Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][CH:10]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N>[Ni].CO>[C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][CH:10]([C:13]3[CH:14]=[C:15]([CH2:16][NH2:17])[CH:18]=[CH:19][CH:20]=3)[CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1cccc(C2CCN(Cc3ccccc3)C2)c1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1cccc(C2CCN(Cc3ccccc3)C2)c1
Yield: 83.7 %

Procedure:
A suspension of 3-[1-(phenylmethyl)-3-pyrrolidinyl]benzonitrile (11.90 g, 45.4 mmol) and Raney nickel (5.0 g) in methanol saturated with ammonia (100 mL) was hydrogenated in a Parr shaker at 3 atm. The resulting suspension was filtered through a pad of Celite and the filtrate concentrated to give an off-green liquid. This crude product was chromatographed (silica gel, chloroform-methanol 2:1) to give the title compound (10.12 g, 84%) as a colorless oil.
Reaction SMILES: [F:1][CH:2]([F:4])Cl.[NH2:5][C:6]1[N:11]=[C:10]([OH:12])[CH:9]=[C:8]([CH3:13])[N:7]=1>O.[OH-].[Na+].O1CCOCC1>[NH2:5][C:6]1[N:11]=[C:10]([O:12][CH:2]([F:4])[F:1])[CH:9]=[C:8]([CH3:13])[N:7]=1
Reactant: Cc1cc(O)nc(N)n1
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(OC(F)F)nc(N)n1

Procedure:
Gaseous difluorochloromethane is passed into a solution of 62.5 g of 2-amino-4-hydroxy-6-methyl-pyrimidine in 500 ml of water, 100 ml of 40% sodium hydroxide solution and 100 ml of dioxane at a temperature of 70°-75° C. over a period of 12 hours. During this period, at hourly intervals, a total of 160 g of solid sodium hydroxide is added in equal portions. The organic phase is separated off and concentrated to about 1/10 of its volume, the residue is poured into water and the solid which has precipitated is separated off to give 39.9 g of 2-amino-4-difluoromethoxy-6-methyl-pyrimidine of melting point 136°-137° C.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.C[Si]([C:28]#[C:29][C:30]1[CH:31]=[N:32][CH:33]=[C:34]([CH:37]=1)[C:35]#[N:36])(C)C>C(N(CC)CC)C.C(OCC)(=O)C>[C:29]([C:30]1[CH:31]=[N:32][CH:33]=[C:34]([CH:37]=1)[C:35]#[N:36])#[CH:28]
Reactant: C[Si](C)(C)C#Cc1cncc(C#N)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#Cc1cncc(C#N)c1
Reaction time: 0.08 h
Yield: 74.1 %

Procedure:
Add a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (50.0 mL, 50.0 mmol) to a suspension of 5-trimethylsilanylethynyl-nicotinonitrile (10.0 g, 50.0 mmol), (prepared as described in PREPARATION 3), in triethylamine (98 mL) at 0° C. After 5 min, dilute the reaction mixture with ethyl acetate and wash twice with water. Back-extract the combined aqueous washes twice with ethyl acetate. Wash the combined organic layers with a saturated aqueous solution of sodium chloride, dry (sodium sulfate), filter, and concentrate. Purify the residue by silica gel chromatography, eluting with a gradient from 98:2 to 90:10 dichloromethane:ethyl acetate, to give the title compound as a white crystalline solid (4.75 g, 74%).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:20]1([C:26]2[N:27]=[C:28]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[S:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12]([N:34]2[CH2:35][CH2:36][N:31]([C:28]3[S:29][CH:30]=[C:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:27]=3)[CH2:32][CH2:33]2)=[O:19])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cn1
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)Nc1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)cs3)CC2)cn1
Temperature: 70 °C
Reaction time: 15 h
Yield: 13.7 %

Procedure:
A mixture of 2,2,2-trichloroethyl [6-(acetylamino)pyridin-3-yl]carbamate (293 mg, 0.897 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (200 mg, 0.815 mmol) and diisopropylethylamine (0.156 ml, 0.897 mmol) in dimethylsulfoxide (2.7 ml) was stirred at 70° C. for 15 hours. Water was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to obtain the desired product (47.3 mg, 13.7%) as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:24])[CH:3]=1.[NH:25]1[CH2:28][CH2:27][C:26]1=[O:29]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:25]4[CH2:28][CH2:27][C:26]4=[O:29])=[CH:3][C:4]=3[F:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: O=C1CCN1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCC4=O)cc3F)CC2)c(C)c1
Yield: 32.1 %

Procedure:
Using (4-bromo-2-fluorophenyl) [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 114 and 2-azetidinone (30 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (47 mg) was obtained.
Reaction SMILES: Cl.Cl.[NH2:3][NH2:4].O[C:6]([CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:22][CH:21]=1)=O)([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7](OCC)=[O:8]>C(O)C>[CH2:27]([O:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]2[CH:17]=[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7](=[O:8])[NH:3][N:4]=2)=[CH:21][CH:22]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NN
Reactant: CCOC(=O)C(O)(CC(=O)c1ccc(OCc2ccccc2)cc1)C(=O)OCC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)n[nH]c1=O
Yield: 78.6 %

Procedure:
1.69 g of hydrazine dihydrochloride were added, at a temperature in the region of 19° C., to 5.6 g of diethyl hydroxy[2-(4-benzyloxyphenyl)-2-oxoethyl]malonate dissolved in 180 cm3 of ethanol. The reaction medium was heated and maintained at reflux for 12 hours. After cooling, the solvent was removed under reduced pressure (2 kPa; 55° C.). The solid residue was triturated in 20 cm3 of ethanol, suction-filtered through a sinter funnel and oven-dried under reduced pressure (10 kPa; 50° C.). 3.85 g of ethyl 6-[4-(benzyloxy)phenyl]-3-oxo-2,3-dihydropyridazine-4-carboxylate were obtained in the form of a green solid melting at 239° C.
Reaction SMILES: [C:1]([S:4][C@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@H:6]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:7]([O:9]C)=[O:8])(=O)[CH3:2].[OH-].[Na+].Br[C:28]1[CH:33]=C[CH:31]=[C:30](C)[C:29]=1[CH3:35].Cl.[CH3:37]O>>[CH3:37][C@:6]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])([C@H:5]([S:4][CH2:1][C:2]1[CH:31]=[CH:30][C:29]([CH3:35])=[CH:28][CH:33]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1cccc(Br)c1C
Reactant: CO
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](SC(C)=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(CS[C@H](c2ccccc2)[C@](C)(NC(=O)OC(C)(C)C)C(=O)O)cc1
Reaction time: 0.33 h
Yield: 79 %

Procedure:
The acetylated thiol 17 (500 mg, 1.4 mmol) was dissolved in methanol (2 mL) and NaOH was added (1.6 mL, 1M aqueous), followed by bromoxilene (300 mg, 1.62 mmol). After 20 min most of the starting material has disappeared (monitored by TLC). The solution was carefully neutralized with dilute HCl. The volatiles were removed in vacuo and the residue was extracted with Cl2CH2 (3×) The organic layer was washed with brine and dried over Na2SO4. The crude product was purified by flash column chromatography (silica, 5% to 20% ethyl acetate/hexane) to give the desired ester 18 (480 mg, 79%) as a white solid, which crystallized. mp 97°-98° C. (ether-hexane); [α]20D =-171.8° (c=1.05, CHCl3); 1H NMR (CDCl3).δ1.384 (s, 9H), 2.326 (s, 3H), 3.393 (d, J=13 Hz, 1H), 3.551 (d, J=13 Hz, 1H), 3.572 (s, 3H, OCH3), 4.126 (d,J=5.4 Hz, H-3), 4.630 (dd, J=8.8, 5.8 Hz, 1H, H-2), 5.220 (bd, J=8.8 Hz, 1H, H--N), 7.028-7.107 (m, 4H), 7.291-7.362 (m, 5H); 13C NMR (CDCl3).δ21.0, 28.3, 35.5, 51.6, 52.1, 57.5, 80.1, 127.8, 128.5, 128.7, 128.9, 129.2, 134.3, 136.9, 138.4, 154.7, 170.8; MS m/z 316 [M+H]+ ; Anal. Calcd for C23H29O4NS.1/4H2O: C, 65.76; H, 7.08; N, 3.33. Found: C, 65.59; H, 7.03; N, 3.36.
Reaction SMILES: COC(=O)[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][S:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:8][CH:7]=1)[CH3:5].[OH-:29].[K+].[CH2:31]([OH:33])C>O>[CH2:16]([S:15][CH2:14][CH2:13][O:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:4][CH2:5][C:31]([OH:33])=[O:29])=[CH:11][CH:10]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCO
Reactant: [OH-]
Reactant: CCCCCCCCCCCCSCCOc1ccc(C(C)C(=O)OC)cc1
Agent: [K+]
Solvent: O
Product: CCCCCCCCCCCCSCCOc1ccc(CCC(=O)O)cc1
Temperature: 55 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A suspension of 2-[4-[2-(dodecylthio)ethoxy]phenyl]propanoic acid methyl ester (4.70 g, 11.5 mmol) in 80% ethanol (100 ml) was treated with a solution of potassium hydroxide (1.33 g, 20.1 mmol) in water (10 ml) and the mixture was stirred at 55° C. for 1 h. The solvent was then concentrated in vacuo and the residue was diluted with water (100 ml) and dichloromethane (250 ml). The solution was then adjusted to pH 2 with diluted hydrochloric acid and the aqueous phase was extracted a second time with dichloromethane. The combined organic extracts were washed with brine and dried (magnesium sulfate). Evaporation of the solvent under reduced pressure and crystallization of the residue from ethyl acetate-hexane gave 3.56 g (78%) of 3-[4-[2-(dodecylthio)ethoxy]phenyl]propanoic acid as white prisms: m.p. 68-69° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])=[CH:4][C:3]=1I.[C:22]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])(=[O:25])[CH:23]=[CH2:24].C([O-])(=O)C.[Na+].O>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])=[CH:4][C:3]=1[CH:24]=[CH:23][C:22]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[O:25]
Reactant: C=CC(=O)OCC(F)(F)F
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(I)c2)c1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(C=CC(=O)OCC(F)(F)F)c2)c1=O
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A suspension of 5.0 g of 3-[4-chloro-3-iodophenyl]-2,4-dioxo-1-methyl-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine, 2.0 g of 2,2,2-trifluoroethyl acrylate, 0.5 mg of palladium acetate and 1.1 g of sodium acetate in 50 ml of dimethylformamide was stirred for 4 hours at 120° C., after which further palladium acetate and 2,2,2-trifluoromethyl acrylate were added and stirring was continued for a further 2 hours at 120° C. The cooled reaction mixture was added to 200 ml of water and the precipitate was isolated, washed with petroleum ether and dried under greatly reduced pressure.
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[CH2:4][CH2:3][CH2:2]1.[Br:13]N1C(=O)CCC1=O>C(O)(=O)C>[Br:13][C:10]1[CH:9]=[CH:8][C:7]2[O:1][CH2:2][CH2:3][CH2:4][CH:5]([OH:12])[C:6]=2[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CCCOc2ccccc21
Solvent: CC(=O)O
Product: OC1CCCOc2ccc(Br)cc21
Temperature: 10 °C
Reaction time: 4 h

Procedure:
104.9 g (0.64 mole) of 2,3-dihydro-1-benzoxepin-5(4H)-one are dissolved at room temperature in 780 ml of glacial acetic acid and then, while stirring vigorously at 10° C., 113.9 g (0.64 mole) of N-bromosuccinimide are introduced in portions so that the temperature does not exceed 18°-20° C. (about 30 min). The reaction is complete after about 4 hours (TLC check) and the mixture is poured into 3 l of vigorously stirred ice-water and then stirred for 30 minutes. The solid produced which is initially oily crystallizes completely after some time. The solid is filtered off with suction and washed with about 5 l of water. It is dried over calcium chloride in vacuo and crystallized in cyclohexane.
Reaction SMILES: Cl.[O:2]=[C:3]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH2:23])=[O:22])[CH:16]=2)[O:11][C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4]1.[CH:27]1([N:30]2[C:38]3[C:33](=[C:34]([C:42]4[NH:46][N:45]=[N:44][N:43]=4)[CH:35]=[C:36]([C:39](O)=[O:40])[CH:37]=3)[CH:32]=[CH:31]2)[CH2:29][CH2:28]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl>CN(C=O)C.O.C(N(CC)CC)C>[CH:27]1([N:30]2[C:38]3[C:33](=[C:34]([C:42]4[NH:46][N:45]=[N:44][N:43]=4)[CH:35]=[C:36]([C:39]([N:8]4[CH2:7][CH2:6][C:5]5([CH2:4][C:3](=[O:2])[C:17]6[C:12](=[CH:13][CH:14]=[C:15]([C:18]7[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=7)[C:21]([NH2:23])=[O:22])[CH:16]=6)[O:11]5)[CH2:10][CH2:9]4)=[O:40])[CH:37]=3)[CH:32]=[CH:31]2)[CH2:28][CH2:29]1
Reactant: NC(=O)c1cccc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)c1
Reactant: O=C(O)c1cc(-c2nnn[nH]2)c2ccn(C3CC3)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)c4cc(-c5nnn[nH]5)c5ccn(C6CC6)c5c4)CC2)O3)c1
Temperature: 50 °C
Reaction time: 23 h

Procedure:
3-(4-Oxospiro[chroman-2,4′-piperidin]-6-yl)benzamide hydrochloride (224 mg), 1-cyclopropyl-4-(tetrazol-5-yl)-1H-indole-6-carboxylic acid (135 mg), EDCI (115 mg), HOBT (91.2 mg) and triethylamine (0.209 ml) were dissolved in DMF (3 mL), and stirred at 50° C. for 23 hours. 1N hydrochloric acid and water were added to the reaction liquid, the formed solid was taken out through filtration, and the resulting solid was purified through silica gel thin-layer column chromatography (chloroform/methanol) to obtain the title compound. 1H-NMR (400 MHz, DMSO-d6) δ: 8.17-8.10 (2.0H, br m), 8.05 (1.0H, d, J=2.2 Hz), 7.99 (1.0H, dd, J=8.5, 2.2 Hz), 7.86-7.78 (4.0H, m), 7.63 (1.0H, d, J=2.9 Hz), 7.52 (1.0H, dd, J=7.7, 7.7 Hz), 7.40 (1.0H, s), 7.25 (1.0H, d, J=8.5 Hz), 7.15-7.13 (1.0H, m), 4.50-4.08 (1.0H, br m), 3.88-3.08 (4.0H, m), 2.96 (2.0H, s), 2.23-1.68 (4.0H, m), 1.15-1.08 (2.0H, m), 1.06-0.96 (2.0H, m). MS [M+H]+=588.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+:4].[Pt:5](Cl)Cl>C(O)C>[Pt:5].[C:2].[CH2:2]([OH:1])[CH3:3].[O-:1][CH2:2][CH3:3].[Na+:4]
Reactant: Cl[Pt]Cl
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: [C]
Product: [Pt]

Procedure:
Sodium ethoxide (0.416 g) was dissolved in 20 mL of ethanol, then combined with platinum chloride (0.333 g) and agitated until it became clear. The resulting mixture was then added to a carbon support slurry which was dispersed in 10 mL of ethanol and further agitated to produce a platinum precursor-carbon-sodium ethoxide ethanol mixture.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].CN(C=O)C.C(Cl)(C([Cl:23])=O)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([Cl:23])=[O:8]
Reactant: COc1cc(Br)cc(C(=O)O)c1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(Br)cc(C(=O)Cl)c1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of compound 56 (3.82 g, 14.3 mmol) in CH2Cl2 (63 mL) was added dropwise DMF (0.20 mL) and (COCl)2 (1.63 mL, 18.7 mmol) at 0° C. under an atmosphere of nitrogen. After being stirred for 20 hours at room temperature, the mixture was concentrated in vacuo to provide the crude acid chloride 59, which was used for the next reaction without further purification.
Reaction SMILES: [C:1]([C:4]1[C:9]([CH3:10])=[C:8](Cl)[C:7]([CH3:12])=[CH:6][N:5]=1)([OH:3])=[O:2].C[O-:14].[Na+].Cl>>[C:1]([C:4]1[C:9]([CH3:10])=[C:8]([OH:14])[C:7]([CH3:12])=[CH:6][N:5]=1)([OH:3])=[O:2]
Reactant: C[O-]
Reactant: Cc1cnc(C(=O)O)c(C)c1Cl
Agent: Cl
Agent: [Na+]
Product: Cc1cnc(C(=O)O)c(C)c1O
Yield: 89 %

Procedure:
Starting with 2-carboxy-4-chloro-3,5-lutidine, a sodium methoxide nucleophilic substitution reaction was conducted as described above for 24 hours. The aqueous layer was acidified to pH 2.5 with concentrated Hydrochloric acid. The precipitate was filtered and washed with water and dried under vacuum at 50ℑ C. The 2-carboxy-4-hydroxy-3,5-lutidine product was obtained as a light brown solid in 89% yield.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[F:8][C:9]([F:41])([F:40])[C:10]1[CH:11]=[C:12]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:13][NH:14][CH:15]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:17]2[CH:28]=[C:29]([Br:32])[CH:30]=[CH:31][C:16]1=2.N1C=CC=CC=1>ClCCl>[C:1]([N:14]([CH2:13][C:12]1[CH:33]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=[C:10]([C:9]([F:8])([F:40])[F:41])[CH:11]=1)[CH:15]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:17]2[CH:28]=[C:29]([Br:32])[CH:30]=[CH:31][C:16]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)OC(=O)N1CCCC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(Br)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 12 h
Yield: 79.3 %

Procedure:
Add 3,5-bis(trifluoromethyl)benzylamine (5.47 g, 22.5 mmol) followed by titanium isopropoxide (5.98 mL, 20.1 mmol) to a solution of isopropyl 8-bromo-5-oxo-2,3,4,5-tetrahydro benzo[b]azepine-1-carboxylate (5.24 g, 16.1 mmol) in tetrahydrofuran (20 mL) at room temperature under nitrogen was and stir the solution for 4 h. Dilute the reaction with methanol (40 mL) and slowly add sodium borohydride (0.912 g, 24.1 mmol) over 15 min to the reaction and stir at room temperature for 3.5 h. Quench the reaction with addition of 2 N NaOH (56 mL) and water (50 mL) and stir for 0.5 h. Filter the mixture and wash the solids with ethyl acetate/ethanol (4:1, 3×100 mL). Separate the filtrate and wash the organic layer with 2 N NaOH, 2 N HCl, and brine (50 mL each), then dry the solution over sodium sulfate, filter and remove the solvent under reduced pressure to afford isopropyl-5-(3,5-bistrifluoromethylbenzylamino)-8-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate as a white solid. Add acetic anhydride (22.6 mL, 241 mmol) dropwise to a suspension of isopropyl 5-(3,5-bistrifluoromethylbenzylamino)-8-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (8.89 g, 16.1 mmol) and pyridine (19.6 mL g, 241 mmol) in dichloromethane (64 mL) under nitrogen cooled to 0° C. After the addition is complete, remove the cooling bath and warm the reaction to room temperature and stir for 12 h. Dilute the mixture with dichloromethane (100 mL) and wash with 2 N hydrochloric acid (2×50 mL), saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL). Dry the organic layer over sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue using chromatography on silica gel, eluting with hexanes/ethyl acetate (60:40), to afford the title compound as a white solid (7.60 g, 79%, 2 steps): ESI MS 595 (M+H).
Reaction SMILES: [CH2:1]([O:3][CH:4]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([OH:13])[C:6]=2[O:5]1)[CH3:2].BrC[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[O:24][CH3:25].[C:26](=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.C1(C=CC=C(O)C=1O)O>CC(C)=O>[CH3:23][O:22][C:19]1[CH:20]=[C:21]([CH:16]=[C:17]([O:24][CH3:25])[CH:18]=1)[CH2:26][O:13][C:12]1[C:6]2[O:5][CH:4]([O:3][CH2:1][CH3:2])[O:8][C:7]=2[CH:9]=[CH:10][CH:11]=1
Reactant: COc1ccc(CBr)c(OC)c1
Reactant: O=C([O-])[O-]
Reactant: CCOC1Oc2cccc(O)c2O1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Oc1cccc(O)c1O
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC1Oc2cccc(OCc3cc(OC)cc(OC)c3)c2O1

Procedure:
2-Ethoxy-benzo[1,3]dioxol-4-ol (1.11 g, 6.08 mmol), 4-bromomethyl-1,3-dimethoxybenzene (1.17 g, 5.08 mmol), potassium carbonate (0.77 g, 5.59 mmol) and 18-crown-6-ether (0.13 g, 0.51 mmol) were stirred together at room temperature in acetone (40 cm3, 99%) under nitrogen for 18 hours. The solution was evaporated under reduced pressure, and the residue was taken up in dichloromethane (30 cm3) and water (30 cm3). The aqueous layer was extracted with dichloromethane (3×30 cm3), and the combined extracts were washed with water (2×50 cm3), dried (MgSO4), and evaporated under reduced pressure. The residue was chromatographed (SiO2, dichloromethane) to give the di protected pyrogallol, (1.56 g, 92%) as a clear oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([Cl:14])=[C:11]([Cl:13])[Cl:12])[CH:9]=1)[CH2:5]Br.[N-:15]=[N+:16]=[N-:17].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([Cl:14])=[C:11]([Cl:13])[Cl:12])[CH:9]=1)[CH2:5][N:15]=[N+:16]=[N-:17]
Reactant: Fc1cc(CBr)cc(C(Cl)=C(Cl)Cl)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Product: [N-]=[N+]=NCc1cc(F)cc(C(Cl)=C(Cl)Cl)c1

Procedure:
A solution of 3-fluoro-5-(trichlorovinyl)benzyl bromide (3.18 g) and sodium azide (0.975 g) in 25 ml of ethanol is heated at reflux for 2 hours. The reaction mixture is concentrated and the residue triturated with 50 ml of hexane. The mixture is filtered and the filtrate concentrated to give the desired azide.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:21]([N:23]1[CH2:30][CH2:29][CH2:28][C@H:24]1[C:25](O)=[O:26])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8].C(OC(Cl)=O)C(C)C.[NH2:39][C@H:40]([C:48]([N:50]1[CH2:88][CH2:87][CH2:86][C@H:51]1[C:52]([NH:54][C@H:55]([C:61]([NH:63][C@H:64]([C:69]([N:71]1[CH2:85][CH2:84][CH2:83][C@H:72]1[C:73]([N:75]1[CH2:82][CH2:81][CH2:80][C@H:76]1[C:77]([OH:79])=[O:78])=[O:74])=[O:70])[C@H:65]([CH2:67][CH3:68])[CH3:66])=[O:62])[CH2:56][CH2:57][C:58](=[O:60])[NH2:59])=[O:53])=[O:49])[CH2:41][CH2:42][CH2:43][NH:44][C:45](=[NH:47])[NH2:46].CCOC(C)=O>CN(C=O)C.CC(O)=O>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:21]([N:23]1[CH2:30][CH2:29][CH2:28][C@H:24]1[C:25]([NH:39][C@H:40]([C:48]([N:50]1[CH2:88][CH2:87][CH2:86][C@H:51]1[C:52]([NH:54][C@H:55]([C:61]([NH:63][C@H:64]([C:69]([N:71]1[CH2:85][CH2:84][CH2:83][C@H:72]1[C:73]([N:75]1[CH2:82][CH2:81][CH2:80][C@H:76]1[C:77]([OH:79])=[O:78])=[O:74])=[O:70])[C@H:65]([CH2:67][CH3:68])[CH3:66])=[O:62])[CH2:56][CH2:57][C:58](=[O:60])[NH2:59])=[O:53])=[O:49])[CH2:41][CH2:42][CH2:43][NH:44][C:45](=[NH:46])[NH2:47])=[O:26])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C1CC[C@@H](C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)N2CCC[C@H]2C(=O)O)N1
Agent: CC(C)COC(=O)Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCC(=O)N1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 0.29 h

Procedure:
The tripeptide, from part C, Pyr-Trp-Pro (23.3 mmoles) is dissolved in DMF (85 ml) and 3.27 ml (23.3 mmoles) TEA, the solution cooled to -20° (inside the flask, or -35° to -40° in the cooling bath) and kept at this temperature for 15-20 minutes. To this cold solution 3.19 ml of isobutyloxycarbonyl chloride is added and then a time of 30 minutes is allowed for the mixed anhydride to be formed at the same temperature. A solution of Arg-Pro-Gln-Ile-Pro-Pro (16.5 g) in DMF (100 ml) is precooled to about 0° and then added into the solution of the mixed anhydride. At this moment, the pH value is adjusted to 8 with TEA (8.5 ml) while the temperature of 0° is maintained. After 20 to 24 hours at room temperature, the volume of the solvents is reduced to 1/3-1/4 and poured into 20-25 volumes of EtOAc containing 3 % of AcOH. The precipitate is washed thoroughly with EtOAc and then dried in vacuo over KOH overnight to yield the title compound. This material is dissolved in water, sterilized by filtration, and the sterile aqueous solution freeze-dried to a free flowing powder. The powder is reconstituted for injection with water for injection or saline.