Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11](SC)=[C:12]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C:13]#[N:14])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:27][CH:28]([NH2:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]([NH:33][CH:28]([CH3:27])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:12]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C:13]#[N:14])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CSC(Nc1ccc2c(c1)OCO2)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CC(N)C(C)(C)C
Product: CC(NC(Nc1ccc2c(c1)OCO2)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1)C(C)(C)C
Yield: 49 %

Procedure:
3-(Benzo[1,3]dioxol-5-ylamino-2-(4-chlorophenylsulfonyl)-3-methylsulfanyl-2-propenenitrile (0.327 g, 0.8 mmol) was stirred in 1,2,2-trimethylpropylamine (1 ml) for 22 h at 100° C. under nitrogen in a sealed flask. Work up as described in Example 1, 2) gave 182 mg (49%) of the title compound. Mp 160.5-162° C. 1H NMR (200 MHz, CDCl3): δ=0.78 (s, 9H), 0.9 (d, 3H), 3.22 (m, 1H), 6.0 (br s, 2H), 6.48 (m, 2H), 6.78 (br d, 1H), 7.48 (d,2H), 7.83 (d, 2H). MA C22H24ClN3O4S.0.30 H2O (corrected bruttoformula); calc 56.54%; C, 5.31%; H, 8.99%; N; found: 56.47%; C, 5.25%; H, 8.90%; N.
Reaction SMILES: [C:1]([P:5](Cl)[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Mg].S(=O)(=O)(O)O>O1CCCC1.[Cu]Br.C1(C)C=CC=CC=1>[C:1]([P:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[C:23]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:13]1[CH:12]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Brc1ccccc1-c1ccccc1
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Agent: [Cu]Br
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Reaction time: 4 h
Yield: 88.5 %

Procedure:
In a 500 ml four-necked flask thoroughly purged with nitrogen, 9.0 g (0.05 mol) of di-tert-butylphosphinous chloride, 0.07 g (0.0005 mol (corresponding to 1% by mol)) of copper(I) bromide and 50 ml of tetrahydrofuran were placed. To the contents of the flask, a Grignard reagent solution previously prepared from 14.0 g (0.060 mol) of 2-bromobiphenyl and 1.7 g (0.072 mol) of metallic magnesium in 100 ml of tetrahydrofuran was dropwise added over a period of 1 hour with maintaining the temperature at 30° C. to 35° C. After the dropwise addition was completed, stirring was conducted at a reflux temperature for 4 hours. After the temperature of the reaction solution was returned to room temperature, disappearance of di-tert-butylphosphinous chloride was confirmed by gas chromatography. Thereafter, 30 ml of toluene and 30 ml of a 5% sulfuric acid aqueous solution were added to the reaction solution to perform liquid separation. Then, the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent and a low-boiling component were distilled off under reduced pressure to obtain coarse crystals. The coarse crystals were recrystallized from MeOH to obtain 13.2 g (purity: 99.0%) of the aimed di-tert-butyl(2-phenylphenyl)phosphine. The yield was 87.5%. Melting point: 84-85° C.
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH3:27])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])[C:11]([C:24]([OH:26])=O)=[CH:10]2)=[O:5].CN(C)CCCN=C=NCC.Cl.[NH2:41][C:42]1[CH:47]=[CH:46][C:45]([NH:48][C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:44][CH:43]=1>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH3:1][C:2]([CH3:27])([CH3:28])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])[C:11]([C:24]([NH:41][C:42]1[CH:43]=[CH:44][C:45]([NH:48][C:49](=[O:55])[O:50][C:51]([CH3:53])([CH3:52])[CH3:54])=[CH:46][CH:47]=1)=[O:26])=[CH:10]2)=[O:5]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Reactant: CC(C)(C)CC(=O)Nc1ccc2c(c1)cc(C(=O)O)n2Cc1ccccc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)CC(=O)Nc1ccc2c(c1)cc(C(=O)Nc1ccc(NC(=O)OC(C)(C)C)cc1)n2Cc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg (0.13 mmol) of 5-[(3,3-dimethylbutanoyl)amino]-1-(2-fluorobenzyl)-1H-indole-2-carboxylic acid from Example XXXIX, 37.6 mg (0.20 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide×HCl and 8 mg (0.07 mmol) of 4-dimethylaminopyridine are initially charged in DMF. 32.7 mg (0.16 mmol) of tert-butyl 4-aminophenylcarbamate are added, and the mixture is stirred at RT overnight. For work-up, the mixture is diluted and extracted with aqueous hydrochloric acid and dichloromethane. The organic phase is washed with sat. sodium chloride solution, dried with sodium sulphate, filtered and dried under reduced pressure.
Reaction SMILES: Cl[C:2]1[C:3]2[S:10][C:9]([S:11][CH3:12])=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[OH:23].C([O-])([O-])=O.[K+].[K+]>O(C1C=CC=CC=1)C1C=CC=CC=1>[F:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[O:23][C:2]1[C:3]2[S:10][C:9]([S:11][CH3:12])=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CSc1cc2ncnc(Cl)c2s1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CSc1cc2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 130 °C
Yield: 88 %

Procedure:
A mixture of 280 (210 mg, 0.97 mmol), 2-fluoro-4-nitrophenol (278 mg, 1.77 mmol) and K2CO3 (560 mg, 3.54 mmol) in Ph2O (10 mL) was heated at 130° C. 60 hours, cooled to room temperature and partitioned between EtOAc and water. Organic phase was collected, dried over anhydrous Na2SO4, filtered, concentrated and purified by flash column chromatography with a gradient elution (hexane to hexane/EtOAc, 1:1) to afford the title compound 281 (288 mg, 88% yield) as a yellowish solid. MS (m/z): 338.1(M+H) (found).
Reaction SMILES: Cl[C@H:2]1[CH2:19][C@@:18]2([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][C@H:11]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C@@H:12]2[OH:21])[CH2:4][C@@H:3]1[OH:28].[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([C@H:2]2[CH2:19][C@@:18]3([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]4[C@@H:17]3[CH2:16][CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][C@H:11]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[C@@H:12]3[OH:21])[CH2:4][C@@H:3]2[OH:28])[CH2:32][CH2:31]1
Reactant: C[C@]12C[C@H](Cl)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCCC3)C[C@@H]12
Reactant: CN1CCNCC1
Product: CN1CCN([C@H]2C[C@@]3(C)[C@@H](CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H](O)[C@@H](N5CCCCC5)C[C@@H]43)C[C@@H]2O)CC1

Procedure:
The compound was prepared according to Example 5 from 2β-chloro-3α-,17β-dihydroxy-16β-piperidino-5α-androstane and from N-methyl-piperazine.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([NH:20][C@@H:21]([C:26]([NH:28][CH2:29][C:30]([O:32]C)=[O:31])=[O:27])[CH2:22][CH2:23][S:24][CH3:25])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O.[OH-].[K+]>CO>[C:1]([NH:8][C@H:9]([C:18]([NH:20][C@@H:21]([C:26]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:27])[CH2:22][CH2:23][S:24][CH3:25])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: COC(=O)CNC(=O)[C@@H](CCSC)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Reaction time: 0.5 h

Procedure:
6.02 Grams of methyl Boc-L-tyrosyl-D-methionyl-glycinate is dissolved in 30 ml of methyl alcohol and water is added until the solution becomes cloudy. A 4 M solution of potassium hydroxide is added to maintain the pH at 12-13. When the pH is stable at 13 for 30 minutes, the methanol is removed under reduced pressure. The aqueous solution is filtered and adjusted to pH 3 with concentrated hydrochloric acid. The product crystallizes and is removed by filtration and washed with water to give Boc-L-tyrosyl-D-methionyl-glycine which is represented by the following formula
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([CH2:15][CH:16]([O:22][CH2:23][CH3:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:11]=[CH:12][C:13]=1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][S:26]([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37]OS(C)(=O)=O)=[CH:32][CH:31]=1)(=[O:28])=[O:27].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:1]([C:8]1[CH:9]=[C:10]([CH2:15][CH:16]([O:22][CH2:23][CH3:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:11]=[CH:12][C:13]=1[O:14][CH2:37][CH2:36][C:33]1[CH:32]=[CH:31][C:30]([O:29][S:26]([CH3:25])(=[O:27])=[O:28])=[CH:35][CH:34]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1ccc(O)c(Cc2ccccc2)c1)OCC
Reactant: CS(=O)(=O)OCCc1ccc(OS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)c(Cc2ccccc2)c1)OCC
Yield: 36.1 %

Procedure:
Ethyl 3-(3-benzyl-4-hydroxyphenyl)-2-ethoxypropanoate (0.50 g, 3.73 mmole) and 4-{2-[(methylsulfonyl)oxy]ethyl}phenyl methanesulfonate (2.20 g, 7.46 mmole) were dissolved in 2-butanone (20 ml). Polyethyleneglycol 400 (0.20 g) and anhydrous potassium carbonate (0.78 g, 5.59 mmole) were added the mixture. After stirring at reflux for 16 hours it was checked using HPLC whether all the starting material was consumed. The mixture was washed with water dried with magnesium sulfate and evaporated. Purification of the crude product with preparative HPLC (Kromasil C8, 10 μm, 50×500 mm) using acetonitrile (60-80%) in ammonium acetate buffer (pH 7) as mobile phase gave 0.71 g (36% yield) of the desired product
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH:11]=O)[C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3].[NH:13]([CH2:15]C(O)=O)[CH3:14]>C1(C)C=CC=CC=1>[CH3:14][N:13]1[CH2:15][CH2:3][CH:2]2[CH:11]1[CH2:10][N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:1]2
Reactant: CNCC(=O)O
Reactant: C=CCN(CC=O)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2CCN(C)C2C1

Procedure:
8.6 g (50 mmol) of ethyl N-allyl-N-(2-oxoethyl) -carbamate are heated under reflux overnight with 4.5 g (50 mmol) of sarcosine in 200 ml of toluene. The mixture is concentrated and the residue is distilled.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[CH:22](O)=O>ClCCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]2[CH:22]=[N:16][CH:15]=[C:11]2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1cc(OCc2ccccc2)ccn1
Reactant: O=CO
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: c1ccc(COc2ccn3cncc3c2)cc1

Procedure:
0.7 g (3.27 mmol) of 1-[4-(benzyloxy)pyridin-2-yl]methanamine (described in stage B) in 16 ml of formic acid is heated at reflux for 5 hours. The reaction medium is concentrated under reduced pressure. The residue obtained is taken up in 7 ml of 1,2-dichloroethane. 0.6 ml (6.54 mmol) of phosphoryl chloride dissolved in 7 ml of 1,2-dichloroethane is added. After heating at reflux for 4 hours, the reaction medium is concentrated under reduced pressure and the residue is then taken up in dichloromethane. The organic phase is washed with a saturated aqueous sodium hydrogencarbonate solution, dried over sodium sulfate and concentrated under reduced pressure. 0.97 g of a brown oil is collected.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[C:9]([N:12]2[CH:16]=[N:15][N:14]=[N:13]2)[CH2:10]Br)=[CH:4][CH:3]=1.[CH3:24][O:25][P:26]([O:29]C)[O:27][CH3:28]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[C:9]([N:12]2[CH:16]=[N:15][N:14]=[N:13]2)[CH2:10][P:26](=[O:29])([O:27][CH3:28])[O:25][CH3:24])=[CH:4][CH:3]=1
Reactant: Fc1ccc(C(=C(CBr)n2cnnn2)c2ccc(F)cc2)cc1
Reactant: COP(OC)OC
Product: COP(=O)(CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1cnnn1)OC
Temperature: 25 °C
Yield: 83.2 %

Procedure:
A suspension of 3,3-bis(4-fluorophenyl)-1-bromo-2-(tetrazol-1-yl)-2-propene (108 mg, 0.29 mmol) and trimethylphosphite (4 mL, 34 mmol) was heated to reflux under an inert atmosphere for five minutes. After cooling to room temperature, excess trimethylphosphite was evaporated under reduced pressure to give a pale crystalline material. The crude product was crystallized from a 10:1 mixture of hexanes: ethyl acetate to give 98 mg (83%) of the title compound as rhombic, colorless crystals; m.p.=132.8-133.7° C.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[CH2:10]([N:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH2:10]([N:17]1[CH2:22][CH2:21][C:20]([C:3]2[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=2)([OH:23])[CH2:19][CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1ccc(Br)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc(C2(O)CCN(Cc3ccccc3)CC2)cc1
Yield: 92.8 %

Procedure:
This compound is prepared according to procedure described in step A) of Preparation 8.3, starting with 2.6 g of magnesium in 15 ml of THF, 15 g of 1-bromo-4-methylbenzene in 100 ml of THF and 16.6 g of 1-benzyl-4-piperidinone in 100 ml of THF. 22.9 g of the expected product are obtained.
Reaction SMILES: C[Mg]Br.[C:4]1(C)C=CC=CC=1.[CH2:11]([O:13][P:14]([N:19]1[CH:25]2[CH:20]1[CH2:21][CH2:22][N:23]([C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[CH2:24]2)([O:16][CH2:17][CH3:18])=[O:15])[CH3:12].O>C1COCC1>[CH2:11]([O:13][P:14]([NH:19][C@H:25]1[C@H:20]([CH3:4])[CH2:21][CH2:22][N:23]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:24]1)([O:16][CH2:17][CH3:18])=[O:15])[CH3:12]
Reactant: Cc1ccccc1
Reactant: CCOP(=O)(OCC)N1C2CCN(C(=O)OCc3ccccc3)CC21
Agent: C[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: CCOP(=O)(N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1C)OCC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 48 %

Procedure:
To a suspension of Cu(I)I (0.10 g, 0.54 mmol) in THF (20 mL) was slowly added 1.40M methylmagnesium bromide (15.5 mL, 21.7 mmol) in 3:1 toluene:THF at −30° C. After stirring at that temperature for 15 minutes, a solution of benzyl 7-(diethoxyphosphoryl)-3,7-diazabicyclo[4.1.0]heptane-3-carboxylate (2.00 g, 5.43 mmol, Example H, Step D) in THF (10 mL) was added at −30° C. The mixture was then slowly warmed to 0° C. in 2 hours and stirred at 0° C. for 2 hours. Water (20 mL) was added and extracted with ethyl acetate (2×30 mL), washed with brine, dried (sodium sulfate) and concentrated in vacuo. The residue obtained was purified by flash chromatography on silica gel (ethyl acetate) to give trans-benzyl 3-(diethoxyphosphorylamino)-4-methylpiperidine-1-carboxylate (1.00 g, 48%) as an oil.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]([C:15]2[CH:19]=[C:18]([CH3:20])[N:17]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:16]=2[CH3:28])=[O:14])=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].C(=O)([O-])[O-].[K+].[K+].Cl[C:36]([O:38][CH3:39])=[O:37]>O.O1CCCC1>[NH2:4]/[C:2](=[N:3]\[C:36](=[O:37])[O:38][CH3:39])/[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]([C:15]2[CH:19]=[C:18]([CH3:20])[N:17]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[C:16]=2[CH3:28])=[O:14])=[CH:7][CH:6]=1
Reactant: COC(=O)Cl
Reactant: Cc1cc(C(=O)NCc2ccc(C(=N)N)cc2)c(C)n1-c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)/N=C(\N)c1ccc(CNC(=O)c2cc(C)n(-c3ccc(F)cc3)c2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
75 mg of N-[(4-carbamimidoylphenyl)methyl]-1-(4-fluorophenyl)-2,5-dimethyl-pyrrole-3-carboxamide hydrochloride and 78 mg of potassium carbonate were dissolved in 0.95 ml of water and 4.75 ml of tetrahydrofuran. The mixture was stirred at room temperature, and 0.016 ml of methyl chloroformate (Sigma-Aldrich) added. Stirring was continued for 1 h, following which the organic layer is removed, and dried in vacuo to obtain the synthetic target. The mass of the compound was verified using LC/MS/MS.
Reaction SMILES: CN(C=O)C.[CH2:6]([C:13]1[CH:14]=[N:15][C:16]2[C:21]([C:22]=1[O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Br)=[CH:20][CH:19]=[CH:18][C:17]=2[C:31]([F:34])([F:33])[F:32])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[O:41]1[C:45]2[CH:46]=[CH:47][C:48]([C:50]3([CH3:57])[NH:54][C:53](=[O:55])[NH:52][C:51]3=[O:56])=[CH:49][C:44]=2[O:43][CH2:42]1>O>[O:41]1[C:45]2[CH:46]=[CH:47][C:48]([C:50]3([CH3:57])[NH:54][C:53](=[O:55])[N:52]([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][O:23][C:22]4[C:21]5[C:16](=[C:17]([C:31]([F:34])([F:33])[F:32])[CH:18]=[CH:19][CH:20]=5)[N:15]=[CH:14][C:13]=4[CH2:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:51]3=[O:56])=[CH:49][C:44]=2[O:43][CH2:42]1
Reactant: FC(F)(F)c1cccc2c(OCCCCCCBr)c(Cc3ccccc3)cnc12
Reactant: CC1(c2ccc3c(c2)OCO3)NC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(c2ccc3c(c2)OCO3)NC(=O)N(CCCCCCOc2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)C1=O
Reaction time: 8 h
Yield: 121 %

Procedure:
A DMF (0.1 mL) solution of 3-benzyl-4-(6-bromohexyloxy)-8-(trifluoromethyl)quinoline (12.5 mg, 0.03 mmol) was added with potassium carbonate (9 mg, 0.06 mmol) and 5-(benzo[d][1,3]dioxol-5-yl)-5-methylimidazolidine-2,4-dione (46.8 mg, 0.20 mmol), and stirred overnight. The reaction solution was added with water, extracted with ethyl acetate, subsequently dried using anhydrous sodium sulfate and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane:ethyl acetate), and the title compound (22.5 mg, yield 49%) was obtained as a colorless oil.
Reaction SMILES: [C:1]([C@@H:3]([NH:12][C:13]([C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]1[NH:21][C:22]([C:24]1[N:25]([CH3:33])[C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)#[N:2].[H-].[Na+].[CH3:36]I>CN(C=O)C>[C:1]([C@@H:3]([NH:12][C:13]([C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]1[NH:21][C:22]([C:24]1[N:25]([CH3:33])[C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:36])=[CH:7][CH:6]=1)#[N:2]
Reactant: Cn1c(C(=O)N[C@H]2CCCC[C@H]2C(=O)N[C@H](C#N)Cc2ccc(O)cc2)cc2ccccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C[C@@H](C#N)NC(=O)[C@@H]2CCCC[C@@H]2NC(=O)c2cc3ccccc3n2C)cc1
Reaction time: 0.08 h
Yield: 70.5 %

Procedure:
To a solution of 1-Methyl-1H-indole-2-carboxylic acid {(1S,2R)-2-[(S)-1-cyano-2-(4-hydroxy-phenyl)-ethylcarbamoyl]cyclohexyl}-amide (compound 34, 102 mg, 0.229 mmol) in 3 mL of anhydrous DMF, was added sodium hydride powder (15 mg, 0.594 mmol). The reaction mixture was stirred for 5 min. while gas evolution subsided, then methyl iodide (0.2 mL, 3.1 mmol) was added. The reaction mixture was partitioned between 50 mL of water and 50 mL of ethyl acetate, the separated organic layer was washed with water (2×50 mL), dried with sodium sulfate, filtered, concentrated and purified by column chromatography (50:50, ethyl acetate/hexanes) to give 74 mg (70%) of 1-methyl-1H-indole-2-carboxylic acid ((1S,2R)-2-{[(S)-cyano-(4-methoxy-benzyl)-methyl]-carbamoyl}-cyclohexyl)-amide as a white amorphous solid. MS: 459 (M+H+).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[BrH:14].N([O-])=O.[Na+]>O>[Br:14][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Nc1cc(C(=O)O)cc(C(=O)O)c1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(Br)cc(C(=O)O)c1

Procedure:
99.18 g (0.55 mol) of 5-aminoisophthalic acid, 165 mL of 48 weight % hydrobromic acid and 150 mL of distilled water were charged in a 1 L four-neck flask equipped with a thermometer, an agitator and a dropping funnel, and then agitated. The flask was cooled to 5° C. or below, and 525 mL of distilled water containing 39.4 g (0.57 mol) of sodium nitrite was added dropwise for an hour, thus obtaining diazonium aqueous solution. 94.25 g (0.66 mol) of cuprous bromide and 45 mL of 48 weight % hydrobromic acid were charged in a 3 L four-neck flask equipped with a thermometer, a Dimroth condenser, a dropping funnel and an agitator, and agitated.
Reaction SMILES: [C:1]12([CH2:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Cl:21][C:22]1[CH:34]=[CH:33][C:25]([O:26][C:27]([CH3:32])([CH3:31])[C:28](Cl)=[O:29])=[CH:24][CH:23]=1.N1C=CC=CC=1>O>[C:1]12([CH2:11][C:12]([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:28](=[O:29])[C:27]([O:26][C:25]4[CH:33]=[CH:34][C:22]([Cl:21])=[CH:23][CH:24]=4)([CH3:32])[CH3:31])=[CH:18][CH:19]=3)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)Cl
Reactant: O=C(CC12CC3CC(CC(C3)C1)C2)c1ccc(O)cc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(Oc1ccc(Cl)cc1)C(=O)Oc1ccc(C(=O)CC23CC4CC(CC(C4)C2)C3)cc1
Reaction time: 4 h

Procedure:
6.75 g (25 mmol) of p-(1-adamantylacetyl)-phenol and 6 g (25.7 mmol) of 2-(p-chlorophenoxy)-isobutyric acid chloride was mixed with 60 ml of dry pyridine and kept at 40° C. for 4 hours. After addition of 40 ml of water a crystalline product was obtained which was sucked off, washed with water and dried.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([C:7]2[C:16]([OH:17])=[CH:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[CH:3][CH:2]=1.Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][CH:21]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:32][CH3:33])[N:23]=[CH:22][CH:21]=[C:20]2[O:17][C:16]1[C:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:18])=[CH:6][CH:5]=2)=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][N:10]=2
Reactant: Cc1ccc(-c2nc3ncccc3cc2O)cc1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3cc4cccnc4nc3-c3ccc(C)cc3)c2cc1OC
Temperature: 130 °C
Reaction time: 14.5 h
Yield: 19.5 %

Procedure:
2-p-Toluyl-[1,8]naphthyridin-3-ol (2 mg), 4-chloro-6,7-dimethoxyquinoline (6 mg), and 4-dimethylaminopyridine (3 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 130° C. for 14.5 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (0.7 mg, yield 20%).
Reaction SMILES: [H-].[Na+].[Br-].[N+:4]([C:7]1[CH:32]=[CH:31][C:10]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:9][CH:8]=1)([O-:6])=[O:5].[O:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1>CS(C)=O>[N+:4]([C:7]1[CH:8]=[CH:9][C:10]([CH:11]=[C:36]2[CH2:37][CH2:38][O:33][CH2:34][CH2:35]2)=[CH:31][CH:32]=1)([O-:6])=[O:5]
Reactant: O=C1CCOCC1
Reactant: O=[N+]([O-])c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(C=C2CCOCC2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
To a 500 mL 3-necked flask is added NaH (2.0 g of a 60% suspension in mineral oil) and 35 mL of DMSO. The resulting solution is heated at 80° C. for 1 h then cooled in an ice-water bath. To this is then added a solution of the (4-nitrobenzyl)(triphenyl)phosphonium bromide (23.92 g) in 200 mL warm DMSO. The mixture is stirred at room temperature for 1 h. Tetrahydro-4H-pyran-4-one (4.62 mL) is then added. The mixture is allowed to stir overnight at room temperature and then at 80° C. for 2 days. The mixture is poured over ice and extracted with Et2O. The combined organic extracts are dried and condensed. Chromatography (Biotage flash 40S, gradient from hexanes to 80% CH2Cl2/hexanes) yields 4.83 g (44%) of 4-(4-nitrobenzylidene)tetrahydro-2H-pyran as a solid.