Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH3:16][O:17][N:18]([CH3:25])[C:19](N(OC)C)=[O:20].Cl>C1COCC1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:19]([N:18]([O:17][CH3:16])[CH3:25])=[O:20])=[C:4]([O:8][CH3:9])[C:3]=1[F:10]
Reactant: CON(C)C(=O)N(C)OC
Reactant: COc1cccc(Cl)c1F
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1c(C(=O)N(C)OC)ccc(Cl)c1F
Temperature: -70 °C
Yield: 38.4 %

Procedure:
1 g (6.2 mmol) 3-Chloro-2-fluoroanisole in 10 ml THF are cooled to −70° C. and 2.7 ml of a 2.5 M n-butyl lithium solution in hexane are added. After 1.5 hours at −70° 1 g (6.9 mmol) N,N′-dimethoxy-N,N′-dimethyl urea in 6 ml THF are added at −70° C. and the mixture is stirred another hour at −70° C. 7.5 ml of a 2 M aqueous HCl are added and the reaction is warmed to ambient temperature over 18 hours. The reaction mixture is partitioned between diethyl ether and water. The aqueous phase is extracted with diethyl ether, the combined organic phases are washed with brine, dried over sodium sulfate and evaporated. The crude product is purified by chromatography on silica gel (ethyl acetate in hexane 0 to 30%) to yield 0.59 g 4-chloro-3-fluoro-2,N-dimethoxy-N-methylbenzamid. 1H-NMR (CDCl3); δ=3.35 (br, 3H), 3.49 (br, 3H), 3.98 (s, 3H), 6.99 (dd, 1H), 7.13 (dd, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][OH:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Br:20][C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+](C(OC(C)C)=O)(C(OC(C)C)=O)=[N-]>O1CCCC1>[C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:24]2[CH:25]=[CH:26][C:21]([Br:20])=[CH:22][CH:23]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCO)cs1
Agent: CC(C)OC(=O)[N+](=[N-])C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(Br)cc2)cs1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.4 %

Procedure:
2-{[4-(2-Hydroxyethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (3.077 g) synthesized in Example 4 and 4-bromophenol (1.75 g) were dissolved in tetrahydrofuran (50 mL), triphenylphosphine (3.20 g) and diisopropyl diazodicarboxylate (40% toluene solution, 6.54 ml) were added under ice-cooling, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=10:1 to 5:1) to give the title compound (3.45 g) as a colorless oil.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[CH:42]1([N:47]2[CH2:52][CH2:51][CH:50]([NH2:53])[CH2:49][CH2:48]2)[CH2:46][CH2:45][CH2:44][CH2:43]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:53][CH:50]5[CH2:51][CH2:52][N:47]([CH:42]6[CH2:46][CH2:45][CH2:44][CH2:43]6)[CH2:48][CH2:49]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCN(C2CCCC2)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CCN(C3CCCC3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.1 %

Procedure:
To a mixture of 0.050 g (0.11 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.08 mL (0.44 mmole) of ethyldiisopropyl amine and 0.021 g (0.12 mmole) of 1-cyclopentyl-piperidin-4-ylamine in 1.5 mL of dimethylformamide was added 0.053 g (0.12 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The resulting solid was collected by filtration, washed with saturated sodium carbonate and water, and dried under vacuum. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-85:15) gave 0.029 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-cyclopentyl-piperidin-4-yl)-3-methoxy-benzamide (I-63).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:6][C:7](=[O:18])[C:8]3([CH2:17][CH2:16]3)[CH2:9][N:10]([CH:13]([CH3:15])[CH3:14])[C:11]=2[N:12]=1.[CH3:19]I.[H-].[Na+]>CC(N(C)C)=O.C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:19])[C:7](=[O:18])[C:8]3([CH2:16][CH2:17]3)[CH2:9][N:10]([CH:13]([CH3:15])[CH3:14])[C:11]=2[N:12]=1
Reactant: CC(C)N1CC2(CC2)C(=O)Nc2cnc(Cl)nc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CC(C)N1CC2(CC2)C(=O)N(C)c2cnc(Cl)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
To a solution of 2′-chloro-9′-isopropyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 209; 5.055 g, 19 mmol) in DMA (300 mL) was added methyl iodide (1.305 mL, 20.9 mmol), followed by sodium hydride (60% mineral oil dispersion; 814 mg, 20.33 mmol). The mixture was stirred at room temperature for 30 minutes. The DMA was removed in vacuo, then water (50 mL) was added. The product precipitated as a sticky gum, which turned into a solid on sonication. The solid was collected by filtration to give a brown powder. This material was dissolved in DCM and dried over sodium sulfate, then purified by column chromatography, eluting with 25% ethyl acetate in hexane, to yield the title compound as a white solid (3.73 g, 70%)
Reaction SMILES: C([C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[CH2:12][CH2:13][CH2:14][C:6]=3[C:5]=2[CH:4]=1)#N.[H-].[Na+].[CH2:17](I)[CH3:18].O.[CH3:21][N:22](C=O)C>>[C:21]([C:10]1[C:9]2[C:5](=[C:6]3[C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=[C:7]3[N:8]=2)[CH:4]=[CH:3][CH:11]=1)#[N:22]
Reactant: CCI
Reactant: CN(C)C=O
Reactant: N#Cc1ccc2[nH]c3c(c2c1)CCC3
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCC1=CC=C2N=c3c(C#N)cccc3=C12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 7-cyano-1,2,3,4-tetrahydrocyclopent[b]indole (0.224 g, 1.23 mmol) in anhydrous DMF (15 mL) was cooled to 0° C. and sodium hydride (60% dispersion in mineral oil, 74 mg, 3.07 mmol) was added. The reaction was stirred for 45 minutes then ethyl iodide (0.171 g, 1.47 mmol) was added and the reaction was allowed to warm to room temperature. The mixture was stirred for 15 hours then water was added. The product precipitated and was collected by filtration, washing with little water, brine and dichloromethane to give 0.287 g of title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][CH2:16][O:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:10][CH2:9]1)=O)(C)(C)C.[C:22]([OH:28])([C:24]([F:27])([F:26])[F:25])=[O:23]>C(Cl)Cl>[F:25][C:24]([F:27])([F:26])[C:22]([OH:28])=[O:23].[NH:8]1[CH2:9][CH2:10][CH:11]([C:14]#[C:15][CH2:16][O:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#CCOS(C)(=O)=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)OCC#CC1CCNCC1
Reaction time: 0.5 h

Procedure:
A solution of 2.96 g (9.4 mmol) of 4-(3-Methanesulfonyloxy-prop-1-ynyl)-piperidine-1-carboxylic acid tert-butyl ester in 50 ml CH2Cl2 was treated at 0° C. with 25.2 ml of TFA (for 20 min). After 30 min at this temperature, the reaction was evaporated, evaporated again with toluene (4 times) and dried to give 3.6 g (quantitative) of methanesulfonic acid 3-piperidin-4-yl-prop-2-ynyl ester; compound with trifluoro-acetic acid, MS: 218 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:16])[N:12]([CH2:14][CH3:15])[CH:13]=2)=[CH:4][CH:3]=1.[NH2:17][NH2:18].CO>CC(O)C.O>[NH:17]([C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:16])[N:12]([CH2:14][CH3:15])[CH:13]=2)=[CH:4][CH:3]=1)[NH2:18]
Reactant: CCn1cc(-c2ccc(Cl)nc2)ccc1=O
Reactant: NN
Solvent: O
Solvent: CO
Solvent: CC(C)O
Product: CCn1cc(-c2ccc(NN)nc2)ccc1=O
Temperature: 140 °C
Yield: 95.8 %

Procedure:
A mixture of 5-(6-chloropyridin-3-yl)-1-ethylpyridin-2(1 H)-one (1.2 g, 5.44 mmol) and hydrazine (820 mg, 25.62 mmol) in 2-propanol (5 ml) was heated in a microwave at 140° C. for 4 hrs. The mixture was co-evaporated with MeOH (3×) and then suspended in water (50 ml). The resulting solid was collected by filtration and dried under high vacuum for one day to give crude title compound, 5-(6-hydrazinylpyridin-3-yl)-1-ethylpyridin-2(1 H)-one (1.2 g, 95.9% yield).
Reaction SMILES: [C:1]1([CH2:7][N:8]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:9][C@@H:10]([C:12]2[CH:13]=[CH:14][C:15]([OH:21])=[C:16]([NH:18][CH:19]=[O:20])[CH:17]=2)[OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:31][Si:32]([CH3:39])([CH3:38])[CH2:33][CH2:34][O:35][CH2:36]Cl.P([O-])([O-])([O-])=O>CN(C=O)C.O>[C:1]1([CH2:7][N:8]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:9][C@@H:10]([C:12]2[CH:13]=[CH:14][C:15]([O:21][CH2:36][O:35][CH2:34][CH2:33][Si:32]([CH3:39])([CH3:38])[CH3:31])=[C:16]([NH:18][CH:19]=[O:20])[CH:17]=2)[OH:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=CNc1cc([C@@H](O)CN(Cc2ccccc2)Cc2ccccc2)ccc1O
Reactant: C[Si](C)(C)CCOCCl
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCOc1ccc([C@@H](O)CN(Cc2ccccc2)Cc2ccccc2)cc1NC=O
Reaction time: 0.17 h

Procedure:
A solution of (5-{(1R)2-[bis(phenylmethyl)amino]-1-hydroxyethyl}-2-hydroxyphenyl)formamide (354 mg) in DMF (10 ml) under nitrogen was treated with sodium hydride (60% dispersion in mineral oil, 38 mg) and the mixture stirred at 20° for 10 min. 2-(Trimethylsilyl)ethoxymethyl chloride (0.17 ml) was added and the mixture was stirred at 20° for 3 h. Phosphate buffer solution (pH 6.5) and water were added and the mixture was extracted with EtOAc. The extract was washed with water and dried (Na2SO4). Solvent evaporation in vacuo gave a residue which was purified on a silica SPE bond elut cartridge (20 g) using a gradient of 0% to 2% MeOH in DCM (Gradmaster™). The appropriate fractions were evaporated in vacuo to give the title compound (286 mg). LCMS RT=3.08 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][NH:21][CH2:22][C:17]=4[O:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl.[CH3:24][N:25]([CH3:32])[CH2:26]/[CH:27]=[CH:28]/[C:29](O)=[O:30].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][N:21]([C:29](=[O:30])/[CH:28]=[CH:27]/[CH2:26][N:25]([CH3:32])[CH3:24])[CH2:22][C:17]=4[O:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(Nc2ncnc3oc4c(c23)CCNC4)cc1Cl
Reactant: CN(C)C/C=C/C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)C/C=C/C(=O)N1CCc2c(oc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
A suspension of N-(3-chloro-4-fluorophenyl)-5,6,7,8-tetrahydropyrido[4′,3′:4,5]furo[2,3-d]pyrimidin-4-amine from Example 39A (100 mg, 0.314 mmol) and (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride from Example 1A (73 mg, 0.44 mmol) in THF (2 mL) was treated with DIPEA (160 mg, 1.26 mmol) and TBTU (150 mg, 0.47 mmol). The mixture was stirred at rt overnight and then purified directly by preparative HPLC. The product crystallized upon trituration with diethyl ether to afford 76 mg (56%) of the title compound.
Reaction SMILES: [CH3:1][CH:2]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH:15]([CH3:20])[CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:10][CH:9]=1)[CH2:3][CH:4]([CH3:6])[CH3:5].[CH2:21]([CH:23]([CH2:26][CH2:27][CH2:28][CH3:29])[CH:24]=O)[CH3:22].[Na].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[CH3:20][CH:15]([N:14]([CH2:24][CH:23]([CH2:21][CH3:22])[CH2:26][CH2:27][CH2:28][CH3:29])[C:11]1[CH:12]=[CH:13][C:8]([N:7]([CH:2]([CH3:1])[CH2:3][CH:4]([CH3:5])[CH3:6])[CH2:24][CH:23]([CH2:21][CH3:22])[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:9][CH:10]=1)[CH2:16][CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)CC(C)Nc1ccc(NC(C)CC(C)C)cc1
Reactant: CCCCC(C=O)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Solvent: O
Product: CCCCC(CC)CN(c1ccc(N(CC(CC)CCCC)C(C)CC(C)C)cc1)C(C)CC(C)C
Yield: 92.8 %

Procedure:
N,N′-di-(1,3-dimethylbutyl)-p-phenylenediamine (17 g, 61.5 mmol) and 2-ethylhexanal (18.53 g, 144.5 mmol) were dissolved in dichloromethane (500 mL) and were stirred together in a 1 liter round bottomed flask fitted with a condenser and magnetic stirring at room temperature whilst sodium triacetoxyhydroborate (30.63 g, 144.5 mmol) was added portionwise over 1 hour. The mixture was left standing for a total of 18 hours. The crude product was stirred with 150 ml water for a few minutes followed by addition of aqueous sodium carbonate solution (60 g in 250 ml water) in portions. Most of the effervescence subsided after 50% of this had been added. The mixture was stirred with a further 100 ml water and separated using a separating funnel. The organic phase was washed with water (500 ml+750 ml) and brine (500 ml). It was then dried with magnesium sulphate, filtered through celite 521 and evaporated to leave a dark brown oil. The product was chromatographed (eluent 5% EtOAc in heptane). Relevent fractions were combined and concentrated to afford the product as a dark oil (28.6 g, 93% yield).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][N:24]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:10]=[C:1]1[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[S:4][C:12]([C:14]2[CH:15]=[C:16]([CH:22]=[CH:23][N:24]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:13]1
Reactant: CCOC(=O)c1ccnc(C#N)c1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccnc(-c2nc(=O)c3ccccc3s2)c1
Yield: 71.9 %

Procedure:
A mixture of methyl thiosalicylate (3.0 g, 17.8 mmol), ethyl 2-cyanoisonicotinate (3.1 g, 17.8 mmol), triethylamine (5.0 ml, 35.8 mmol) and toluene (10 ml) was refluxed for 8 hrs as described in Example 1. The precipitated crystals were collected by filtration and recrystallized from diisopropylether-chlorobenzene to give the titled compound (4.0 g, 71%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br.[NH2:12][CH:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([OH:24])[C:19]=2[OH:23])[CH:14]1[OH:25]>C(O)C>[C:1]1([CH2:7][CH2:8][CH:9]=[N:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([OH:24])[C:19]=3[OH:23])[CH:14]2[OH:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC1CCc2c(ccc(O)c2O)C1O
Reactant: O=CCCc1ccccc1
Agent: Br
Solvent: CCO
Product: Oc1ccc2c(c1O)CCC(N=CCCc1ccccc1)C2O

Procedure:
In 200 volume parts of ethanol is dissolved 2 parts of 2-amino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide, followed by the addition of 20 parts of β-phenylpropionaldehyde to produce 2-(3-phenylpropylideneamino)-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene. Using palladium-on-carbon as a catalyst, the reaction mixture is subjected to catalytic reduction at ordinary temperature and pressure. After a stoichiometric amount of hydrogen has been absorbed, the reaction mixture is filtered to remove the catalyst and, then, 5000 volume parts of ethyl ether is added to the filtrate. The procedure yields 2 parts of 2-(3-phenylpropylamino)-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide as white crystals melting at 136°-139° C (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].ClC(OCC)=O.[OH-].[NH4+:23]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([NH2:23])=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: [NH4+]
Reactant: COc1ccc(CCC(=O)O)cc1OC
Agent: CCOC(=O)Cl
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(CCC(N)=O)cc1OC
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3-(3,4-dimethoxy-phenyl)-propionic acid (10.0 g, 47.6 mmol) in dry THF (175 mL), under nitrogen, is added TEA (7.3 ml, 52.4 mmol). The resulting mixture is cooled to −10° C. before ethyl chloroformate (5.0 ml, 52 mmol) is added dropwise. After stirring at −10° C. (20 min), ammonium hydroxide (25% in water, 105 ml) in THF (105 mL) is added and the mixture is stirred at −15° C. for 30 min and then at rt for 1.5 h. The reaction mixture is concentrated in vacuo, extracted three times with CH2Cl2 and the combined organic extracts are washed with saturated aqueous NaHCO3 and brine. The organic phase is dried over anhydrous MgSO4, filtered and concentrated to give the title compound as a colorless solid.
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7](Cl)[C:6]=1[Cl:15])=[O:3].[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[OH:24].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][C:2]([NH:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([O:24][C:18]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:17]=2[Cl:16])[C:6]=1[Cl:15])=[O:3]
Reactant: CC(=O)Nc1c([N+](=O)[O-])ccc(Cl)c1Cl
Reactant: Oc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)Nc1c([N+](=O)[O-])ccc(Oc2ccc(Cl)cc2Cl)c1Cl
Temperature: 0 °C

Procedure:
A mixture of N-methylcarbonyl 2,3-dichloro-6-nitroaniline (0.90 g, 3.6 mmol), 2,4-dichloro-phenol (0.59 g, 3.6 mmol) and potassium carbonate (1.0 g, 7.2 mmol), in 20 ml of DMSO, is stirred at 90° for 3 hours. The reaction is then cooled and poured onto about 60 g of ice. A yellow solid is collected by filtration to give N-methylcarbonyl 2-chloro-3-(2,4-dichloro-phenoxy)-6-nitroaniline.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][C:22](O)=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:25][CH:26]([C:29]1[CH:34]=[CH:33][C:32]([CH2:35][OH:36])=[CH:31][CH:30]=1)[CH2:27][CH3:28].[CH:37]1C=CC2N(O)N=NC=2C=1>C(Cl)CCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][C:22](=[O:23])[NH:25][CH:26]1[C:29]2[C:34](=[CH:33][C:32]([CH2:35][OH:36])=[CH:31][CH:30]=2)[CH2:37][CH2:28][CH2:27]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: On1nnc2ccccc21
Reactant: CCC(N)c1ccc(CO)cc1
Reactant: CC(C)(C)OC(=O)N1CC(OCc2ccccc2)CC1CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC(OCc2ccccc2)CC1CC(=O)NC1CCCc2cc(CO)ccc21

Procedure:
4-Benzyloxy-2-carboxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester was coupled to [4-(1-aminopropyl)-phenyl]-methanol using EDC and HOBt as described earlier to afford the title compound as a white solid (MS,495, M+H).
Reaction SMILES: [ClH:1].C([O:6][C:7](=[O:25])[C@H:8]([CH2:17][CH2:18][CH2:19][NH:20][CH2:21][O:22][CH:23]=[NH:24])[NH:9]C(OC(C)(C)C)=O)(C)(C)C.Cl>O1CCOCC1>[ClH:1].[ClH:1].[NH:24]=[CH:23][O:22][CH2:21][NH:20][CH2:19][CH2:18][CH2:17][C@@H:8]([C:7]([OH:25])=[O:6])[NH2:9]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNCOC=N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: N=COCNCCC[C@H](N)C(=O)O
Temperature: 22 °C
Reaction time: 8 h
Yield: 206.3 %

Procedure:
A solution of 0.75 g (1.96 mmol) N2-(tert-butoxycarbonyl)-N5-(iminomethoxymethyl)-L-ornithine tert-butyl ester hydrochloride in 2 mL dioxane at 0° C. was treated with 15 mL of 4N hydrochloric acid in dioxane solution. The solution was stirred overnight at 22° C., concentrated to a crude paste, and freeze-dried from 8 mL of water. The product was freeze-dried a second time to yield 0.53 g N5-(iminomethoxymethyl)-L-ornithine dihydrochloride. The product analyzed solvated with an additional 0.2 molar hydrochloric acid 0.1 molar water, and 0.3 molar dioxane.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:13]=[CH:12][CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.C(Cl)Cl.[N+:18]([O-])([OH:20])=[O:19].C(OCC)(=[O:24])C>>[OH:24][C:12]1[CH:13]=[C:4]([C:3]([O:2][CH3:1])=[O:14])[C:5]([N+:18]([O-:20])=[O:19])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CCOC(C)=O
Reactant: COC(=O)c1cccc(C(=O)OC)c1
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Product: COC(=O)c1cc(O)cc(C(=O)OC)c1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
To a suspension of 60 g. of dimethylisophthalate in 600 ml. of methylene chloride are added 200 ml. of concentrated nitric acid, and the mixture is rapidly stirred at room temperature for about 45 min. After this time, 300 ml. of ice water are added, followed by 700 ml. of ethyl acetate. The organic layer is separated, washed with two portions of saturated brine, and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure, leaving a sticky solid which is triturated with 100 ml. of warm benzene. The insoluble material is collected and washed with benzene to give 19.5 g. (27%) of white to pale yellow solid, m.p. 183°-186° C.
Reaction SMILES: [CH3:1][N:2]([CH3:5])[CH:3]=O.[Br:6][C:7]1[CH:8]=[C:9]([N+:14]([O-:16])=[O:15])[C:10]([CH3:13])=[N:11][CH:12]=1.COC(OC)N(C)C.O>C(O)(C)C>[Br:6][C:7]1[CH:8]=[C:9]([N+:14]([O-:16])=[O:15])[C:10](/[CH:13]=[CH:3]/[N:2]([CH3:5])[CH3:1])=[N:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: Cc1ncc(Br)cc1[N+](=O)[O-]
Agent: COC(OC)N(C)C
Solvent: O
Solvent: CC(C)O
Product: CN(C)/C=C/c1ncc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
N,N-Dimethylformamide (270 kg), 5-bromo-2-methyl-3-nitropyridine (90.0 kg, 415 mol), and N,N-dimethylformamide dimethyl acetal (108.0 kg, 906.3 mol) were added to a 2000 L vessel at RT. The reaction mixture was stirred at RT for 30 minutes, then heated to 90±5° C. over a 3-hour period and maintained at this temperature for 4 hours. The mixture was subsequently cooled to 25±5° C. Water (945 kg) was added while keeping the temperature of the mixture at 25±5° C. After the addition of water, the reaction mixture was stirred for 2 hours. The solids were centrifuged to obtain wet product, which was slurried in isopropanol (207 kg) for 1 hour at 25±5° C. The solids were centrifuged again to obtain the title compound as a wet solid (105 kg, 92.5 wt % assay). The product was used in the next step without additional drying.
Reaction SMILES: [C:1]([NH-:4])(O)=[O:2].[NH2:5][C:6]1[CH:7]=[N:8][C:9](CC(N)=O)=[CH:10][CH:11]=1.[CH3:16][CH:17]([N:22]=[C:23]=[S:24])[C:18]([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[C:1]([C:9]1[N:8]=[CH:7][C:6]([NH:5][C:23]([NH:22][CH:17]([CH3:16])[C:18]([CH3:21])([CH3:20])[CH3:19])=[S:24])=[CH:11][CH:10]=1)(=[O:2])[NH2:4]
Reactant: NC(=O)Cc1ccc(N)cn1
Reactant: [NH-]C(=O)O
Reactant: CC(N=C=S)C(C)(C)C
Solvent: CN(C)C=O
Product: CC(NC(=S)Nc1ccc(C(N)=O)nc1)C(C)(C)C
Yield: 53 %

Procedure:
The carboxyamide compound (0.37 g, 27 mmol) obtained in (a) described above and 1,2,2-trimethylpropyl isothiocyanate (1.15 g, 8.03 mmol) were added to 2 ml of DMF, followed by reaction at 80°-90° C. for about 40 hours. DMF was removed by distillation, and the residue was purified by silica gel column chromatography (eluent: chloroform: methanol=13:1 (v/v)). Recrystallization from methanol-ether gave 0.4 g of the intended product (yield: 53%).