Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17]([C:18](O)=[O:19])[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:27][CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:42][O:43][C:44](=[O:61])[C@@H:45]([NH2:60])[CH2:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]2[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=2)=[CH:49][CH:48]=1>>[C:1]([O:5][C:6]([N:8]1[CH:17]([C:18](=[O:19])[NH:60][C@H:45]([C:44]([O:43][CH3:42])=[O:61])[CH2:46][C:47]2[CH:52]=[CH:51][C:50]([C:53]3[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=3)=[CH:49][CH:48]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:27][CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(F)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1Cc2cc3c(cc2CC1C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(F)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Yield: 72.5 %

Procedure:
(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]-isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester (50 mg) was coupled with (S)-2-amino-3-(4′-fluoro-biphenyl-4-yl)-propionic acid methyl ester hydrochloride (29 mg) according to General Procedure L to give (S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-8-[(S)-2-(4′-fluoro-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (52 mg). This intermediate was deprotected as described in General Procedure C to give (S)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-fluoro-biphenyl-4-yl)-propionic acid methyl esterhydrochloride. This compound was further reacted with 2-acetyl-amino-4-methyl-thiazole-5-sulfonyl chloride to furnish (S)-2-({(S)-7-(2-acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-fluoro-biphenyl-4-yl)-propionic acid methyl ester as described in General Procedure E. This compound, upon reaction with ethyl iodide and K2CO3 in DMF, gave (S)-2-({(S)-7-[2-(acetyl-ethyl-amino)-5-methyl-thiazole-4-sulfonyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-fluoro-biphenyl-4-yl)-propionic acid methyl ester according to General Procedure O. This product (15 mg) was hydrolyzed according to General Procedure B to furnish the title compound. LCMS (m/z): 934.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8]Cl.[H-].[K+].[CH:12]([N:25]1[C:33]2[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=2)[C:27]([CH2:35][CH2:36][O:37][C:38]2[CH:48]=[CH:47][C:41]([C:42]([O:44]CC)=[O:43])=[CH:40][CH:39]=2)=[C:26]1[CH2:49][OH:50])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[CH:12]([N:25]1[C:33]2[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=2)[C:27]([CH2:35][CH2:36][O:37][C:38]2[CH:48]=[CH:47][C:41]([C:42]([OH:44])=[O:43])=[CH:40][CH:39]=2)=[C:26]1[CH2:49][O:50][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=1)([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: ClCc1ccccn1
Reactant: CCOC(=O)c1ccc(OCCc2c(CO)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Agent: Cl
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(OCCc2c(COCc3ccccn3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 10.6 %

Procedure:
2-Picolyl chloride hydrochloride (164 mg, 1 mmol) was added to potassium hydride (228 mg of 40% KH, 2 mmol, in mineral oil, washed with hexanes) in 5 mL of dry N,N-dimethylformamide at room temperature. Ethyl 4-{2-[1-benzhydryl-5-chloro-2-(hydroxymethyl)-1H-indol-3-yl]ethoxy}benzoate (140 mg, 0.25 mmol) in 3 mL of N,N-dimethylformamide was added via syringe. After stirring at room temperature for 2 hours, the reaction was quenched with iced water, extracted with CH2Cl2, dried over magnesium sulfate and purified by preparative thin layer chromatography (20% methanol/CH2Cl2 as the developing solvents) to yield 16 mg (11%) of the desired product as a pale yellow solid. m/z (M−1) 600.9.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([CH2:18][C:19]3[CH:40]=[CH:39][C:22]([CH2:23][NH:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[C:27]([F:38])[CH:26]=4)=[CH:21][C:20]=3[O:41][CH3:42])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[ClH:45].C(OCC)(=O)C>CO.O1CCCC1.C(OCC)(=O)C>[ClH:45].[ClH:45].[C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([CH2:18][C:19]3[CH:40]=[CH:39][C:22]([CH2:23][NH:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[C:27]([F:38])[CH:26]=4)=[CH:21][C:20]=3[O:41][CH3:42])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCc1ccc(NCc2ccc(Cn3nc(-c4ccccc4)cc3-c3ccccc3)c(OC)c2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(CNc2ccc(CCC(=O)O)c(F)c2)ccc1Cn1nc(-c2ccccc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To a solution of ethyl 3-[4-({4-[(3,5-diphenyl-1H-pyrazol-1-yl)methyl]-3-methoxybenzyl}amino)-2-fluorophenyl]propanoate (0.57 g, 1.01 mmol) in a mixture of methanol (4.0 mL) and tetrahydrofuran (8.0 mL) was added 1 N aqueous sodium hydroxide solution (2.02 mL, 2.02 mmol), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with 10% aqueous citric acid solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1-hexane/ethyl acetate=1/2) to give a colorless oil. The obtained oil was dissolved in ethyl acetate, and 4 N hydrogen chloride/ethyl acetate solution was added. The precipitated crystals were collected by filtration, washed with ethyl acetate and dried to give the title compound (0.48 g, yield 77%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:12]([C:13]([OH:15])=O)[C:11]=2[C:19]([OH:21])=O)[O:5][C:6]=1[CH3:7].[O:22]=[C:23]1[CH:28]([N:29]2C(=O)C3C(=CC=CC=3NCCOC)C2=O)[CH2:27][CH2:26][C:25](=[O:45])[NH:24]1>>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:12]3[C:11]=2[C:19](=[O:21])[N:29]([CH:28]2[CH2:27][CH2:26][C:25](=[O:45])[NH:24][C:23]2=[O:22])[C:13]3=[O:15])[O:5][C:6]=1[CH3:7]
Reactant: Cc1cc(CNc2cccc(C(=O)O)c2C(=O)O)oc1C
Reactant: COCCNc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Product: Cc1cc(CNc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)oc1C
Yield: 22 %

Procedure:
3-[(4,5-Dimethyl-furan-2-ylmethyl)-amino]-phthalic acid (3 mmol) was treated in the same manner as described above for the synthesis of 2-(2,6-dioxo-piperidin-3-yl)-4-(2-methoxy-ethylamino)-isoindole-1,3-dione. The solid yellow residue was purified by preparative HPLC (Symmetry C18, isocratic, 40% acetonitrile/water) to give 0.25 g (22%) of product as a yellow solid: mp 127–129° C.; 1H NMR (DMSO-d6) δ 11.10 (s, 1H), 7.58 (dd, J=7.4 Hz and 8.4 Hz, 1H), 7.17 (d, J=8.6 Hz, 1H), 7.06 (d, J=7.1 Hz, 1H), 6.91 (t, J=6.1 Hz, 1H), 5.11 (s, 1H), 5.06 (dd, J=5.4 and 12.5 Hz, 1H), 4.45 (d, J=6.0 Hz, 2H), 2.97–2.82 (m, 1H), 2.63–2.44 (m, 2H), 2.13 (s, 3H), 2.08–1.99 (m, 1H), 1.85 (s, 3H); 13C NMR (DMSO-d6) δ 172.75, 170.02, 168.77, 167.21, 148.75, 146.18, 145.82, 136.05, 132.07, 117.57, 114.16, 110.94, 110.55, 109.61, 48.56, 38.94, 30.95, 22.10, 11.08, 9.50; Anal. Calcd. For C20H19N3O5: C, 62.99; H, 5.02; N, 11.02. Found: C, 62.75; H, 4.97; N, 10.72.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(C(C)C)CC)(C)C.[CH2:25]([O:32][CH2:33][C:34](Cl)=[O:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[CH2:25]([O:32][CH2:33][C:34]([N:12]1[CH2:13][CH2:14][CH2:15][N:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH2:10][CH2:11]1)=[O:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: Clc1ccc(N2CCCNCC2)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(COCc1ccccc1)N1CCCN(c2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 452 %

Procedure:
To a solution of 1-(2,4-dichloro-phenyl)-[1,4]diazepane (0.11 g, 0.45 mmol) in dichloromethane (5 mL) was added diisopropyl-ethylamine (0.082 mL, 0.47 mmol) and benzyloxyacetyl chloride (0.086 g, 0.47 mmol). The solution was stirred at room temperature for 1 h. The residue was chromatographed on silica gel using dichloromethane/ethyl acetate from 100% to 95% dichloromethane in a gradient fashion, to obtain the title compound as a gum (0.80 g, 46%). 1H NMR (300 MHz, CDCl3): δ 7.33 (m, 6H), 7.14 (m, 1H), 6.96 (m. 1H), 4.64 (m, 2H), 4.21 (m, 2H), 3.79 (m, 2H), 3.65 (m, 2H), 3.19 (m, 4H), 2.04 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.[NH2:16][C@H:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]1[OH:23].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([NH:16][C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[OH:23])=[O:15])[CH:3]=1
Reactant: N[C@H]1CCCC[C@@H]1O
Reactant: O=C(O)c1cc(Br)c2cccc(F)c2n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CCCC[C@@H]1O)c1cc(Br)c2cccc(F)c2n1
Reaction time: 17 h

Procedure:
To a solution of 4-bromo-8-fluoroquinoline-2-carboxylic acid (C6) (1.34 g, 4.96 mmol) in dichloromethane (20 mL) was added (1S,2S)-2-aminocyclohexanol (0.857 g, 7.44 mmol), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (2.63 g, 5.95 mmol), and triethylamine (1.04 mL, 7.44 mmol). After 17 h, the mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate (1×) and brine (1×), dried over sodium sulfate, filtered, and concentrated in vacuo. The resultant residue was purified via silica gel chromatography eluting with 0-3% methanol in dichloromethane to provide 4-bromo-8-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide (C7) that gave a mass ion (ES+) of 368.8 (81Br) for M+H+.
Reaction SMILES: [N:1]#CBr.[F:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH:14]3[CH2:20][CH:19]4[N:21]([CH3:22])[CH:16]([CH2:17][CH2:18]4)[CH2:15]3)=[N:10][NH:11]2)=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[C:22]([N:21]1[CH:19]2[CH2:18][CH2:17][CH:16]1[CH2:15][CH:14]([C:9]1[C:8]3[C:12](=[CH:13][C:5]([F:4])=[CH:6][CH:7]=3)[NH:11][N:10]=1)[CH2:20]2)#[N:1]
Reactant: N#CBr
Reactant: CN1C2CCC1CC(c1n[nH]c3cc(F)ccc13)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: N#CN1C2CCC1CC(c1n[nH]c3cc(F)ccc13)C2
Reaction time: 2 h
Yield: 22.5 %

Procedure:
Cyanogen bromide (2.75 g) was added in one portion to a suspension of 3-(6-fluoro-1H-indazol-3-yl)-8-methyl-8-azabicyclo[3.2.1]octane (4.90 g) and potassium carbonate (2.75 g) in 70 ml of THF at room temperature. The mixture was stirred for 2 hours, then diluted with water and the product was extracted into ethyl acetate. The organic solution was washed with brine, dried over MgSO4, filtered and concentrated to leave 3.4 g of crude solids. The solids were purified by flash chromatography over silica gel and recrystallized from ethanol to yield 1.15 g of the desired product, m.p. 182°-184° C.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([F:11])[C:5]([F:12])=[C:4](F)[C:3]=1[F:14].C(=O)([O-])[O-:16].[K+].[K+].[OH:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])=[CH:24][CH:23]=1.O>CN1CCCC1=O.C(OCC)(=O)C>[N+:8]([C:7]1[C:6]([F:11])=[C:5]([F:12])[C:4]([O:21][C:22]2[CH:37]=[CH:36][C:25]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[CH:24][CH:23]=2)=[C:3]([F:14])[C:2]=1[OH:16])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1c(F)c(F)c(F)c(F)c1F
Reactant: O=C([O-])[O-]
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)c1ccc(Oc2c(F)c(O)c([N+](=O)[O-])c(F)c2F)cc1
Temperature: -5 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
42.6 g of pentafluoronitrobenzene (0.2 mol) are dissolved in 300 ml of N-methylpyrrolidone. After 30 g of potassium carbonate (0.22 mol) have been added, the mixture is cooled to -5° C., and a solution of 45.6 g of benzyl 4-hydroxybenzoate (0.2 mol) in 300 ml of N-methylpyrrolidone is then added drop wise over the course of 30 minutes with stirring. After 1 hour, the reaction temperature is raised to 23° C. for 24 hours, and 800 ml of water and 300 ml of ethyl acetate are then added. The organic phase is separated, washed three times with water and dried over sodium sulphate. The solution is then concentrated in a rotary evaporator until yellow crystals precipitate. The reaction product is washed with petroleum ether (boiling range 60-80° C.) collected on a Buchner funnel and dried in a vacuum dryer under nitrogen at 40° C./10 mbar (Yield 89%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][NH:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH3:2].[C:16]1(=[O:22])[O:21][C:19](=[O:20])[CH2:18][CH2:17]1>CN(C=O)C>[C:11]([O:10][C:8]([NH:7][N:6]([C:16](=[O:22])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCOC(=O)CNNC(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)O1
Solvent: CN(C)C=O
Product: CCOC(=O)CN(NC(=O)OC(C)(C)C)C(=O)CCC(=O)O
Temperature: 75 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
Into a solution of (N′-tert-Butoxycarbonyl-hydrazino)-acetic acid ethyl ester 4 (1.85 g, 18.5 mmol) in DMF (30 mL) was added succinic anhydride (4.84 g, 22.2 mmol) and the mixture was stirred at 75° C. for 18 h. DMF was evaporated and the crude mixture was purified by flash column chromatography using hexane:ethylacetate (1% acetic acid) as an eluent (yield 50%). 1H NMR (500 MHz, CDCl3) 1.28 (3H, CH2—CH3, t), 1.48 (9H, C—CH3, s), 2.55-3.00 (6H, NH—CH2—CO, N—CH2—CH2—CO, m), 4.20 (2H, CH2CH3, q); MS Anal. Mol. Wt. 318.25 (M−1).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:23])[NH:11][C:12]([C:15]1[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=1[F:22])([CH3:14])[CH3:13])[CH2:2]2.[CH3:24][CH:25]([CH3:30])[CH2:26]B(O)O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:23])[NH:11][C:12]([C:15]1[CH:20]=[C:19]([CH2:24][CH:25]([CH3:30])[CH3:26])[CH:18]=[CH:17][C:16]=1[F:22])([CH3:14])[CH3:13])[CH2:2]2
Reactant: CC(C)CB(O)O
Reactant: CC(C)(NC(=O)OC1CN2CCC1CC2)c1cc(Br)ccc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CC(C)Cc1ccc(F)c(C(C)(C)NC(=O)OC2CN3CCC2CC3)c1
Yield: 32.7 %

Procedure:
Using general procedure E, 1-azabicyclo[2.2.2]oct-3-yl[2-(5-bromo-2-fluorophenyl)propan-2-yl]carbamate (120 mg, 0.312 mmol), 2-methylpropylboronic acid (79.4 mg, 0.779 mmol) and palladium (II) acetate gave the title as a white solid compound (37 mg, 33%). 1H NMR (400 MHz, CDCl3) 7.08 (dd, J=2.0, 8.2 Hz, 1H), 6.95 (d, J=4.9 Hz, 1H), 6.93-6.85 (m, 1H), 5.23 (s, 1H), 4.72-4.52 (m, 1H), 3.20-2.47 (m, 6H), 2.41 (d, J=7.1 Hz, 2H), 1.89-1.76 (m, 1H), 2.02-1.26 (m, 5H), 1.70 (d, J=7.6 Hz, 6H), 0.88 (d, J=6.6 Hz, 6H) ppm. 13C NMR (100 MHz, CDCl3) δ 160.4, 158.0, 137.1, 137.1, 129.2, 129.1, 128.1, 116.2, 116.0, 71.2, 55.8, 54.2, 47.6, 46.7, 45.1, 30.5, 29.9, 28.6, 27.0, 25.6, 24.8, 22.5, 19.8, 19.5 ppm. Purity: 95.0% UPLCMS (210 nm); retention time 1.02 min; (M+1) 363.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>C1(C)C=CC=CC=1>[N+:8]([C:5]1[CH:4]=[N:3][C:2]([NH:1][C:11](=[O:13])[CH3:12])=[N:7][CH:6]=1)([O-:10])=[O:9]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ncc([N+](=O)[O-])cn1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ncc([N+](=O)[O-])cn1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
To 2-amino-5-nitropyrimidine (0.42 g, 3.0 mmol) dissolved in toluene (2 ml) was added acetic anhydride (1.4 ml, 15 mmol). The reaction mixture was stirred at 90° C. for 15 hr, after which an additional amount of acetic anhydride was added (0.7 mL) and the mixture was stirred at reflux for another 16 h. The solvent was removed in vacuo and to the residue was added hexane (10 mL) and DCM (1 mL). The solid was collected by filtration, dried to give N-(5-nitropyrimidin-2-yl)acetamide as an off-white solid. MS (ESI, pos. ion) m/z: 183 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[CH:7]=[N:8][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:11]=1)[CH3:2].[H-].[Na+].C1OCCOCCOCCOCCOCC[O:21][CH2:20]1.C(OC=O)C.Cl>C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:16])[C:5]([C:6]1[CH:7]=[N:8][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:10][CH:11]=1)=[CH:20][OH:21])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(C(F)(F)F)nc1
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=CO)c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.46 g (14.8 mmol) of the compound from Example 40A are initially introduced into 50 ml anhydrous toluene under argon, 712 mg (17.8 mmol) sodium hydride suspension (60% strength in paraffin oil) are added in portions and the mixture is stirred at RT for 1 h and then at 80° C. for 20 min. After cooling, 392 mg (1.48 mmol) 18-crown-6 and then, while cooling with ice, 2.20 g (29.7 mol) formic acid ethyl ester are added dropwise. The mixture is stirred first at 0° C. for 1 h and then at RT for 1 h. A mixture of 100 ml ethyl acetate and 150 ml 0.1 M hydrochloric acid is added, the phases are separated, the aqueous phase is extracted several times with ethyl acetate and the combined organic phases are dried over sodium sulfate, filtered and concentrated. The residue is purified by means of flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate gradient).
Reaction SMILES: C([PH:5](=[O:7])[OH:6])CCC.C(N(CC)CC)C.C[Si](Cl)(C)C.[CH2:20]=[C:21]([CH2:32][CH2:33][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>ClCCl>[CH2:25]([O:24][C:22]([CH:21]([CH2:32][CH2:33][C:34]([O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:35])[CH2:20][PH:5](=[O:6])[OH:7])=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCCC[PH](=O)O
Reactant: C=C(CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCC(C[PH](=O)O)C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 46.4 %

Procedure:
Butylphosphinic acid (2.0 g, 16 mmol) in 80 mL of dry dichloromethane was cooled to 0° C. under an atmosphere of nitrogen. Triethylamine (6.7 g, 66 mmol) was added followed by trimethylsilyl chloride (58 mL, 58 mmol, 1.0 M in dichloromethane). The mixture was stirred at 0° C. for 10 minutes and dibenzyl 2-methylenepentanedioate (2)(6.4 g, 20 mmol) in 20 mL of dichloromethane was added. The cold bath was removed and the reaction warmed to room temperature and stirred overnight. The mixture was then cooled to 0° C. and quenched by the slow addition of 5% hydrochloric acid. The dichloromethane layer was then removed and washed with 5% hydrochloric acid and with brine. The organic layer was dried (MgSO4) and evaporated to give a clear light golden liquid. The liquid was purified by flash chromatography and eluted with 3:1 hexane/ethyl acetate containing 5% acetic acid. The desired fractions were combined and evaporated to give butyl[2,4-di(benzyloxycarbonyl)butylphosphinic acid (3,R=n-butyl, R1=H) (2.9 g, 40%) as a clear and colorless oil. Rf0.12 (3:1, Hex./EtOAc 5% AcOH). 1H NMR (d6-DMSO): 7.3 ppm (m, 10), 5.0 ppm (s,4H), 2.7 ppm (m, 1H) 2.3 ppm (y, 2H), 1.8 ppm (m, 2H), 1.3 ppm (m, 4H), 0.8 ppm (t, 3H)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]([S:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])[C:5]([Cl:25])=[CH:4][N:3]=1.[N:26]1([CH2:31][CH2:32][CH2:33][NH2:34])[CH:30]=[CH:29][N:28]=[CH:27]1>O1CCOCC1>[Cl:25][C:5]1[C:6]([CH:8]([S:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])=[CH:7][C:2]([NH:34][CH2:33][CH2:32][CH2:31][N:26]2[CH:30]=[CH:29][N:28]=[CH:27]2)=[N:3][CH:4]=1
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(Cl)ncc2Cl)c1
Reactant: NCCCn1ccnc1
Solvent: C1COCCO1
Product: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(NCCCn3ccnc3)ncc2Cl)c1
Temperature: 25 °C
Yield: 39 %

Procedure:
A 1,4-dioxane (1.5 ml) solution of the 2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine (200 mg, 0.48 mmol) obtained in Example 54 and 3-(imidazol-1-yl)propylamine (400 μl) was stirred at 120° C. for 5 days under an argon atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the title compound (94 mg, 39%) as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[C:4]([CH3:16])=[N:3]1.[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20]>>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:19](=[O:20])[N:18]([CH3:17])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:11][CH:10]=2)[C:4]([CH3:16])=[N:3]1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Cc1nn(C)c(C)c1Cc1ccc(O)cc1
Product: Cc1nn(C)c(C)c1Cc1ccc(OC(=O)N(C)c2ccccc2)cc1

Procedure:
The title product was prepared from 4-[(1,3,5-trimethyl-1H-pyrazol-4-yl)methyl]phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (88%, oil). HPLC-MS: m/z=350.0 (M+1); Rt: 3.52 min. (66% purity).
Reaction SMILES: C1(C(C2C=CC=CC=2)=[N:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])C=CC=CC=1.FC(F)(F)S(O[CH2:26][CH2:27][C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])(=O)=O.[ClH:37]>C1COCC1>[ClH:37].[F:33][C:28]([F:34])([C:29]([F:32])([F:31])[F:30])[CH2:27][CH2:26][C@@H:9]([C:10]([O:12][CH3:13])=[O:11])[NH2:8]
Reactant: COC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(OCCC(F)(F)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)[C@@H](N)CCC(F)(F)C(F)(F)F
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
Under argon, 132 g (521.0 mmol) of methyl N-(diphenylmethylene)glycinate [described in: WO2010/123792 A1, 2010, 11-13; additionally: commercially available] were initially charged in 1000 ml of THF (anhydrous) and cooled to −40° C. 625.2 ml (625.2 mmol) of bis(trimethylsilyl)lithium amide (1 M in THF) were added dropwise over 30 min. After 10 min, the cooling bath was replaced by a water/ice bath, and the internal temperature was allowed to increase to 0° C. over a period of 35 min. At 0° C., 192.86 g (651.25 mmol) of 3,3,4,4,4-pentafluorobutyl trifluoromethanesulphonate from Example 132A, dissolved in 400 ml of THF, were added dropwise to the reaction solution. After 10 min, the cooling bath was removed and the mixture was stirred at RT for 3 days. The reaction mixture was then cooled to 0° C., and 410 ml (1.33 mol) of 3 N hydrochloric acid were added dropwise. The cooling bath was removed and the reaction solution was stirred at RT for 2 hours. The mixture was then concentrated. This gave 141.5 g of the target compound as a crude mixture which was used without any further purification for the next step.