Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH:9]([C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1)([CH3:11])[CH3:10].O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:5]1[CH:4]=[CH:3][C:2]([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:9]([CH3:11])[CH3:10])[CH:17]=2)=[CH:7][N:6]=1
Reactant: CC(C)c1cccc(B(O)O)c1
Reactant: Clc1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1cccc(-c2ccc(Cl)nc2)c1
Temperature: 80 °C
Yield: 58.6 %

Procedure:
To a stirred solution of 5-bromo-2-chloropyridine (1.27 g, 6.63 mmol) in toluene (30 mL) was added an ethanolic solution (10 mL) of 3-isopropyl-phenylboronic acid (1.8 g, 11.28 mmol) followed by water (10 mL) and potassium carbonate (2.76 g, 20.0 mmol). The resulting mixture was degassed for 15 min (by purging with argon). At this time, Pd(PPh3)4 (0.613 g, 0.53 mmol) was added under argon and the reaction mixture was heated at 80° C. for 4 h. The reaction mixture was then cooled to room temperature and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with water (2×10 mL), dried over Na2SO4 and concentrated in vacuo to obtain the crude product, which was purified over silica gel (Biotage column chromatography, 2% ethyl acetate in hexane) to afford 0.900 g (59%) of 2-chloro-5-(3-isopropyl-phenyl)-pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].CCN(C(C)C)C(C)C.[C:27]([CH:30]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@@H:31]1C(O)=O)(O)=[O:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:27]([CH:30]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31]3)=[O:28])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)[C@H]1C(=O)O
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
To a stirred solution of N-(3,4-dichlorophenyl)piperazine-1-carboxamide (2.00 g, 7.30 mmol) in DMF (150 ml) was added DIPEA (3.8 ml, 21.9 mmol), 3-carboxy-N-boc-proline (Arch Corporation) (1.727 g, 8.02 mmol) and HATU (3.051 g, 8.02 mmol) and the reaction stirred at ambient temperature for overnight (convenience). The solvents were then removed under reduced pressure. The resulting gum was then partitioned between EtOAc and water, extracted, the organic phase washed with saturated sodium bicarbonate solution and evaporated to dryness. The resulting foam was then purified on Isco™ Companion (40 g column. EtOAc) to give the product tert-butyl 3-[(4-{[(3,4-dichlorophenyl)amino]carbonyl}piperazin-1-yl)carbonyl]pyrrolidine-1-carboxylate as a pale yellow foam (3.396 g, 7.20 mmol, 99%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH:13]1([CH2:16][CH2:17][NH:18][C:19]([C:21]2[N:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:25][CH:26]=2)=[O:20])[CH2:15][CH2:14]1>>[CH:13]1([CH2:16][CH2:17][NH:18][C:19]([C:21]2[N:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:7](=[O:9])[C:6]4[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[O:11][CH3:12])[CH2:29][CH2:28]3)=[CH:25][CH:26]=2)=[O:20])[CH2:15][CH2:14]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: COc1ccc(F)cc1C(=O)O
Product: COc1ccc(F)cc1C(=O)N1CCN(c2ccc(C(=O)NCCC3CC3)nn2)CC1

Procedure:
Following the procedure of Example 9, making variations only as required to use 5-fluoro-2-methoxybenzoic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)-amide, the title compound was obtained as a white solid (61% yield). 1H NMR (300 MHz, CDCl3) δ 8.03, 7.96, 7.10-6.98, 6.86-6.84, 4.03-3.37, 1.51, 0.80-0.72, 0.49-0.44, 0.15-0.10. MS (ES+) m/z 428.1 (M+1).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[O:10][C:8](=[O:9])[NH:7][C:5]=2[CH:6]=1.[Br:11]N1C(=O)CCC1=O.O>C(O)(=O)C>[Br:11][C:2]1[CH:1]=[CH:6][C:5]2[NH:7][C:8](=[O:9])[O:10][C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2ccccc2o1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c2ccc(Br)cc2o1
Temperature: 25 °C
Reaction time: 63 h
Yield: 79.2 %

Procedure:
To a solution of benzoxazolinone (20 g, 0.148 mol) in 220 mL glacial acetic acid was added N-bromosuccinimide (NBS, 26.36 g, 0.148 mol), and the reaction mixture was stirred at room temperature for 63 hours before pouring into 1500 mL water. The precipitated product was washed thoroughly with water upon collection and recrystallized from EtOH to give 6-bromo-3H-benzoxazol-2-one (9) (25.09 g, 79%): Theory: C, 39.28; H, 1.88; N, 6.54; Br, 37.33. Found: C, 39.36; H, 2.02; N, 6.36; Br, 37.43. MP 192-194° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[O:10]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH2:49]([O:51][C:52](=[O:55])[CH2:53][NH2:54])[CH3:50]>CN(C=O)C.O>[CH2:49]([O:51][C:52](=[O:55])[CH2:53][NH:54][C:21](=[O:23])[C:20]1[CH:19]=[CH:18][C:17]([O:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:25][CH:24]=1)[CH3:50]
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNC(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 102.2 %

Procedure:
DIPEA (12.1 g, 16.2 mL, 93.6 mmol) was added to a stirred solution of 4-phenoxy benzoic acid (4.011 g, 18.73 mmol) in DMF (40 mL). HOBT (2.78 g, 20.57 mmol) and EDCI.HCl (9 g, 47 mmol) were then added. After 2 minutes, glycine ethyl ester hydrochloride (3.14 g, 22.5 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with cold water and the product extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over sodium sulphate and concentrated under reduced pressure to afford 5.73 g of (4-phenoxy-benzoylamino)-acetic acid ethyl ester as a white powder. 1H NMR (DMSO): δ 8.85 (t, 1H), 7.85 (d, 2H), 7.4 (t, 2H), 7.2 (t, 1H), 7.0 (m, 4H), 4.1 (q, 2H), 3.9 (d, 2H), 1.2 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:23]=[CH:22][C:11]3[CH:12]([NH:15][C:16]([C:18]4([NH2:21])[CH2:20][CH2:19]4)=[O:17])[CH2:13][O:14][C:10]=3[CH:9]=2)[CH:7]=1.[CH3:31][O:32][C:33]1[CH:37]=[C:36]([C:38](O)=[O:39])[O:35][N:34]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:23]=[CH:22][C:11]3[CH:12]([NH:15][C:16]([C:18]4([NH:21][C:38]([C:36]5[O:35][N:34]=[C:33]([O:32][CH3:31])[CH:37]=5)=[O:39])[CH2:20][CH2:19]4)=[O:17])[CH2:13][O:14][C:10]=3[CH:9]=2)[CH:7]=1
Reactant: COc1cc(C(=O)O)on1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)OCC3NC(=O)C2(N)CC2)no1
Product: COc1cc(C(=O)NC2(C(=O)NC3COc4cc(-c5cc(Cl)cc(F)c5-c5noc(C)n5)ccc43)CC2)on1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(rac)-6-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-2,3-dihydro-benzofuran-3-yl}-amide (example 45) has been coupled with 3-methoxy-isoxazole-5-carboxylic acid to yield the title compound as light yellow oil. MS: 554.1 (MH+, 1Cl).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][CH3:12])=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[CH:5]=O.[C:13](Br)(Br)([Br:15])[Br:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[C:4]([CH:5]=[C:13]([Br:15])[Br:14])[C:3]=1[CH2:11][CH3:12]
Reactant: BrC(Br)(Br)Br
Reactant: CCc1c(Cl)ccc(F)c1C=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCc1c(Cl)ccc(F)c1C=C(Br)Br

Procedure:
1-Chloro-3-(2,2-dibromo-vinyl)-2-ethyl-4-fluoro-benzene was prepared from 3-chloro-2-ethyl-6-fluoro-benzaldehyde, carbon tetrabromide and triphenylphosphine in analogy to Example 1d): colourless oil; 1H-NMR (CDCl3): 1.15 (3H, t, CH3), 2.72 (2H, q, CH2), 6.90 (1H, dd, ArH), 7.29 (1H, s, CH═CBr2), 7.33 (1H, dd, ArH).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[Cl:5][CH2:6][CH2:7][CH2:8][S:9](Cl)(=[O:11])=[O:10].[OH-].[Na+].Cl>O>[Cl:5][CH2:6][CH2:7][CH2:8][S:9]([N:3]([CH3:4])[CH3:2])(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CNC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)S(=O)(=O)CCCCl
Temperature: -5 °C

Procedure:
10 g of dimethylamine hydrochloride are placed in 60 ml of water, a nitrogen atmosphere is applied and the solution is cooled to between 0° C. and −5° C., and then 18 ml of 3-chloro-1-propanesulphonyl chloride are added dropwise. 10.6 g of sodium hydroxide in 40 ml of water are added while maintaining at −5° C., then the mixture is allowed to return to AT and stirring is maintained for 1 hour. 1 ml of concentrated HCl is added and then extraction is carried out with DCM. The organic phase is washed with a 10% NaOH solution and then with an NaCl solution. 15.1 g of the expected compound are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH:18]1[CH:19]=[CH:20][N:21]2[CH2:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[NH:24][CH2:23][C:22]=12.C(N(CC)C(C)C)(C)C>S(Cl)(Cl)=O.ClCCl>[CH:18]1[CH:19]=[CH:20][N:21]2[CH2:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[N:24]([C:15]([C:12]3[CH:11]=[CH:10][C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)=[CH:14][CH:13]=3)=[O:17])[CH2:23][C:22]=12
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)cc1
Reaction time: 2 h
Yield: 86.8 %

Procedure:
A suspension of the carboxylic acid of Step B (1.0 g, 4.38 mmol) in thionyl chloride (6 mL) was heated at reflux for 1 hour. After cooling, the thionyl chloride was removed in vacuo. The residue was dissolved in toluene and concentrated in vacuo to give the crude acid chloride as a light brown solid. The acid chloride was then dissolved in dichloromethane (10 mL) and slowly added to a solution of 10,11-dihydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine (1.2 g, 6.52 mmol) and N,N-diisopropylethyl amine (1.7 mL, 9.76 mmol) in dichloromethane (25 mL). After stirring for 2 hours, the reaction was quenched with water. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a yellow foam. Purification of the residue by flash chromatography using a solvent gradient from 15% to 50% of ethyl acetate in hexane provided the title compound (1.5 g, 86.8%) as a white solid, m.p. 187-189° C.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2([NH:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[C:13](=[O:37])[CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[C].[Pd]>[C:27]([O:26][C:24]([N:21]1[CH2:20][CH2:19][C:18]([CH2:17][N:14]2[CH2:15][CH2:16][NH:11][CH2:12][C:13]2=[O:37])([NH:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:23][CH2:22]1)=[O:25])([CH3:28])([CH3:29])[CH3:30]
Reactant: CCOC(=O)NC1(CN2CCN(C(=O)OCc3ccccc3)CC2=O)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)NC1(CN2CCNCC2=O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 110 %

Procedure:
10% Palladium carbon (600 mg) was added to a solution of 4-benzyloxycarbonyl-1-{[1-(tert-butoxycarbonyl)-4-ethoxycarbonylamino-4-piperidinyl]methyl}-2-piperazinone (1.79 g) in ethanol (50 ml), and the mixture was stirred at room temperature for 15 hours under a nitrogen atmosphere. After the catalyst was filtered, the solvent was distilled off to obtain the colorless amorphous title compound (1.46 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]([O:20][CH3:21])=[O:19])=[CH:7][N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:48]1[CH:53]=[CH:52][CH:51]=[C:50]([CH2:54]O)[CH:49]=1>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]([O:20][CH3:21])=[O:19])=[CH:7][N:8]2[C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:54][C:50]2[CH:49]=[N:48][CH:53]=[CH:52][CH:51]=2)=[CH:24][CH:23]=1
Reactant: OCc1cccnc1
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2cc(Cl)c(-c3ccc(O)cc3)cc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cn(C(=O)OC(C)(C)C)c2cc(Cl)c(-c3ccc(OCc4cccnc4)cc3)cc12
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A mixture of 1-tert-butyl 3-methyl 6-chloro-5-(4-hydroxyphenyl)-1H-indole-1,3-dicarboxylate (30 mg, 0.075 mmol), polymer supported triphenylphosphine (50 mg, 0.15 mmol), anhydrous tetrahydrofuran (1.0 mL), pyridin-3-ylmethanol (0.015 mL, 0.15 mmol), and bis(2-methoxyethyl)-diazene-1,2-dicarboxylate) (35 mg, 0.15 mmol) was sealed in a vial and stirred vigorously at 70° C. for 18 hours. The cooled reaction mixture was filtered through a pad of Celite, and the filter pad was washed with diethyl ether twice. The filtrate was concentrated in vacuo, and the residue partitioned between diethyl ether and water. The organic layer was separated and washed sequentially with water and then brine. The ether layer was concentrated in vacuo and to give the title compound, which was used directly in the next step. MS (ES+) 493 (M+1)+.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:3]=1[C:4]#[N:5].[CH3:15][O-:16].[Na+]>CO>[CH3:15][O:16][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:3]=1[C:4]#[N:5]
Reactant: Cc1cc(C(F)(F)F)c(C#N)c(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(C)cc(C(F)(F)F)c1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
To a solution of 2-chloro-6-methyl-4-(trifluoromethyl)nicotinonitrile (1 g, 4.5 mmol) in anhydrous methanol (20 mL) was added sodium methoxide (540 mg, 10 mmol). After stirring at room temperature for 2 hours, the resultant mixture was concentrated to give a residue. And the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=1:1) to give 2-methoxy-6-methyl-4-(trifluoromethyl)nicotinonitrile (0.9 g, 92%). LRMS (M+H) m/z: calcd 216.05. found 216.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[F:13])[O:9][CH2:8][CH2:7][CH:6]2[C:14]([O:16]C)=[O:15])#[N:2].[OH-].[Na+].O.CO>C1COCC1.C(OCC)(=O)C.Cl>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[F:13])[O:9][CH2:8][CH2:7][CH:6]2[C:14]([OH:16])=[O:15])#[N:2]
Reactant: COC(=O)C1CCOc2cc(F)c(C#N)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cc2c(cc1F)OCCC2C(=O)O
Reaction time: 3 h
Yield: 95.2 %

Procedure:
Methyl 6-cyano-7-fluoro-3,4-dihydro-2H-chromene-4-carboxylate (45 mg, 0.19 mmol) was diluted with THF (1 mL) followed the addition of NaOH (0.19 mL, 0.96 mmol), 200 μL of water and methanol. After stirring for 3 hours, the reaction was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield the title compound (40 mg, 95% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)[CH:8]=1)[NH2:5].[NH:14]1[CH2:21][CH2:20]C[C@H:15]1[C:16](O)=[O:17].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CS(C)=O.O1CCOCC1.[Cu]I>[O:17]1[CH2:16][CH2:15][N:14]([C:2]2[CH:3]=[C:4]([CH:6]=[C:7]([N:9]3[CH:13]=[CH:12][CH:11]=[N:10]3)[CH:8]=2)[NH2:5])[CH2:21][CH2:20]1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: Nc1cc(Br)cc(-n2cccn2)c1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: Nc1cc(N2CCOCC2)cc(-n2cccn2)c1
Temperature: 120 °C
Reaction time: 96 h
Yield: 149.3 %

Procedure:
The mixture of 3-bromo-5-(1H-pyrazol-1-yl)aniline (200 mg, 0.84 mmol), morphoine (0.22 mL, 2.52 mmol), proline (39 mg, 0.34 mmol), CuI (33 mg, 0.17 mmol) and K3PO4 (540 mg, 2.52 mmol) in 10 mL DMSO was stirred at 120° C. in a sealed tube for 4 days. It was diluted with dioxane, filtered through celite, concentrated in vacuo and subjected to reverse phase preparative HPLC to isolate 3-morpholino-5-(1H-pyrazol-1-yl)aniline (124 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]([OH:21])=O)[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:22]([F:25])([F:24])[F:23])([O-:3])=[O:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[F:55][C:56]([F:74])([F:73])[C:57]1[CH:58]=[CH:59][C:60]2[O:64][CH:63]([CH2:65][N:66]3[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]3)[CH2:62][C:61]=2[CH:72]=1>ClCCl.O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:12][CH2:13][CH:14]([O:17][CH2:18][C:19]([N:69]3[CH2:70][CH2:71][N:66]([CH2:65][CH:63]4[CH2:62][C:61]5[CH:72]=[C:57]([C:56]([F:74])([F:55])[F:73])[CH:58]=[CH:59][C:60]=5[O:64]4)[CH2:67][CH2:68]3)=[O:21])[CH2:15][CH2:16]2)=[CH:6][C:5]=1[C:22]([F:25])([F:23])[F:24])([O-:3])=[O:2]
Reactant: O=C(O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reactant: FC(F)(F)c1ccc2c(c1)CC(CN1CCNCC1)O2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(CC2Cc3cc(C(F)(F)F)ccc3O2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
To a solution of 2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]acetic acid (100 mg, 0.28 mmol) in dichloromethane (30 ml) was added EDAC.HCl (79.6 mg, 0.42 mmol, 1.5 eq), HOBt (55.9 mg, 0.41 mmol, 1.5 eq), triethylamine (55.9 mg, 0.55 mmol, 1.5 eq) and 1-[[5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl]piperazine (86.9 mg, 0.30 mmol, 1.1 eq). The solution was stirred at room temperature overnight. The reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (3×30 ml). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The crude material was purified by silica gel chromatography using 25% ethyl acetate in dichloromethane to elute. The product-containing fractions were combined and concentrated under vacuum to afford 2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]-1-(4-[[5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl]piperazin-1-yl)ethan-1-one as a yellow solid (69.9 mg, 40%); (ES, m/z): [M+H]+ 631.20; 1H NMR (300 MHz, CDCl3): δ 8.01 (d, J=9.0 Hz, 1H), 7.44 (m, 2H), 6.84 (m, 2H), 6.62 (dd, J=2.7 Hz, 9.0 Hz, 1H), 5.10 (broad s, 1H), 4.47 (d, J=8.1 Hz, 1H), 4.22 (s, 2H), 3.61-3.82 (m, 3H), 3.36-3.48 (m, 3H), 3.01-3.07 (dd, J=7.8 Hz, 16.2 Hz, 1H), 2.80-2.95 (m, 1H), 2.54-2.74 (m, 4H), 2.12-2.18 (m, 4H), 1.43-1.59 (m, 3H), 1.24-1.35 (m, 3H).
Reaction SMILES: B.[CH2:2]([S:9][C:10]1[CH:49]=[CH:48][CH:47]=[CH:46][C:11]=1[C:12]([NH:14][CH2:15][C:16]([CH3:45])([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)[CH2:17][NH:18][C:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>C1COCC1.O>[CH2:2]([S:9][C:10]1[CH:49]=[CH:48][CH:47]=[CH:46][C:11]=1[CH2:12][NH:14][CH2:15][C:16]([CH3:45])([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)[CH2:17][NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(CNC(=O)c1ccccc1SCc1ccccc1)(CNC(=O)c1ccccc1SCc1ccccc1)Cc1ccc([N+](=O)[O-])cc1
Agent: B
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(CNCc1ccccc1SCc1ccccc1)(CNCc1ccccc1SCc1ccccc1)Cc1ccc([N+](=O)[O-])cc1

Procedure:
27.6 ml of a 1M borane solution in THF was added dropwise to a solution of 2,98 g [69] (4.6 mmol) in 10 ml THF at 0° C., reflux-heated for two hours, cooled and 10 ml of a 1:1 mixture of HCl in water was added and the solvlent was removed in a rotary evaporator. After neutralising with 1N NaOH the mixture was extracted with dichloromethane, and dried over sodium sulphate and the solvent was removed, leaving a faintly yellow oil.
Reaction SMILES: [CH2:1]([N:3]([C:15]1[C:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:23][C:22]2[C:21]([CH3:33])([CH3:32])[CH2:20][CH:19]=[C:18]([CH3:34])[C:17]=2[CH:16]=1)[C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][CH:5]=1)[CH3:2].[OH-].[K+]>>[CH2:1]([N:3]([C:15]1[C:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:23][C:22]2[C:21]([CH3:32])([CH3:33])[CH2:20][CH:19]=[C:18]([CH3:34])[C:17]=2[CH:16]=1)[C:4]1[CH:14]=[CH:13][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCCCCCOc1cc2c(cc1N(CC)c1ccc(C(=O)OCC)cc1)C(C)=CCC2(C)C
Agent: [K+]
Agent: [OH-]
Product: CCCCCCOc1cc2c(cc1N(CC)c1ccc(C(=O)O)cc1)C(C)=CCC2(C)C
Yield: 26.5 %

Procedure:
Following General Procedure E ethyl 4-[ethyl-(3-n-hexyloxy-5,5,8-trimethyl-5,6-dihydronaphthalen-2-yl)amino]benzoate (Compound 125, 0.036 g, 0.078 mmol) was saponified with KOH to give 0.0090 g (27%) of the title compound as a yellow oil.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[OH:6][CH2:7][CH:8]([CH2:42][OH:43])[CH2:9][CH2:10][N:11]1[C:19](NC(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:18][C:17]2[C:12]1=[N:13][C:14](OC)=[N:15][CH:16]=2.C(=O)(O)[O-].[Na+].[N:49]1C=CC=CC=1>O>[NH2:49][C:14]1[N:13]=[C:12]2[C:17]([N:18]=[CH:19][N:11]2[CH2:10][CH2:9][CH:8]([CH2:7][OH:6])[CH2:42][OH:43])=[CH:16][N:15]=1
Reactant: COc1ncc2nc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n(CCC(CO)CO)c2n1
Reactant: c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Nc1ncc2ncn(CCC(CO)CO)c2n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To an ice-cooled solution of phosphorus oxychloride (93 μl, 1.0 mmol) in pyridine (2 ml) was added dropwise over 45 minutes a solution of 9-(4-hydroxy-3-hydroxymethylbut-1-yl)-2-monomethoxytritylaminopurine (0.46 g, 0.9 mmol) in pyridine (4 ml). The solution was stirred for a further 20 minutes at room temperature and was then added dropwise to a solution of sodium bicarbonate (0.34 g, 4.0 mmol) in water (6 ml). The solvent was removed and the residue was taken up in 80% acetic acid (9 ml) and the solution was stirred at 70° for 25 minutes. The solvent was removed and the residue was taken up in water and brought to pH 6 by addition of ammonia. The solution was extracted twice with chloroform and the solvent was removed. The residue was purified by preparative high pressure liquid chromatography on a C18 reverse-phase μ-Bondapack column eluting with 4% methanol in ammonium acetate buffer (pH 4.5, 50 mM) to afford 2-amino-9-(4-hydroxy-3-hydroxymethylbut-1-yl) purine 4':4"-phosphate as a white powder (225 mg, 75%); λmax (H2O) 220, 242, and 303 nm; νmax (KBr) 2900-3200 (br), 1705, 1615, and 1580 cm-1 ; δH [(CD3)2SO] 1.63 (1H, m, 3'-H), 1.74 (2H, q, J 7.0 Hz, 2'-H), 3.80 (2H, q, J 9.2 Hz, 2×Hax), 3.98 (2H, ddd, J 14.3, 10.9, and 3.5 Hz, 2×Heq), 4.08 (2H, t, J 7.1 Hz, 1'-H), 6.51 (2H, s, D2O exchangeable, 2-NH2), 8.10 (1H, s, 8-H), and 8.56 (1H, s, 6-H); (Found: C, 36.41; H, 5.18; N, 22.38%. C10H14N5O4P.0.3 NH3. 1.5H2O requires C, 36.25; H, 5.45; N, 22.40%).