Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24].CC(C)([O-])C.[K+]>C1COCC1>[O:24]=[C:23]1[CH2:22][CH2:21][CH2:20][CH2:19][N:17]1[C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2
Reactant: O=C(Cl)CCCCBr
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2cc(N3CCCCC3=O)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 50.1 %

Procedure:
Part H. To tert-butyl-5-amino-1-indolinecarboxylate (1.90 g, 8.2 mmol) was added 5-bromovaleryl chloride (1.4 mL, 9.0 mmol) and 18 mL of THF. After stirring for 5 min at rt under N2, potassium tert-butoxide (9 mL, 9 mmol; 1.0 M in THF) was added in one portion, and the resulting brown solution was stirred under N2 for 30 min. A second portion of potassium tert-butoxide (9 mL) was added, and the resulting brown suspension was stirred for 15 min. An additional 0.10 mL-portion of 5-bromovaleryl chloride and a 4.5 mL-portion of potassium tert-butoxide were added, and the mixture was stirred for 30 min. The reaction was then poured into H20 (80 mL). The aqueous layer was washed with EtOAc (3×50 mL), and the combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated and the resulting residue was purified by radial chromatography (50% EtOAc in hexanes) to afford tert-butyl 5-(2-oxo-1-piperidinyl)-1-indolinecarboxylate as a pink solid (1.30 g, 50%). LRMS (AP+): 317.2 (M+H)+. 1H NMR (CDCl3) δ 7.40-7.80 (br m, 1H), 7.01 (s, 1H), 6.97 (d, 1H), 3.94 (t, 2H), 3.55 (br m, 2H), 3.09 (t, 2H), 2.49 (br m, 2H), 1.91 (br m, 4H), 1.52 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)=[CH:11][C:10]([C:20]([O:22]CC)=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C(O)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)=[CH:11][C:10]([C:20]([OH:22])=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cccc(Cl)c2)n(-c2cccc(Cl)c2)n1
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Product: O=C(O)c1cc(-c2cccc(Cl)c2)n(-c2cccc(Cl)c2)n1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 24A in analogy to the synthesis of the compound of Example 71A. 5.97 g (94% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[N:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[CH:60]=O>>[CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[CH2:60][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][N:54]=1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: O=Cc1ccccn1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1Cc1ccccn1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-3-(4′-cyano-biphenyl-4-yl)-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)-propionic acid methyl ester (40 mg) was treated with pyridine-2-carbaldehyde according to General Procedure D to give (S)-3-(4′-cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-pyridin-2-ylmethyl-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester (42 mg). LCMS (m/z): 842. The methyl ester (25 mg) was hydrolyzed according to General Procedure B to give the title compound (20 mg). LCMS (m/z): 827.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[CH2:22])=[CH:19][CH:18]=1.[H-].[Na+]>CN(C=O)C>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][CH2:22][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)=[CH:19][CH:18]=1
Reactant: C=Cc1ccc(Cl)cc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(Cl)cc2)CCN(C)C1
Yield: 1.8 %

Procedure:
The title compound was prepared according to General Method 2. 5-(4-Chlorophenethyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole was prepared from 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (See Example 1) (500 mg, 2.5 mmol), 4-chlorostyrene (3.18 mL, 25 mmol) and NaH (300 mg, 7.5 mmol) in DMF (10 ml) at 180° C. for overnight (16 h) to obtain 15 mg of 5-(4-chlorophenethyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole after purification.
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]2[CH:11]=[CH:12][C:13]([N+:15]([O-])=O)=[CH:14][C:7]=2[NH:6][CH2:5][CH2:4]1)[CH3:2].C(O)C>[Pd]>[NH2:15][C:13]1[CH:12]=[CH:11][C:8]2[C:9](=[O:10])[N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][NH:6][C:7]=2[CH:14]=1
Reactant: CCN1CCNc2cc([N+](=O)[O-])ccc2C1=O
Agent: [Pd]
Solvent: CCO
Product: CCN1CCNc2cc(N)ccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a Round bottom flask, 4-Ethyl-8-nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (3.80 g, 0.0162 mol), Ethanol (100 mL, 2 mol;) and 10% Pd/C (10:90, Palladium:carbon black, 0.50 g) were added. The mixture was evacuated and charged with hydrogen (3 times). The reaction was stirred at room temperature overnight under an atmosphere of Hydrogen via a balloon. The solid was filtered and washed with ethanol. The solvent was removed under vacuum to give 8-amino-4-ethyl-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one as a white solid. 1H-NMR (DMSO-D6, 400 MHz): δ 7.35 (d, 1H), 5.95 (d, 1H), 5.85 (s, 1H), 5.78 (s, 1H), 5.20 (s, 2H), 3.26-3.50 (m, 6H), 1.08 (t, 3H)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH2:20][CH:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)=[O:18])=[CH:12][CH:11]=2)=[C:4]([NH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[N:3]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][C:17]([O:19][CH2:20][CH:21]3[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]3)=[O:18])=[CH:14][CH:15]=2)=[C:4]([NH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[N:3]=1
Reactant: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)OCC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To the product of step (i) (237 mg) in DCM (7 ml), TFA (2 ml) was added and stirred at rt for 7 h. The solvent was removed and the crude product was partitioned between DCM/NaHCO3 (aq), dried and evaporated under reduced pressure. The residue was purified by RPHPLC to give a white solid, 54 mg.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:21])=[O:20]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Brc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1ccc2c(Br)cccc21
Reaction time: 0.08 h

Procedure:
To a solution of 4-bromoindole (1.00 g, 5.10 mmol) in DMF (50 mL) at ambient temperature was added sodium hydride (220 mg of a 60% dispersion in mineral oil, 5.50 mmol). The reaction mixture was stirred for 5 min, then benzenesulfonyl chloride (901 mg, 5.10 mmol) was added and stirring was continued for 15 min. The reaction was quenched with saturated aqueous NaHCO3 (50 mL) and extracted with CHCl3 (2×75 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 90:10, to give the title compound. MS: n2/z=336 (M+1).
Reaction SMILES: C(O[C:4]([NH:6][C:7]([N:22]1[CH:26]=[C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:24]=[N:23]1)=[N:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]=1)=[O:5])C.CCO>ClC(Cl)C.Cl[Ti](Cl)(Cl)Cl>[O:5]=[C:4]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:13]=2)[N:8]=[C:7]([N:22]2[CH:26]=[C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:24]=[N:23]2)[NH:6]1
Reactant: CCOC(=O)NC(=Nc1cccc(Oc2ccccc2)c1)n1cc(C(=O)OCC)cn1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2nc3cc(Oc4ccccc4)ccc3c(=O)[nH]2)c1
Reaction time: 3 h
Yield: 81.5 %

Procedure:
To a solution of ethyl 1-(N-(ethoxycarbonyl)-N′-(3-phenoxyphenyl)carbamimidoyl)-1H-pyrazole-4-carboxylate (1.51 g, ca 2.51 mmol) in dichloroethane (DCE) (18 mL), neat TiCl4 (1.18 mL, 10.7 mmol) was added over 2 min. The mixture was then heated to reflux for 2 h, and then cooled in an ice bath. EtOH (50 mL) was added, and the mixture was stirred for 3 h. The resulting precipitate was collected by filtration, washed with cold EtOH, and dried to provide the titled compound (0.77 g, 57%). MS (ESI/CI): mass calcd. for C20H16N4O4, 376.1; m/z found, 377.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 12.85 (s, 1H), 9.00 (d, J=0.5 Hz, 1H), 8.31 (s, 1H), 8.13 (d, J=8.8 Hz, 1H), 7.58-7.45 (m, 2H), 7.38-7.27 (m, 1H), 7.26-7.20 (m, 2H), 7.18 (dd, J=8.8, 2.4 Hz, 1H), 6.98 (s, 1H), 4.39-4.13 (m, 2H), 1.42-1.21 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][OH:12]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[C:3]([CH2:10][CH2:11][OH:12])=[CH:4][CH:5]=[CH:6][C:7]=1[CH:8]=[O:9]
Reactant: OCCc1cccc(CO)c1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cccc(CCO)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Manganese (IV) dioxide (1.599 g) was added to a solution of 2-(2-chloro-3-(hydroxymethyl)phenyl)ethanol (example 80, step c) (0.342 g) in DCM (20 mL), and the resulting suspension was stirred at room temperature overnight. The mixture was then concentrated onto silica and purified by flash chromatography on silica eluted with 25% ethyl acetate in isohexane to afford the subtitled compound as a white crystalline solid. Yield 0.223 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>C1COCC1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:25]([NH:24][C:21]3[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=3)=[O:26])=[CH:14][CH:15]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: COc1ccc(Cc2ccc(N)cc2)cn1
Solvent: C1CCOC1
Product: COc1ccc(Cc2ccc(NC(=O)Nc3ccc(C)cc3)cc2)cn1

Procedure:
The title compound is prepared from 4-(6-methoxy-pyridin-3-ylmethyl)-phenylamine (Stage 95.1; 300 mg, 1.40 mmol) and 4-methyl-phenyl-isocyanate (0.35 ml, 2.8 mmol) in THF (11 ml) analogously to Example 89: 1H-NMR (DMSO-d6): 8.68 (s, 2 HN), 8.02 (d, 1H), 7.49 (dd, 1H), 7.33 (d, 2H), 7.29 (d, 2H), 7.09 (d, 2H), 7.03 (d, 2H), 6.70 (d, 1H), 3.79 (2s, 5H), 2.21 (s, 3H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].Cl.[NH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(N(C(C)C)CC)(C)C>ClCCl>[C:13]([O:12][C:10]([CH2:9][NH:8][C:2](=[O:3])[O:4][CH2:5][Cl:6])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: O=C(Cl)OCCl
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CNC(=O)OCCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of chloromethyl chloroformate (1.69 g) in dichloromethane (5 ml) was added dropwise with stirring to an ice-cold solution of tert-butyl glycinate, hydrochloride (2.0 g) and diisopropylethylamine (3.7 g) in dichloromethane (20 ml). After stirring for a further 2 hours at room temperature, the mixture was extracted with ice-cold 0.5 M hydrochloric acid followed by water and aqueous sodium bicarbonate. Drying over magnesium sulfate and evaporation in vacuo gave the title compound as a colourless powder.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]=2[C:20]([F:23])([F:22])[F:21])[CH2:4][CH2:3]1>CO.[C].[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([CH2:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]=2[C:20]([F:21])([F:23])[F:22])[CH2:6][CH2:7]1
Reactant: CCOC(=O)c1ccc(C=C2CCN(C)CC2)c(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1ccc(CC2CCN(C)CC2)c(C(F)(F)F)c1
Reaction time: 24 h
Yield: 97.5 %

Procedure:
1.57 g of ethyl 4-(1-methylpiperidin-4-ylidenemethyl)-3-trifluoromethylbenzoate (Reference Example 7 (step 2)) was dissolved in 32 ml of methanol and 78 mg of 10% palladium-carbon was added, and then the mixture was hydrogenated at room temperature under 1 atm for 24 hours. The catalyst was removed by filtration and the solvent in the filtrate was distilled off under reduced pressure. The mixture was again dissolved in 32 ml of methanol and 78 mg of 10% palladium-carbon was added thereto, and then the mixture was hydrogenated at room temperature under 1 atm for 4 hours. Further, 78 mg of palladium-carbon was added and the mixture was hydrogenated at room temperature under 1 atm for 24 hours. 78 mg of palladium-carbon was further added and the mixture was hydrogenated at room temperature under 1 atm for 19 hours. The catalyst was removed by filtration and the solvent in the filtrate was distilled off under reduced pressure to obtain 1.54 g of the objective compound as a green oily product.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]([F:38])([F:37])[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([N:24]2[CH2:32][CH:31]3[C:26]([C:27]4[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=4[CH2:29][CH2:30]3)=[N:25]2)=[O:23])=[CH:17][CH:16]=1.Cl[C:40]([O:42][CH3:43])=[O:41]>C1COCC1.CCCCCC>[CH3:43][O:42][C:40]([C:31]12[CH2:30][CH2:29][C:28]3[CH:33]=[CH:34][CH:35]=[CH:36][C:27]=3[C:26]1=[N:25][N:24]([C:22]([NH:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:37])[F:38])=[CH:20][CH:19]=1)=[O:23])[CH2:32]2)=[O:41]
Reactant: COC(=O)Cl
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)N1CC2CCc3ccccc3C2=N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: COC(=O)C12CCc3ccccc3C1=NN(C(=O)Nc1ccc(C(F)(F)F)cc1)C2
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 0.9 ml of diisopropylamine in 10 ml of THF, at -78° C., was added 2.3 ml of 2.5M n-butyl lithium in hexane and the mixture was stirred for 5 mins. To this solution was added a solution of 1.0 g of the title compound of Step A in 5 ml of THF. The reaction was warmed to 0° C., recooled to -78° C. and then 0.75 ml of methyl chloroformate was added. The reaction mixture was then stirred for 24 h, with gradual warming to room temperature, quenched with 0.5 ml of glacial acetic acid, and poured into a 5% solution of aqueous NaHCO3. The mixture was extracted with chloroform, dried over magnesium sulfate and concentrated. Chromatography on silica gel with 30% ethyl acetate hexane afforded 0.25 g of the title compound, m.p. 177° to 180° C.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]#[N:20])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4].[C:21]1(=[O:32])[O:27][C:25](=[O:26])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]2[CH2:22]1.C(Cl)Cl.CCOCC.CCCCCC>O1CCOCC1>[CH2:1]([N:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]#[N:20])=[CH:9][CH:8]=1)[C:21](=[O:32])[CH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([OH:27])=[O:26])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNCc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C1Cc2ccccc2C(=O)O1
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCCN(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)Cc1ccccc1C(=O)O

Procedure:
The starting material can be prepared, for example, as follows: A solution of 2.64 g of N-butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-amine and 2.43 g of homophthalic acid anhydride in 50 ml of dioxane is heated under reflux for hour. After removal of the solvent, the residue is taken up in 100 ml of ethyl acetate and washed twice with 50 ml of water each time. After customary treatment, the organic phase yields a crude product that yields, from CH2Cl2 /ether/hexane, 2-carboxy-phenylacetic acid N-butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-amide, m.p. 137°-139°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([OH:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=O)[CH:5]=[CH:6][CH:7]=1.C1(C)C(C)=CC=CC=1.[NH2:27][CH2:28][CH2:29][CH2:30][OH:31].C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([OH:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]2[NH:27][CH2:28][CH2:29][CH2:30][OH:31])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1Nc2ccccc2C1(O)c1cccc(Cl)c1
Reactant: NCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: OCCCNC1=Nc2ccccc2C1(O)c1cccc(Cl)c1
Reaction time: 24 h

Procedure:
3-(m-Chlorophenyl)-3-hydroxy-3H-indol-2-one (25.9 g., U.K. specification No. 1,125,671), xylene (400 ml.), 3-aminopropanol (15 g.) and toluene-p-sulphonic acid (150 mg.) were heated under reflux, with stirring, in an apparatus fitted with a water separator. After 24 hours, 6.9 ml. of water and 3-aminopropanol had been collected. The mixture was cooled and the xylene removed under reduced pressure leaving a yellow crystalline material which was recrystallised from ethyl acetate to give the title compound (14.33 g.), m.p. 164° to 165°C. (Found C, 64.45; H, 5.4; N, 8.85. C17H17Cl2N2O2 requires C, 64.75; H, 5.6; N, 8.7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=[C:5]([NH2:17])[N:4]=1.[C:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28]([N:31]=[C:32]=[O:33])(=[O:30])=[O:29])([O:20][CH3:21])=[O:19].CCOCC>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][O:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:6]=[C:5]([NH:17][C:32]([NH:31][S:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:18]([O:20][CH3:21])=[O:19])(=[O:30])=[O:29])=[O:33])[N:4]=1
Reactant: COc1cc(COc2ccccc2)nc(N)n1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(COc2ccccc2)cc(OC)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
To a mixture of 0.23 g (1.0 mmol) of 4-methoxy-6-(phenoxymethyl)-2-pyrimidinamine in 15 ml dry acetonitrile was added 0.48 g (2.0 mmol) o-carbomethoxybenzenesulfonyl isocyanate and stirred at ambient temperature overnight. Ether was added to the suspension of white solids which were then collected by filtration to afford 0.37 g of the title compound, m.p. 178°-180°. NMR (90 MHz, CDCl3 +DMSO-d6): δ 3.91 (s, 3H); 4.02 (s, 3H); 5.20 (s, 2H); 6.69 (s, 1H); 7.0-7.9 (m, 8H); 8.5 (m, 1H); 9.20 (s, NH); 12.9 (s, NH) ppm; IR (nujol) 1725, 1700 cm-1.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][Si:26]([CH3:34])([CH3:33])[CH2:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:17][N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].C(O)C.C(OCC)(=O)C>[CH3:34][Si:26]([CH3:33])([CH2:27][CH2:28][C:29]([F:32])([F:30])[F:31])[CH2:25][CH2:24][CH2:23][CH2:22][O:21][C:18]1[CH:19]=[N:20][C:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)=[N:16][CH:17]=1
Reactant: C[Si](C)(CCCCOc1cnc(-c2ccc(OCc3ccccc3)cc2)nc1)CCC(F)(F)F
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: C[Si](C)(CCCCOc1cnc(-c2ccc(O)cc2)nc1)CCC(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of compound 40 (0.321 g, 0.658 mmol), palladium on charcoal (0.0343 g, 0.033 mmol) in ethanol/ethyl acetate (6.5 ml, 1:2) was stirred under an atmosphere of hydrogen at room temperature for 24 hours. The reaction mixture was filtered (celite), the solvent removed in vacuo and the residues recrystallized from acetonitrile to yield colorless crystals.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([NH:12][C:13](=[O:40])[O:14][CH2:15][C@@H:16]([N:26]([CH3:39])[C:27]([NH:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=3[Cl:38])=[O:28])[CH2:17][C@@H:18]([OH:25])[CH2:19][O:20][P:21]([OH:24])([OH:23])=[O:22])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:42]>>[P:21]([O-:24])([O-:23])([O:20][CH2:19][C@H:18]([OH:25])[CH2:17][C@H:16]([N:26]([CH3:39])[C:27]([NH:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=1[Cl:38])=[O:28])[CH2:15][O:14][C:13](=[O:40])[NH:12][C:10]1[O:9][N:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:11]=1)=[O:22].[Na+:42].[Na+:42]
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc(-c2ccccc2)no1)C[C@@H](O)COP(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc(-c2ccccc2)no1)C[C@@H](O)COP(=O)([O-])[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of (2S,4R)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-4-hydroxy-5-(phosphonooxy)pentyl 3-phenylisoxazol-5-ylcarbamate (48 mg, 0.08 mmol, 1.0 equiv.) at 0° C., was added NaOH (0.1 N, 1.6 mL, 2.0 equiv.) dropwise. The mixture was stirred at RT for 1 h followed by concentration to give sodium (2R,4S)-4-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-2-hydroxy-5-(3-phenylisoxazol-5-ylcarbamoyloxy)pentyl phosphate (55 mg, quant.) as a white solid. LRMS (M-2Na+3H+) m/z 601.5.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>ClCCl>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([N:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1)=[O:6]
Reactant: C1COCCN1
Reactant: O=C(O)c1cc(F)c(F)cc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(F)c(F)cc1Br)N1CCOCC1
Reaction time: 2 h
Yield: 96.8 %

Procedure:
2-Bromo-4,5-difluorobenzoic acid (2.00 g, 8.44 mmol), DIPEA (2.18 g, 16.88 mmol) and HATU (3.85 g, 10.13 mmol) were stirred at room temperature for 20 min in dichloromethane (120 mL). Morpholine (0.88 g, 10.13 mmol) was added then the reaction was stirred for 2 hours. The dichloromethane was removed and the resulting residue was partitioned between ethyl acetate and water. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic extracts were passed through a phase separation cartridge and concentrated. The resulting residue was purified via silica gel column chromatography (0-100% ethyl acetate/isohexane) to afford (2-Bromo-4,5-difluorophenyl)(morpholino)methanone (2.5 g, 97%). 1H NMR (400 MHz, CDCl3): δ 7.44 (dd, J=9.42, 6.99 Hz, 1H), 7.14 (dd, J=9.57, 7.88 Hz, 1H), 3.88-3.69 (m, 5H), 3.64-3.57 (m, 1H), 3.33-3.17 (m, 2H).
Reaction SMILES: C1(N2B[C@H:10]([C:12]3[CH:17]=CC=CC=3)[C@@H:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:8]2)C=CC=CC=1.C1([C@@H]2[C@@H](C3C=CC=CC=3)ON(C)B2)C=CC=CC=1>>[C@H:9]1([OH:8])[C:18]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:17][CH2:12][CH2:10]1
Reactant: B1[C@H](c2ccccc2)[C@@H](c2ccccc2)ON1c1ccccc1
Agent: CN1B[C@H](c2ccccc2)[C@@H](c2ccccc2)O1
Product: O[C@@H]1CCCc2ccccc21

Procedure:
Using substantially the same procedure as recited in Example 4 but substituting the title compound of Example 2 for the title compound of Example 1, the title compound of Example 12 was prepared in 88% e.e.