Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](=[NH:7])[NH2:6].O=[C:12]1[CH2:16][CH2:15][S:14][CH:13]1[C:17](OC)=[O:18].C[O-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:6]=[C:17]([OH:18])[C:13]3[S:14][CH2:15][CH2:16][C:12]=3[N:7]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: N=C(N)c1cccc(Cl)c1
Reactant: COC(=O)C1SCCC1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: Oc1nc(-c2cccc(Cl)c2)nc2c1SCC2
Temperature: 85 °C
Reaction time: 16 h
Yield: 23 %

Procedure:
To a solution of 3-chlorobenzimidamide (4.8 g, 31.2 mmol) in ethanol (150 mL) was added methyl 3-oxotetrahydrothiophene-2-carboxylate (5.0 g, 31.2 mmol) and sodium methoxide (1.7 g, 31.2 mmol). The mixture was stirred at 85° C. for 16 h. The mixture was concentrated after which ethanol (10 mL) was added and the suspension was chilled to 0° C. HCl (2 M, 50 mL) was added and the suspension was filtered and washed with water. The solid was purified by column chromatography (silica, dichloromethane/methanol) to afford the title compound (1.9 g, 23%) as a brown solid. MW=264.73. 1H NMR (DMSO-d6, 500 MHz) δ 12.85 (s, 1H), 8.13 (s, 1H), 8.07-8.01 (m, 1H), 7.63-7.59 (m, 1H), 7.56-7.51 (m, 1H), 3.41-3.24 (m, 4H); APCI MS m/z 265 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:14])[C:5]([C:7]1[S:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)=[O:6])C>[OH-].[K+].CO.O>[CH3:13][O:12][C:9]1[S:8][C:7]([C:5](=[O:6])[C:4]([OH:14])=[O:3])=[CH:11][CH:10]=1
Reactant: CCOC(=O)C(=O)c1ccc(OC)s1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C(=O)C(=O)O)s1

Procedure:
The latter ester (25 g) is stirred in 500 ml of 5% aqueous KOH in methanol (250 ml H2O, 250 ml CH3OH, 25 g KOH) at room temperature for about 2 hr. The mixture is diluted with water and extracted several times with ether to remove all neutral material. The aqueous fraction is cooled with crushed ice, acidified with 10% HCl and extracted with ether. The ether extract is washed with water and brine, dried (MgSO4) and concentrated to give 5-methoxy-2-thiopheneglyoxylic acid (3; X1 = CH3O, X2 and X3 = H and R10 = H); γmaxCHCl3 3000, 1630, 1625, 1530 cm-1.
Reaction SMILES: O1CCCC1.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[N:16]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:15](=O)[C@@H:14]([CH2:23][C:24](O)=[O:25])[O:13][C@H:12]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])[C:11]=2[CH:34]=1.[H-].[Li+].[Al+3].[H-].[H-].[H-]>O>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[N:16]([CH2:17][C:18]([CH3:20])([CH3:21])[CH3:19])[CH2:15][C@@H:14]([CH2:23][CH2:24][OH:25])[O:13][C@H:12]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])[C:11]=2[CH:34]=1
Reactant: CC(C)(C)CN1C(=O)[C@@H](CC(=O)O)O[C@H](c2ccccc2Cl)c2cc(Cl)ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)CN1C[C@@H](CCO)O[C@H](c2ccccc2Cl)c2cc(Cl)ccc21
Yield: 88.2 %

Procedure:
To tetrahydrofuran (20 ml) were added (3R,5S)-7-Chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid (2 g) and aluminum lithium hydride (0.4 g). The mixture was heated for 6 hours under reflux, to which was added water. Insolubles were then filtered off. The filtrate was concentrated, which was purified by means of a silica gel column chromatography (hexane:acetic acid ethyl ester=2:1 v/v as an eluent) to give 1.65 g of non-crystalline solid matter.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([CH2:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)=[N:2]1.C([N-]C(C)C)(C)C.[Li+].[C:23]1(=[O:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.O>O1CCCC1>[OH:29][C:23]1([CH:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[C:3]2[N:4]=[CH:5][NH:1][N:2]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C1CCCCC1
Reactant: N#Cc1ccc(Cc2nc[nH]n2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(C(c2nc[nH]n2)C2(O)CCCCC2)cc1
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
5 g of 4-[1-(1,2,4-triazolyl)methyl]benzonitrile is dissolved in 100 ml of tetrahydrofuran and combined at -50° with 20 ml of 1.5-molar solution of lithium diisopropylamide in tetrahydrofuran, stirred for 0.5 hour, further agitated with 2.9 g of cyclohexanone for 1 hour at -70° and heated to 25°. Then water is added, the mixture is extracted with ethyl acetate, washed neutral with water, dried over sodium sulfate, and concentrated to dryness under vacuum, thus obtaining 7.24 g of crude 4-[1-hydroxycyclohex-1-yl-1-(1,2,4-triazolyl)methyl]benzonitrile.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH2:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[C:16]([F:24])[CH:15]=1>CN(C1C=CN=CC=1)C>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:12][C:10]2[CH:11]=[C:2]([F:1])[CH:3]=[C:4]3[C:9]=2[N:8]=[CH:7][CH:6]=[CH:5]3)(=[O:21])=[O:22])=[C:16]([F:24])[CH:15]=1
Reactant: Nc1cc(F)cc2cccnc12
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1F
Agent: CN(C)c1ccncc1
Product: O=S(=O)(Nc1cc(F)cc2cccnc12)c1ccc(Cl)cc1F
Yield: 42.4 %

Procedure:
In a similar fashion using route 14 general procedure 27, 6-fluoroquinolin-8-amine (Intermediate 48) (150 mg, 0.93 mmol), 4-chloro-2-fluorobenzenesulfonyl chloride (250 mg, 1.11 mmol) and DMAP (cat.) gave the title compound (140 mg, 43%) after purification by column chromatography with DCM/n-hexane (4:1) as the eluent.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[O:7][C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl.[S:23]([C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1)(=[O:26])(=[O:25])[NH2:24]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:7])[N:32]([CH2:31][C:30]1[CH:29]=[CH:28][C:27]([S:23](=[O:25])(=[O:26])[NH2:24])=[CH:34][CH:33]=1)[C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Reactant: O=C(O)c1oc(=O)c2ccc(Br)cc2c1-c1ccccc1
Agent: Cl
Product: NS(=O)(=O)c1ccc(Cn2c(C(=O)O)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Yield: 71 %

Procedure:
The title compound (3.64 g, 71%) was synthesized by a method similar to that in Example 331 and using 6-bromo-1-oxo-4-phenyl-1H-isochromen-3-carboxylic acid and 4-sulfamoylbenzylamine hydrochloride.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[F:10][C:11]([F:26])([F:25])[C:12]([N:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[CH2:16][CH2:15]1)=[O:13].Cl>ClC(Cl)C>[Cl:1][CH2:2][C:3]([C:23]1[CH:22]=[CH:21][C:18]2[CH2:19][CH2:20][N:14]([C:12](=[O:13])[C:11]([F:25])([F:10])[F:26])[CH2:15][CH2:16][C:17]=2[CH:24]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: O=C(N1CCc2ccccc2CC1)C(F)(F)F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: O=C(CCl)c1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.8 %

Procedure:
To a solution of chloroacetyl chloride (7.0 g) in dichloroethane (50 ml) was added aluminum chloride (8.2 g) at room temperature, and then a solution of 3-(trifluoroacetyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (3.0 g) in dichloroethane (50 ml) was added. The obtained mixture was stirred at room temperature for 3 hr, and poured into ice-cooled 1N is hydrochloric acid (80 ml). Dichloroethane was evaporated under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane (1:1, volume ratio) to give the title compound (3.5 g) as a colorless powder.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:8])[CH:7]=1)[CH3:2].[CH:14](=O)[CH:15]([CH3:17])[CH3:16]>>[CH2:1]([C:3]1[NH:4][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:8])[C:7]=1[CH2:14][CH:15]([CH3:17])[CH3:16])[CH3:2]
Reactant: CCOC(=O)c1[nH]c(CC)cc1C
Reactant: CC(C)C=O
Product: CCOC(=O)c1[nH]c(CC)c(CC(C)C)c1C

Procedure:
The crude product, obtained as in Example 74 but using 2-ethyl-4-methyl-5-carbethoxypyrrole and isobutyraldehyde was sublimed (80° C. 1 × 10-4 mm) and recrystallized from aqueous ethanol, m.p. 94°-96° C (44%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:40])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21]CC3C=CC=CC=3)=[C:17]([S:29]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)(=[O:31])=[O:30])[CH:16]=2)=[C:9]([CH3:39])[CH:8]=1)[CH3:2]>C(O)C.[Pd]>[F:38][C:35]1[CH:34]=[CH:33][C:32]([S:29]([C:17]2[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=2[OH:21])[CH2:14][C:10]2[C:11]([CH3:13])=[CH:12][C:7]([O:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:40])=[CH:8][C:9]=2[CH3:39])(=[O:31])=[O:30])=[CH:37][CH:36]=1
Reactant: CCOC(=O)COc1cc(C)c(Cc2ccc(OCc3ccccc3)c(S(=O)(=O)c3ccc(F)cc3)c2)c(C)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)COc1cc(C)c(Cc2ccc(O)c(S(=O)(=O)c3ccc(F)cc3)c2)c(C)c1
Reaction time: 2 h

Procedure:
50 mg (0.09 mmol) of ethyl (4-{4-(benzyloxy)-3-[(4-fluorophenyl)sulphonyl]benzyl}-3,5-dimethylphenoxy)acetate (Example XI) are dissolved in 20 ml of ethanol. 10 mg of palladium on activated carbon (10%) are added, and the mixture is hydrogenated at 1013 mbar and room temperature for 2 hours. The reaction mixture is then filtered through Celite and the solvent is removed under reduced pressure. This gives 37 mg (86% of theory) of ethyl (4-{3-[(4-fluorophenyl)sulphonyl]-4-hydroxybenzyl}-3,5-di-methylphenoxy)acetate.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:36])[CH3:35])[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1>>[C:34]([NH:33][C:29]1[CH:28]=[C:27]([CH:24]2[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][CH2:18][NH:17][C:8](=[O:9])[CH:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:22][CH2:23]2)[CH:32]=[CH:31][CH:30]=1)(=[O:36])[CH3:35]
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Example 3 was prepared from diphenylacetyl chloride and N-{3-[1-(3-aminopropyl)-4-piperidinyl ]phenyl}acetamide according to the procedures described in Scheme 8: 1H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 7.40 (s, 1H), 7.32–7.20 (m, 12H), 6.96 (t, 1H, J=4.8 Hz), 6.91 (d, 1H, J=7.6 Hz), 4.87 (s, 1H), 3.39 (dd, 2H, J=6.0, 12.4 Hz), 2.90 (d, 2H, J=11.6 Hz), 2.43 (m, 1H), 2.36 (t, 2H, J=6.4 Hz), 2.11 (s, 3H), 1.94 (m, 2H), 1.76 (d, 2H, J=12.4 Hz), 1.68 (t, 2H, J=6.8 Hz), 1.60 (dd, 2H, J=1.2, 8.4 Hz); ESMS m/e: 470.3 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([NH2:15])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(Cl)Cl.O>[C:23]([NH:15][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([O:25][CH2:26][CH3:27])=[O:24]
Reactant: NC(Cc1ccccc1)c1ccccc1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)NC(Cc1ccccc1)c1ccccc1
Temperature: 10 °C
Reaction time: 3 h

Procedure:
To a stirred two phase solution of 1,2-diphenylethylamine (30.0 g, 0.15 mol) in 300 ml of methylene chloride and 500 ml of water was added sodium carbonate (23.9 g, 0.225 mol) and the solution was cooled to 10° C. under nitrogen. Ethyl chloroformate (21.5 ml, 0.225 mol) was added dropwise over a one hour period. The reaction was warmed to ambient temperature and stirred at that temperature for 3 hours. The phases were separated and the aqueous phase was extracted with methylene chloride (75 ml). The combined methylene chloride extracts were washed with 1N HCl (200 ml), brine (200 ml), dried and evaporated to a white solid, 40.3 g. Recrystallization from cyclohexane gave N-carboethoxy-1,2-diphenylethylamine, mp 74°-75° C.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][C:8]([O:10]C)=[O:9])=[CH:5][N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.Cl[CH2:19][C:20]1[CH:38]=[CH:37][C:23]([O:24][CH2:25][C:26]2[N:27]=[C:28]([C:32]3[O:33][CH:34]=[CH:35][CH:36]=3)[O:29][C:30]=2[CH3:31])=[C:22]([O:39][CH3:40])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:33]1[CH:34]=[CH:35][CH:36]=[C:32]1[C:28]1[O:29][C:30]([CH3:31])=[C:26]([CH2:25][O:24][C:23]2[CH:37]=[CH:38][C:20]([CH2:19][O:1][C:2]3[C:6]([CH2:7][C:8]([OH:10])=[O:9])=[CH:5][N:4]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:3]=3)=[CH:21][C:22]=2[O:39][CH3:40])[N:27]=1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: COC(=O)Cc1cn(-c2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COc2nn(-c3ccccc3)cc2CC(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 60 °C
Reaction time: 4 h
Yield: 87.9 %

Procedure:
A mixture of methyl (3-hydroxy-1-phenyl-1H-pyrazol-4-yl)acetate (406 mg), 4-(4-chloromethyl-2-methoxyphenoxymethyl)-2-(2-furyl)-5-methyloxazole (551 mg), potassium carbonate (484 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 4 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. A mixture of the obtained colorless crystals, 1N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml) and methanol (4 ml) was stirred at room temperature for 1 hr. 1N Hydrochloric acid (2 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give [3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyloxy]-1-phenyl-1H-pyrazol-4-yl]acetic acid (748 mg, yield 88%). The crystals were recrystallized from ethyl acetate-hexane. melting point: 179–180° C.
Reaction SMILES: C([N:8]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:9][CH:10]([O:23][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=1)[CH2:11][O:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH2:15][C:16](=[O:22])[NH:17]2)C1C=CC=CC=1.[H][H]>O1CCCC1.[Pd]>[C:32]([NH:8][CH2:9][CH:10]([O:23][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=1)[CH2:11][O:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH2:15][C:16](=[O:22])[NH:17]2)([CH3:35])([CH3:33])[CH3:34]
Reactant: [H][H]
Reactant: CC(C)(C)N(Cc1ccccc1)CC(COc1cccc2c1CC(=O)N2)OC(=O)c1cccnc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)NCC(COc1cccc2c1CC(=O)N2)OC(=O)c1cccnc1

Procedure:
5 g of 4-[3-(N-benzyl-tert-butylamino)-2-nicotinoyloxypropoxy]oxindole are debenzylated with hydrogen in 25 cc of tetrahydrofuran, in the presence of 1 g of a palladium catalyst (10% of palladium on charcoal). The title compound is obtained, the dihydrochloride thereof having a M.P. of 215°-218°.
Reaction SMILES: [CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[C:18]([Cl:19])=[CH:17][C:16]([Cl:20])=[CH:15][N:14]=2)[CH:9]=[CH:8][C:7]=1[N+:21]([O-:23])=[O:22])(=[O:5])[OH:4])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]([O:34][CH3:35])=[O:33]>CC(=O)CC>[CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[C:18]([Cl:19])=[CH:17][C:16]([Cl:20])=[CH:15][N:14]=2)[CH:9]=[CH:8][C:7]=1[N+:21]([O-:23])=[O:22])(=[O:4])[O:5][CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH3:2]
Reactant: COC(=O)CBr
Reactant: CCP(=O)(O)c1cc(Oc2ncc(Cl)cc2Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCP(=O)(OCC(=O)OC)c1cc(Oc2ncc(Cl)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
A mixture of P-ethyl-2-nitro-5-(3,5-dichloro-2-pyridyloxy)phenylphosphinic acid (0.42 g., 1.2 mmol), potassium carbonate (2.0 mg), methyl bromoacetate (0.2 ml., 2.4 mmol), and 2-butanone (20 ml.) is heated under reflux for 2 hours. The reaction mixture is filtered and concentrated, and the crude product is purified by prep. TLC (50% ethyl acetate/hexane) to give methoxycarbonylmethyl P-ethyl-2-nitro-5-(3,5-dichloro-2-pyridyloxy)phenylphosphinate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:11]=[C:12]([C@H:16]2[CH2:20][CH2:19][C@:18]3([CH2:24][CH2:23][NH:22][C:21]3=[O:25])[N:17]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:13]=[CH:14][CH:15]=1.[H-].[Na+].[CH3:35]I>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:11]=[C:12]([C@H:16]2[CH2:20][CH2:19][C@:18]3([CH2:24][CH2:23][N:22]([CH3:35])[C:21]3=[O:25])[N:17]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:13]=[CH:14][CH:15]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2cccc(OCc3ccccc3F)c2)CC[C@]12CCNC2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CC[C@]2(CC[C@H](c3cccc(OCc4ccccc4F)c3)N2C(=O)OC(C)(C)C)C1=O
Reaction time: 0.25 h
Yield: 110 %

Procedure:
To a solution of 1,1-dimethylethyl (2R,5R)-2-(3-{[(2-fluorophenyl)methyl]oxy}phenyl)-6-oxo-1,7-diazaspiro[4.4]nonane-1-carboxylate (D46, 60 mg, 0.14 mmol) in DMF (1 mL) cooled at 0° C., was added NaH (8 mg of a 60% dispersion in mineral oil, 0.20 mmol) in one portion. The ice-bath was removed and the reaction mixture left under stirring for 15 min. Methyl iodide (25 μL, 0.41 mmol) was added to the mixture and after 1 h the reaction was quenched with water. The aqueous layer was extracted with ethyl acetate, dried (Na2SO4) and evaporated. The crude material was purified by chromatography on silica gel using cyclohexane/ethyl acetate (7:3) affording the title compound (70 mg, quant.); Rt (HPLC): 6.03 min; MS: (ES/+) m/z: 477 [M+Na+]; C26H31FN2O4 requires 454.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][C:6]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)([CH3:22])[C:7]([C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)=[O:8].[Br:29][C:30]([CH3:35])([CH3:34])[C:31](Br)=[O:32]>ClCCl>[Br:29][C:30]([CH3:35])([CH3:34])[C:31]([C:19]1[CH:20]=[CH:21][C:16]([S:15][C:12]2[CH:13]=[CH:14][C:9]([C:7](=[O:8])[C:6]([CH3:5])([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[CH3:22])=[CH:10][CH:11]=2)=[CH:17][CH:18]=1)=[O:32]
Reactant: CC(C)(C(=O)c1ccc(Sc2ccccc2)cc1)N1CCOCC1
Reactant: CC(C)(Br)C(=O)Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(Br)C(=O)c1ccc(Sc2ccc(C(=O)C(C)(C)N3CCOCC3)cc2)cc1
Reaction time: 2.5 h
Yield: 100 %

Procedure:
4.30 (32.20 mol) of AlCl3 were added in portion under stirring to a solution of 2.5 g (7.32 mmol) of 2-methyl-2-morpholin yl-1-(4-phenylsulphanyl-phenyl)-propan-1-one and 1.81 g (7.69 mmol) of α-bromoisobutyrylbromide (97.5% w/w) in 50 ml of dichloromethane, between 0 e 5° C. At the end of the addition the temperature was brought to 25° C. then, after 2.5 h, the reaction was quenched in 200 ml of iced water. The organic phase was separated and washed with water and 5% NaOH then dried with sodium sulphate, filtered and evaporated obtaining 3.59 g of product as a reddish oil.
Reaction SMILES: C(OC([NH:8][C:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:23]([Cl:24])=[CH:22][N:21]=[C:20](Cl)[N:19]=2)=[CH:14][CH:13]=1)([CH3:11])[CH3:10])=O)(C)(C)C.[NH2:26][C:27]1[CH:35]=[CH:34][C:30]([CH2:31][CH2:32][OH:33])=[CH:29][CH:28]=1.FC(F)(F)C(O)=O>C(OCCO)C>[NH2:8][C:9]([C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:23]([Cl:24])=[CH:22][N:21]=[C:20]([NH:26][C:27]3[CH:35]=[CH:34][C:30]([CH2:31][CH2:32][OH:33])=[CH:29][CH:28]=3)[N:19]=2)=[CH:16][CH:17]=1)([CH3:10])[CH3:11]
Reactant: Nc1ccc(CCO)cc1
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1ccc(-c2nc(Cl)ncc2Cl)cc1
Solvent: CCOCCO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(N)c1ccc(-c2nc(Nc3ccc(CCO)cc3)ncc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-[4-(1-tertbutoxycarbonylamino-1-methylethyl)phenyl]-2,5-dichloropyrimidine (1.53 g, 4.0 mmol) and 4-aminophenethyl alcohol (1.10 g, 8.0 mmol) in 2-ethoxyethanol (15 ml) was heated to reflux for 18 h. The reaction was cooled to room temperature, trifluoroacetic acid (2 ml) added and the reaction stirred for 30 min. Solvent was removed in vacuo and the residue partitioned between CH2Cl2 (100 ml) and saturated, aqueous Na2CO3 (80 ml). The aqueous layer was re-extracted with CH2Cl2 (2×80 ml) and the combined CH2Cl2 layer washed with aqueous Na2CO3 (80 ml), brine (80 ml), dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 10-15% methanol in CH2Cl2) to give the title compound as a buff solid (1.30 g) m.p. 162-163°. δH (d6DMSO) 9.74 (1H, s), 8.55 (1H, s), 7.76 (2H, d, J 8.5 Hz), 7.68 (2H, d, J 8.5 Hz), 7.62 (2H, d, J 8.5 Hz), 7.12 (2H, d, J 8.5 Hz), 4.57 (1H, bs), 3.55 (2H, m), 2.65 (2H, t, J 7.2 Hz), 1.41 (6H, s); MS (ESI) 383 (MH+, 35Cl, 100%).
Reaction SMILES: [F:1][C:2]([F:43])([CH3:42])[C:3]([NH:5][C@@H:6]([CH3:41])[C@@H:7]([C:31]1[CH:40]=[CH:39][C:34]2[O:35][CH2:36][CH2:37][O:38][C:33]=2[CH:32]=1)[O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]1[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=1)[C:21]([O:23]CC(C)C)=[O:22])[N:13]=[CH:12]2)=[O:4].[OH-].[Na+].Cl>C1COCC1.C(#N)C>[F:43][C:2]([F:1])([CH3:42])[C:3]([NH:5][C@@H:6]([CH3:41])[C@@H:7]([C:31]1[CH:40]=[CH:39][C:34]2[O:35][CH2:36][CH2:37][O:38][C:33]=2[CH:32]=1)[O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]1[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=1)[C:21]([OH:23])=[O:22])[N:13]=[CH:12]2)=[O:4]
Reactant: CC(C)COC(=O)c1cccc(-n2ncc3cc(O[C@H](c4ccc5c(c4)OCCO5)[C@H](C)NC(=O)C(C)(F)F)ccc32)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC#N
Product: C[C@H](NC(=O)C(C)(F)F)[C@H](Oc1ccc2c(cnn2-c2cccc(C(=O)O)c2)c1)c1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A solution of isobutyl 3-(5-((1R,2S)-2-(2,2-difluoropropanamido)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propoxy)-1H-indazol-1-yl)benzoate (I4a) (350 mg, 0.59 mmol) in THF (5 mL) and acetonitrile (2 mL) was treated with 0.25 M NaOH (4.72 mL, 1.18 mmol). The mixture was stirred at ambient temperature for 23 hours, additional 1M NaOH (0.590 mL, 0.59 mmol) was added and the mixture was stirred at +45° C. for 2 hours. The reaction mixture was allowed to cool down and acidified to pH 2.5-3 by adding 1 N HCl. Addition of THF and MeCN until solution followed by purification by HPLC, using an Kromasil 100-10-C18, 50×250 mm column, an 30 min gradient from 50% to 90% MeCN in water+0.1% TFA in solvents with flow=40 mL/min and UV=254 nm to collect fractions. Fractions containing the product was combined and freezedried. The material was redissolved in tBuOMe, addition of Heptane gave precipitation, the formed slurry was evaporated to afford the subtitle compound as a colourless solid. Yield 315 mg (99%)
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N+]([O-])=O)[N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:19][C:20]1[N:21]=[C:22]([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]3[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3][B:2]([OH:1])[C:6]=3[CH:7]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Reactant: O=[N+]([O-])c1cccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cccc(Cl)n3)cc(C)c21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of ethyl 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (0.1 g, 0.4 mmol, 1 eq.) and 2-chloro-6-nitropyridine (158 mg, 1 mmol, 2.5 eq.) in 5 ml DMF was added cesium carbonate (392 mg, 1.2 mmol, 3 eq.). The reaction was stirred at room temperature for three hours. It was then quenched by water, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude was purified by column chromatography on silica gel (DCM/methanol=39:1 to 19:1) to give desired product as light yellow oil. MS (ESI) m/z=362 [M+H]+.