Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:21]1[N:30]=[CH:29][C:28]2[C:23](=[C:24]([F:35])[CH:25]=[C:26]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:27]=2)[C:22]1=[O:36])(=O)C.Cl[C:38]1[CH:39]=[C:40]([NH:46][C:47]2[CH:52]=[N:51][C:50]([C@H:53]3[CH2:57][O:56][C:55]([CH3:59])([CH3:58])[O:54]3)=[CH:49][N:48]=2)[C:41](=[O:45])[N:42]([CH3:44])[N:43]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[Cl-].[NH4+]>C(O)CCC.O>[C:31]([C:26]1[CH:27]=[C:28]2[C:23](=[C:24]([F:35])[CH:25]=1)[C:22](=[O:36])[N:21]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:38]3[CH:39]=[C:40]([NH:46][C:47]4[CH:52]=[N:51][C:50]([C@H:53]5[CH2:57][O:56][C:55]([CH3:58])([CH3:59])[O:54]5)=[CH:49][N:48]=4)[C:41](=[O:45])[N:42]([CH3:44])[N:43]=3)[C:6]=1[CH2:5][OH:4])[N:30]=[CH:29]2)([CH3:34])([CH3:32])[CH3:33]
Reactant: Cn1nc(Cl)cc(Nc2cnc([C@H]3COC(C)(C)O3)cn2)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: CCCCO
Solvent: O
Product: Cn1nc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2cnc([C@H]3COC(C)(C)O3)cn2)c1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 35.8 %

Procedure:
A solution of 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (307 mg, 0.62 mmol), (S)-6-chloro-4-(5-(2,2-dimethyl-1,3-dioxolan-4-yl)pyrazin-2-ylamino)-2-methylpyridazin-3(2H)-one (150 mg, 0.44 mmol), potassium phosphate (236 mg, 0.01 mmol) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (21.2 mg, 0.04 mmol) in butanol (4 ml) and water (1 mL) was flushed with argon before (bis[dibenzylideneacetone]dipalladium) (12.8 mg, 0.02 mmol) was added and the resulting solution heated at 100° C. in for 2 h. The resulting mixture was cooled, poured into a saturated solution of ammonium chloride and extracted with methylene chloride (2×100 mL). The layers were separated and the organic phase dried over magnesium sulfate. The mixture was filtered and concentrated in vacuo. The residue was dissolved in dioxane (10 mL) and treated with a lithium hydroxide solution (0.5 mL, 2.0 M), and the resulting mixture was stirred at room temperature overnight. The resulting mixture was poured into a saturated ammonium chloride solution and extracted with methylene chloride (2×150 mL). The layers were separated and the organic phase dried over magnesium sulfate. The mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 24 g, 1% to 7% methanol in dichloromethane) to give (S)-6-tert-butyl-2-(3-(5-(5-(2,2-dimethyl-1,3-dioxolan-4-yl)pyrazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(hydroxymethyl)phenyl)-8-fluorophthalazin-1(2H)-one (99 mg, 36%) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:22])[CH2:13][CH2:12][C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:14]#[N:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[K+].Br[CH2:26][CH:27]1[CH2:29][CH2:28]1.O>CS(C)=O>[CH:27]1([CH2:26][O:22][C:8]2([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:13][CH2:12][C:11]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)([C:14]#[N:15])[CH2:10][CH2:9]2)[CH2:29][CH2:28]1
Reactant: BrCC1CC1
Reactant: N#CC1(c2ccccc2)CCC(O)(c2ccc(F)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: N#CC1(c2ccccc2)CCC(OCC2CC2)(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
500 mg of 4-(4-fluorophenyl)-4-hydroxy-1-phenylcyclohexanecarbonitrile were dissolved in 10 ml of dry dimethyl sulfoxide, treated with 190 mg of potassium hydroxide and stirred for 30 min at room temperature. Subsequently, 0.17 ml of bromomethylcyclopropane were slowly added dropwise. The reaction mixture was stirred for 24 h, treated with water and extracted with EA. The combined organic phases were dried over magnesium sulfate and the solvent was removed in vacuo. The crude product, a clear oil, was purified by chromatography on silica gel using HEP/EA (2:1). 510 mg of the title compound were obtained as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[N:7]([CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH:8]1[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][C:18]1[C:19]([CH:25]=O)=[N:20][CH:21]=[C:22]([CH3:24])[CH:23]=1.[BH4-].[Na+]>CO>[C:1]([O:5][C:6](=[O:16])[N:7]([CH:8]1[CH2:9][CH2:10]1)[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:25][C:19]1[C:18]([CH3:17])=[CH:23][C:22]([CH3:24])=[CH:21][N:20]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCCCN)C1CC1
Reactant: Cc1cnc(C=O)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cnc(CNCCCCN(C(=O)OC(C)(C)C)C2CC2)c(C)c1
Yield: 89 %

Procedure:
Using General Procedure B, (4-amino-butyl)-cyclopropyl-carbamic acid tert-butyl ester and 3,5-dimethyl-pyridine-2-carbaldehyde in MeOH were reacted with NaBH4 to obtain cyclopropyl-{4-[(3,5-dimethyl-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester as a colorless oil (0.217 g, 89%). 1H NMR (CDCl3) δ 0.52-0.58 (m, 2H), 0.68-0.74 (m, 2H), 1.44 (s, 9H), 1.53-1.65 (m, 4H), 2.26 (s, 6H), 2.45-2.50 (m, 1H), 2.70 (t, 2H, J=6.9 Hz), 3.19 (t, 2H, J=7.2 Hz), 3.82 (s, 2H), 7.23 (s, 1H), 8.20 (s, 1H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:11].C(C(O)=O)(F)(F)F.[C:25]1([CH2:31][CH2:32]Br)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([CH:12]1[CH2:17][CH2:16][N:15]([CH2:32][CH2:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:14][CH2:13]1)=[O:11]
Reactant: BrCCc1ccccc1
Reactant: O=C(c1nc2ccccc2s1)C1CCNCC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1nc2ccccc2s1)C1CCN(CCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Mix (2-benzothiazolyl)(4-piperidinyl)methanone.CF3CO2H (2.56 g, 7.13 mmol), 2-phenylethyl bromide (1.45 g, 7.84 mmol), 18-Crown-6 (188 mg, 0.71 mmol), potassium carbonate (9.85 g, 71.3 mmol) and methylene chloride (100 mL). Stir at room temperature under an argon atmosphere for 2 hours, then add potassium iodide (200 mg). Stir at room temperature for an additional 2 hours then heat at reflux overnight. Add additional 2-phenylethyl bromide (1.45 g, 7.84 mmol) and heat at reflux overnight. Add additional 2-phenylethyl bromide (1.45 g, 7.84 mmol) and heat at reflux overnight. Cool the reaction to room temperature and pour into water (150 mL). Separate the organic phase, wash with water (100 mL) and dry (Na2SO4). Evaporate the solvent in vacuo and purify by chromatography (20% ethyl acetate/hexane with 2% triethylamine) to give the title compound as a yellow solid; mp 108.5°-109.5° C.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][Cl:8].FC(F)(F)S(O[C@@H:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=O)=O.FC(F)(F)S([O-])(=O)=O>[OH-].[Na+].O1CCCC1>[CH2:19]([O:18][C:16](=[O:17])[C@@H:15]([CH3:21])[N:5]([CH2:6][CH2:7][Cl:8])[CH2:4][CH2:3][Cl:2])[CH3:20]
Reactant: ClCCNCCCl
Reactant: CCOC(=O)[C@H](C)OS(=O)(=O)C(F)(F)F
Agent: Cl
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](C)N(CCCl)CCCl
Temperature: 25 °C
Reaction time: 24 h
Yield: 134.8 %

Procedure:
A suspension of bis(2-chloroethyl)amine hydrochloride (0.392 g; 2.1 mmol) in 5N aqueous sodium hydroxide (3 mL) is extracted with ether (2×10 mL) and the combined extracts are washed with a minimum amount of water and saturated brine. The ethereal solution is dried quickly over magnesium sulfate and filtered. Tetrahydrofuran (2 mL) is added to the filtrate, and ether is carefully removed under reduced pressure on a rotavapor unit without heating. The residue is mixed with a solution of ethyl (S)-2-[(trifluoromethylsulfonyl)oxy]-propionate (0.5 g; 2 mmol) in tetrahydrofuran (1 mL). After stirring the reaction mixture for 24 hrs at room temperature, there is no visible precipitate. The volatiles are removed under reduced pressure and the remaining viscous oil is dissolved in ether (8 mL), and the slightly turbid solution is filtered after 60 minutes. The filtrate is treated dropwise with n-heptane to induce crystallization; the final ratio of n-heptane/ether is 1:3. The crystalline salt is collected by filtration and washed quickly with a small portion of ether. There is obtained 0.653 g (yield 83.3%) of N,N-bis(2-chloroethyl)-(R)-alanine ethyl ester, trifluoromethanesulfonate; mp 73–74.5° C.; 1H NMR (300 MHz, CDCl3) δ 1.35 (t, J=7.1 Hz, 3H), 1.76 (d, J=7.2 Hz, 3H), 3.87 (m, 2H), 4.00 (m, 2H), 4.35 (q, J=7.1 Hz, 2H), 4.57 (q, J=7.2 Hz, 1H), 9.02 (b, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][C:13]1[C:18](=[O:19])[CH2:17][CH2:16][CH2:15][C:14]=1[CH2:20][C:21](O)=[O:22])=[CH:7]2.[CH3:24][O:25][C:26]([N:28]=C=NC(C)(C)C)=[O:27]>C1COCC1>[CH3:24][O:25][C:26](=[O:27])[NH:28][C:21](=[O:22])[CH2:20][C:14]1[CH2:15][CH2:16][CH2:17][C:18](=[O:19])[C:13]=1[CH2:12][C:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[Br:1])[CH:7]=1
Reactant: O=C(O)CC1=C(Cc2ccc3c(Br)cccc3c2)C(=O)CCC1
Reactant: COC(=O)N=C=NC(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)NC(=O)CC1=C(Cc2ccc3c(Br)cccc3c2)C(=O)CCC1
Yield: 74.8 %

Procedure:
A mixture of [2-(5-bromo-naphthalen-2-ylmethyl)-3-oxo-cyclohex-1-enyl]-acetic acid (1.1 g, 2.95 mmol), N-methoxycarbonyl-N'-tert-butylcarbodiimide (0.51 g, 3.25 mmol), and THF (20 mL) was refluxed for 4 hours. The volatiles were removed in vacuo and the residue was purified by flash chromatography on silica gel (eluting solvent hexane/EtOAc 2/1) to give a white solid (0.95 g, 76% yield, m.p. 128°-129° C.).
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])O[C:2]1=O.C([O-])([O-])OCC.[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH2:36][CH2:37][NH2:38])[CH2:30][CH2:29]1)[CH3:20]>>[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:29][CH2:30][N:31]([CH2:34][CH2:35][CH2:36][CH2:37][N:38]2[C:4](=[O:11])[C:5]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:1]=[CH:2]2)[CH2:32][CH2:33]1)[CH3:20]
Reactant: CCOc1ccccc1N1CCN(CCCCN)CC1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: CCOC([O-])[O-]
Product: CCOc1ccccc1N1CCN(CCCCn2cnc3ccccc3c2=O)CC1
Yield: 37 %

Procedure:
A mixture comprising 1.63 g of 2H-3,1-benzoxazine-2,4(1H)-dione, 1.78 g of ethyl orthoformate and 2.77 g of 4-(2-ethoxyphenyl)-1-(4-aminobutyl)piperazine was heated on a boiling water bath for about 10 minutes and further heated on an oil bath of 120° to 130° C. for about 2 hours. After the completion of the reaction, the reaction mixture was concentrated under a reduced pressure and the residue was columnchromatographed over silica gel column and eluted with an ethyl acetatetriethylamine solvent (30:1) to give 1.5 g of 3-{4-[4-(2-ethoxyphenyl)-1-piperazinyl]butyl}-4(3H)-quinazolone as an oil (yield: 66.7%). ##STR15## 1.50 g of this oily free base was dissolved in a small amount of acetone. The obtained solution was added to a saturated solution of 0.857 g of fumaric acid in acetone to precipitate a crude crystal. The crude crystal was recrystallized from ethanol to give 1.65 g of the corresponding monofumarate having a melting point of 197° to 198° C. as a colorless prisms.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]([OH:21])=O)=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:6][N:7]=1.Cl.[CH3:23][O:24][NH:25][CH3:26].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.O>[NH2:1][C:2]1[C:3]([C:19]([N:25]([O:24][CH3:23])[CH3:26])=[O:21])=[N:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([S:14]([CH2:17][CH3:18])(=[O:15])=[O:16])[CH2:12][CH2:13]2)=[CH:6][N:7]=1
Reactant: CCS(=O)(=O)N1CCN(c2cnc(N)c(C(=O)O)n2)CC1
Reactant: CNOC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(C(=O)N(C)OC)n2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
A mixture of 3-amino-6-(4-ethylsulfonylpiperazin-1-yl)pyrazine-2-carboxylic acid (1 g, 3.171 mmol), N-methoxymethanamine hydrochloride (371.2 mg, 3.805 mmol) and triethylamine (705.9 mg, 972.3 μL 6.976 mmol) were dissolved in DMF (10 mL) and treated with TBTU (1.527 g, 4.756 mmol). The mixture was allowed to stir at ambient temperature for 1 hour. The reaction was treated with water, extracted with EtOAc (4×), and the organics separated, dried (MgSO4) and concentrated. The resultant residue was purified on silica gel by flash column chromatography (0-100% EtOAc/Petrol) to afford the title compound as a yellow solid (864 mg, 76% Yield). 1H NMR (400.0 MHz, DMSO) d 1.21 (t, 3H), 3.10 (q, 2H), 3.27-3.30 (m, 4H), 3.34 (s, 3H), 3.38-3.40 (m, 4H), 3.68 (s, 3H), 5.87 (br s, 2H) and 7.99 (s, 1H) ppm; MS (ES+) 359.0
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[NH:8][C:7]([C:15]([OH:17])=O)=[CH:6]2.[NH2:18][C@@H:19]([CH2:28][S:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[CH2:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[NH:8][C:7]([C:15]([NH:18][C@@H:19]([CH2:28][S:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[CH2:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:17])=[CH:6]2
Reactant: COc1ccc(CSC[C@H](N)COC(=O)C(C)(C)C)cc1
Reactant: O=C(O)c1cc2cc(CO)cc([N+](=O)[O-])c2[nH]1
Product: COc1ccc(CSC[C@@H](COC(=O)C(C)(C)C)NC(=O)c2cc3cc(CO)cc([N+](=O)[O-])c3[nH]2)cc1

Procedure:
5-Hydroxymethyl-7-nitro-1H-indole-2-carboxylic acid prepared in Preparation 38 and 2,2-dimethyl-propionic acid (R)-2-amino-3-(4-methoxy-benzylsulfanyl)-propyl ester prepared in Preparation 31 were reacted according to the same procedure as Step B of Preparation 40 to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[C:3]=1[N+:13]([O-:15])=[O:14].COC(OC)N(C)C.CN(C)C=O.C(OCC)(=O)C>>[Br:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:7])[O:8][CH:9]=[CH:12]2
Reactant: COC(=O)c1ccc(Br)c([N+](=O)[O-])c1C
Agent: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1occc2c([N+](=O)[O-])c(Br)ccc12
Temperature: 120 °C
Reaction time: 12 h

Procedure:
A pressure tube (150 mL) was charged with methyl 4-bromo-2-methyl-3-nitrobenzoate (2.1 g, 0.0077 mol), 1,1-dimethoxy-N,N-dimethylmethanamine (3.6 mL, 0.027 mol) and N,N-dimethylformamide (5 mL, 0.06 mol) and heated at 120° C. for 20 hours. The reaction gave multiple products. The solvent was removed and the residue was dissolved in Ethyl acetate (100 mL, 1 mol). Silica Gel (20 g, 0.3 mol) was then added and the reaction stirred at room temperature for 12 h. The reaction was filtered and the solvent removed and the residue purified by flash chromatography. MS m/z=271.2 (M+H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:22][CH2:21][CH2:20]3)[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].CCN(CC1C=CC=CC=1)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.Cl.[F:54][C:55]1[CH:56]=[C:57]2[C:61](=[CH:62][CH:63]=1)[CH2:60][NH:59][CH2:58]2>C(Cl)Cl>[ClH:2].[Cl:2][C:3]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:22][CH2:21][CH2:20]3)[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:4]=1[C:5]([N:59]1[CH2:58][C:57]2[C:61](=[CH:62][CH:63]=[C:55]([F:54])[CH:56]=2)[CH2:60]1)=[O:6]
Reactant: Fc1ccc2c(c1)CNC2
Reactant: O=C(Cl)c1ccc(OC2CCN(C3CCC3)CC2)cc1Cl
Agent: C=Cc1ccc(C=C)cc1
Agent: CCN(CC)Cc1ccccc1
Agent: Cl
Solvent: C=Cc1ccccc1
Solvent: ClCCl
Product: O=C(c1ccc(OC2CCN(C3CCC3)CC2)cc1Cl)N1Cc2ccc(F)cc2C1
Reaction time: 16 h
Yield: 109.7 %

Procedure:
A stirred mixture of 2-chloro-4-[(1-cyclobutyl-4-piperidinyl)oxy]benzoyl chloride hydrochloride (D36) (0.20 g) and diethylaminomethyl polystyrene (3.2 mmol/g, 0.8 g) in DCM (10 ml) at rt was treated with 5-fluoroisoindoline hydrochloride (D8) (0.10 g) and stirred for 16 h. The reaction mixture was chromatographed directly [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM]. Fractions containing the required product were evaporated, redissolved in DCM, treated with excess hydrogen chloride (1M solution in diethyl ether) and then concentrated. The residue was crystallised from acetone to yield the title compound (E65) as a white solid (0.14 g). MS electrospray (+ion) 430/432 (MH+). 1H NMR δ (DMSO-d6): 10.48 (1H, s), 7.46-7.06 (6H, m), 4.88-4.60 (3H, m), 4.51 (2H, m), 3.80-3.55 (1H, m), 3.46-3.18 (2H, m), 2.88 (2H, m), 2.38-1.64 (10H, m).
Reaction SMILES: ClCl.[Cl:3]P(Cl)C1C=CC=CC=1.[N+]([C:15]1[CH:25]=[CH:24][CH:23]=[C:17]2[C:18]([O:20][C:21](=[O:22])[C:16]=12)=[O:19])([O-])=O.[OH-].[Na+]>ClP(=O)(Cl)C1C=CC=CC=1>[Cl:3][C:15]1[CH:25]=[CH:24][CH:23]=[C:17]2[C:18]([O:20][C:21](=[O:22])[C:16]=12)=[O:19]
Reactant: ClP(Cl)c1ccccc1
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Agent: ClCl
Agent: O=P(Cl)(Cl)c1ccccc1
Agent: [Na+]
Product: O=C1OC(=O)c2c(Cl)cccc21
Temperature: 150 °C
Yield: 82.5 %

Procedure:
Chlorine gas (363 milligrams, 5.18 millimoles) was bubbled into a solution of dichlorophenylphosphine (927 milligrams, 5.18 millimoles) in dichlorophenylphosphine oxide (10 milliliters). To this yellow solution was added 3-nitrophthalic anhydride (1 gram, 5.18 millimoles), then the reaction mixture was heated to 150° C. for 12 hours. The cooled solution was poured onto ice (20 milliliters) and neutralized with 50% aqueous sodium hydroxide. The aqueous mixture was extracted twice with 20 milliliter portions of ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated in vacuo to yield 3-chlorophthalic anhydride (780 milligrams, 83 weight percent) as a dark solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:26])=[C:4]([C:18]([NH:20][CH2:21][CH:22]([OH:25])[CH2:23][OH:24])=[O:19])[C:5]([I:17])=[C:6]([C:15]=1[I:16])[C:7]([NH:9][CH2:10][CH:11]([OH:14])[CH2:12][OH:13])=[O:8].[Cl:27][CH2:28][C:29](Cl)=[O:30]>CN(C)C(=O)C.C(#N)C>[Cl:27][CH2:28][C:29]([O:25][CH:22]([CH2:23][O:24][C:29](=[O:30])[CH2:28][Cl:27])[CH2:21][NH:20][C:18](=[O:19])[C:4]1[C:3]([I:26])=[C:2]([NH:1][C:29](=[O:30])[CH2:28][Cl:27])[C:15]([I:16])=[C:6]([C:7]([NH:9][CH2:10][CH:11]([O:14][C:29](=[O:30])[CH2:28][Cl:27])[CH2:12][O:13][C:29](=[O:30])[CH2:28][Cl:27])=[O:8])[C:5]=1[I:17])=[O:30]
Reactant: Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Reactant: O=C(Cl)CCl
Solvent: CC#N
Solvent: CC(=O)N(C)C
Product: O=C(CCl)Nc1c(I)c(C(=O)NCC(COC(=O)CCl)OC(=O)CCl)c(I)c(C(=O)NCC(COC(=O)CCl)OC(=O)CCl)c1I

Procedure:
reacting 5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisopthalamide with chloroacetyl chloride in N,N-dimethylacetamide and acetonitrile, to produce N,N'-bis[2,3-di(2-chloroacetoxy)propyl]-5-(2-chloroacetamido)-2,4,6-triiodoisophthalamide;
Reaction SMILES: C[O:2][C:3](=[O:33])[C@H:4]([CH2:29][CH2:30][S:31][CH3:32])[N:5]([C:7](=[O:28])[C:8]1[CH:13]=[CH:12][C:11](=[CH:14][NH:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:10][C:9]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:6].O.[OH-].[Li+].CO>C1COCC1.O>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([NH:15][CH2:14][C:11]2[CH:12]=[CH:13][C:8]([C:7]([N:5]([CH3:6])[C@H:4]([C:3]([OH:33])=[O:2])[CH2:29][CH2:30][S:31][CH3:32])=[O:28])=[C:9]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:10]=2)[CH:17]=1
Reactant: COC(=O)[C@H](CCSC)N(C)C(=O)C1=C(c2ccccc2)CC(=CNc2cccnc2)C=C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CSCC[C@@H](C(=O)O)N(C)C(=O)c1ccc(CNc2cccnc2)cc1-c1ccccc1
Reaction time: 1.5 h
Yield: 92 %

Procedure:
To a 0° C. solution in THF (3.0 mL) of [4-(3-Pyridylaminomethylene)-2-phenylbenzoyl-]N-methylmethionine methyl ester (135 mg, 0.29 mmol), prepared as in Example 158, was added a solution of lithium hydroxide hydrate (20 mg, 0.49 mmol) in water (1 mL). Methanol (1 mL) and water (0.5 mL) were then added to obtain a clear solution. The reaction mixture was stirred for 1.5 hours and then the cold bath was removed and stirring was continued for 2.5 hours. The reaction mixture was partitioned between water which was taken to pH 4 with HCl and ethyl acetate. The aqueous phase was extracted three times with chloroform. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was dissolved in acetonitrile-methanol. The solution was diluted with water, frozen, and lyophilized to give [4-(3-pyridylaminomethyl)-2-phenylbenzoyl]-N-methylmethionine (120 mg) as a white powder. 1H NMR (300 MHz, D3COD) δ 7.93 (d, 1H), 7.78 (dd, 1H), 7.50 (d, 1H), 7.38 (m, 7H), 7.20 (m, 1H), 7.12 (m, 1H), 5.20 and 4.55 (both m, total 1H), 4.45 (s, 2H), 2.70 and 2.45 (both br s, total 3H), 2.24 and 2.10 (both m, total 2H), 2.00 (br s, 3H), 1.80 and 1.68 (both m, 2H); MS (DCI-NH3) m/e 450 (M+H)+. Anal calcd for C25H27N3O3S.0.65 HCl: C, 63.45; H, 5.89; N, 8.88. Found: C, 63.51; H, 5.54; N, 8.53.
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[S:20](Cl)(=[O:22])=[O:21])#[N:12]>C([O-])(O)=O.[Na+].C(OCC)C.O>[C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[S:20]([O:5][C:4]1[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=1)(=[O:21])=[O:22])#[N:12]
Reactant: Cc1ccc(C#N)c(S(=O)(=O)Cl)c1
Reactant: Cc1cc(O)cc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(O)cc(OS(=O)(=O)c2cc(C)ccc2C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
Orcinol monohydrate (1.42 g, 10.0 mmol) and 2-cyano-5-methylbenzene-sulfonyl chloride (2.0 g, 9.0 mmol), as prepared in the preceding step, were mixed in saturated aqueous NaHCO3 (30 mL) and diethyl ether (30 mL). The biphasic mixture was stirred vigorously at ambient temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted into ethyl acetate (3×50 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane to 4% ethyl acetate in dichloromethane) to give the title compound as a pale yellow oil (2.1 g, 69%). 1H-NMR (300 MHz, CDCl3) δ 7.91 (s, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.57 (d, J=7.9 Hz, 1H), 6.59 (s, 1H), 6.58 (s, 1H), 6.51 (s, 1H), 5.61 (s, 1H), 2.51 (s, 3H), 2.29 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:20]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[C:18]([F:25])=[CH:17][C:3]=1[O:4][CH2:5][CH:6]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1.[CH:26]1(B(O)O)[CH2:28][CH2:27]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].F[B-](F)(F)F.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:26]1([C:2]2[CH:20]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[C:18]([F:25])=[CH:17][C:3]=2[O:4][CH2:5][CH:6]2[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]2)[CH2:28][CH2:27]1
Reactant: OB(O)C1CC1
Reactant: COC(=O)c1cc(Cl)c(OCC2CN(C(=O)OC(C)(C)C)C2)cc1F
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cc(C2CC2)c(OCC2CN(C(=O)OC(C)(C)C)C2)cc1F
Temperature: 100 °C
Yield: 82.4 %

Procedure:
To a mixture of tert-butyl 3-((2-chloro-5-fluoro-4-(methoxycarbonyl)- phenoxy)methyl)-azetidine-1-carboxylate (1.2 g, 3.2 mmol), cyclopropylboronic acid (415 mg, 4.8 mmol), potassium phosphate (2.04 g, 9.6 mmol) and tricyclohexylphosphine tetrafluoroborate (118 mg, 0.32 mmol) in toluene (20 mL) and water (1 mL) under a nitrogen atmosphere was added palladium acetate (36 mg, 0.16 mmol). The reaction mixture was heated to 100° C. for 16 h and then cooled to ambient temperature. The mixture was quenched by water (50 mL) and extracted with ethyl acetate (50 mL×3), the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column (eluting with petroleum ether/ethyl acetate, from 10/1 to 2/1) to afford target compound (1.0 g, 83%) as a pale yellow solid. LCMS (ESI) m/z: 324.3 [M−56+H]+.