.5 ml triethylamine on ice, followed by further stirring at room temperature for 1 hour. Saturated aqueous sodium bicarbonate was added to the reaction mixture, which was then extracted with ethyl acetate, washed with water, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give a residue, which was then purified via column chromatography on silica gel (chloroform:methanol=50:1) to provide (E)-3-[4-[(2-methoxyethoxy)methoxy]phenyl]-N-(3-pyridylmethyl)-2-propenoic acid amide as a pale yellow oil (4.54 g, 89%).
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([OH:18])[CH:10]=1.[Cl:19][C:20]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>ClCCl>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([Br:8])=[CH:10][C:11]=1[O:18][C:22](=[O:23])[C:21]1[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:20]=1[Cl:19])(=[O:17])[CH3:16]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: CC(=O)c1ccc(Br)cc1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(Br)cc1OC(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
Triethylamine (14.6 mL, 104.6 mmol) was added to a solution of 1-(4-Bromo-2-hydroxy-phenyl)-ethanone (15.0 g, 96.8 mmol) dissolved in dichloromethane (200 mL). The resulting solution was cooled to 0° C. at which time 2,4-dichloro-benzoyl chloride, dissolved in 50 mL dichloromethane was added dropwise over 30 minutes. The resulting mixture was allowed to warm to ambient temperature and stir at this temperature for an additional 16 hours. After this time, the reaction mixture was concentrated via rotary evaporation and then dissolved in EtOAc and washed twice with water and once with a saturated NaHCO3 solution. The organic portion was dried (MgSO4), filtered and concentrated to give the desired product (22.7 g, 84%) which was used without further purification. 1H-NMR (DMSO) δ 8.18 (d, 1H), 7.96 (d, 1H), 7.82 (s, 1H), 7.64 (m, 3H), 2.53 (s, 3H).
Reaction SMILES: [C:1]1([CH:7]([C:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH2:22][CH2:23][CH2:24][NH2:25])=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS[C:28]1[NH:29][CH2:30][C:31](=[O:33])[N:32]=1.C(N(CC)CC)C>C(O)C.CN(C=O)C>[C:1]1([CH:7]([C:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH2:22][CH2:23][CH2:24][NH:25][C:28]4[NH:29][CH2:30][C:31](=[O:33])[N:32]=4)=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][C:9]([OH:11])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCCCOc1ccc2c(C(CC(=O)O)c3ccccc3)c[nH]c2c1
Reactant: CSC1=NC(=O)CN1
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(O)CC(c1ccccc1)c1c[nH]c2cc(OCCCNC3=NC(=O)CN3)ccc12

Procedure:
130 mg (0.29 mmol) of 36, prepared analogously to Example 14, are stirred for 24 hours at RT with 115 mg (0.87 mmol) of 2-methylsulfanyl-1,5-dihydroimidazol-4-one and 0.12 ml (0.87 mmol) of triethylamine in a mixture of 2 ml of ethanol and 1 ml of DMF, giving 3-phenyl-3-{6-[3-(1,5-dihydroimidazol-4-on-2-ylamino)propoxy]indol-3-yl}propionic acid. Purification by preparative HPLC on RP-18 gives 3-phenyl-3-{6-[3-(1,5-dihydroimidazol-4-on-2-ylamino)propoxy]indol-3-yl}propionic acid trifluoroacetate.
Reaction SMILES: C(O[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1)(=S)C.C(OC(=O)C)(=O)C.[S:20](Cl)([Cl:23])(=O)=[O:21]>ClCCl>[Cl:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[CH2:5][S:20]([Cl:23])=[O:21]
Reactant: CC(=S)OCc1cccc(Cl)c1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: O=S(Cl)Cc1cccc(Cl)c1
Reaction time: 1 h

Procedure:
To a -20° C. solution of the thioester from Step G (1 mmol) in 3 mL of dichloromethane under argon are added 1 mmol acetic anhydride and 2 mmol sulfuryl chloride. The reaction is stirred for 1 hr during which time the temperature is allowed to rise to -5° C. The mixture is concentrated in vacuo and the crude product used for coupling in the next step.
Reaction SMILES: Cl.[NH:2]([C:6]1[CH:7]=[C:8]([CH:16]=[CH:17][CH:18]=1)[C:9](=[O:15])[NH:10][CH2:11][C:12]([OH:14])=O)[C:3]([NH2:5])=N.Cl.[NH2:20][CH:21]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:22][C:23]([O:25][CH3:26])=[O:24].C[N:33]1CCOCC1>CN(C=O)C.N1C=CC=CC=1.CN(C1C=CN=CC=1)C.O>[NH2:33][N:5]=[CH:3][NH:2][C:6]1[CH:7]=[C:8]([C:9]([NH:10][CH2:11][C:12]([NH:20][CH:21]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH2:27][C:28]([O:30][CH3:31])=[O:29])=[O:14])=[O:15])[CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)CC(N)CC(=O)OC
Reactant: CN1CCOCC1
Reactant: N=C(N)Nc1cccc(C(=O)NCC(=O)O)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)CC(CC(=O)OC)NC(=O)CNC(=O)c1cccc(NC=NN)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of m-guanidinohippuric acid HCl (1.5 g) in DMF (4.5 ml) and pyridine (4.5 ml) was treated with DSC (1.8 g) and a catalytic amount of DMAP. After 2 hours, a solution of-dimethyl 3-aminoglutarate HCl (1.1 g) and NMM (350 μl) in H2O (3 ml) was added to the reaction. The reaction was stirred overnight at room temperature and the product was isolated by HPLC. 3-[[2-[[[3-[(aminoiminomethyl)amino]phenyl]carbonyl]-amino]acetyl]amino]pentanedioic acid, bis methyl ester (1.5 g) as a white solid was obtained. MS and 1H-NMR were consistent with the desired product.