Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:8][N:7]([C:9]([NH:11][C:12]2[CH:13]=[C:14]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH:15]=[CH:16][C:17]=2[N+:18]([O-])=O)=[O:10])[CH2:6]1)[CH3:3]>CO.[Pd]>[NH2:18][C:17]1[CH:16]=[CH:15][C:14]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)=[CH:13][C:12]=1[NH:11][C:9]([N:7]1[CH2:6][CH:5]([CH2:4][N:2]([CH3:3])[CH3:1])[CH2:8]1)=[O:10]
Reactant: CN(C)CC1CN(C(=O)Nc2cc(-c3ccc(F)cc3)ccc2[N+](=O)[O-])C1
Agent: [Pd]
Solvent: CO
Product: CN(C)CC1CN(C(=O)Nc2cc(-c3ccc(F)cc3)ccc2N)C1
Reaction time: 2 h
Yield: 2.2 %

Procedure:
To a solution of 3-((dimethylamino)methyl)-N-(4′-fluoro-4-nitro-[1,1′-biphenyl]-3-yl)azetidine-1-carboxamide (1.7 g, 4.57 mmol, 1.0 eq.) in methanol (100 mL) and was added 10% Pd/C (1.0 g, 0.94 mmol). The reaction mixture was stirred 2 h under a hydrogen atmosphere. The reaction was then filtered and the filtrate was concentrated under reduced pressure to give N-(4-amino-4′-fluoro-[1,1′-biphenyl]-3-yl)-3-((dimethylamino)methyl)azetidine-1-carboxamide (35 mg, 3% yield) as an off-white solid. ESI+ MS: m/z 343 ([M+H]+), 1HNMR (500 MHz, DMSO-d6): δ 7.61 (s, 1H), 7.53-7.51 (m, 2H), 7.36 (d, J=2.0 Hz, 1H), 7.21-7.15 (m, 3H), 6.76 (d, J=8.5 Hz, 1H), 4.98 (s, 2H), 3.99 (t, J=8.0 Hz, 2H), 3.58 (dd, J12=6.0 Hz, J13=8.0 Hz, 2H), 2.72-2.69 (m, 1H), 2.45-2.44 (m, 2H), 2.13 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:23]([OH:25])=O)=[N:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:27]>C1(C)C=CC=CC=1.O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:23]([Cl:27])=[O:25])=[N:9]2)=[CH:4][CH:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(=O)O)nn2-c2ccc(F)cc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(-c2cc(C(=O)Cl)nn2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 118.5 %

Procedure:
A mixture of 1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole-3-carboxylic acid (1.1 g) and phosphorus pentachloride (0.67 g) in toluene (16 ml) and tetrahydrofuran 9 ml) was stirred at ambient temperature for 2 hours. The insoluble material was filtered and the filtrate was concentrated to give an oil of 1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole-3-carbonyl chloride (1.37 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:5])[CH3:2].[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][Br:19])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:5])[CH3:2]
Reactant: CCOC(=O)Nc1cccc(C)c1C(=O)OCC
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)Nc1cccc(CBr)c1C(=O)OCC
Yield: 73.9 %

Procedure:
A solution of ethyl 2-ethoxycarbonylamino-6-methylbenzoate (10 mmol, 2.513 g.), N-bromosuccinimide (11 mmol, 1.957 g.), and catalytic amount (100 mg) of AIBN (2,2'-azobisisobutyronitrile) in 50 ml carbon tetrachloride was refluxed for 2 hours. The insoluble succinimide was removed by filtration. The filtrate was washed with saturated NaHCO3 solution (25 ml), water (30 ml), dried over MgSO4, and filtered. The filtrate was evaporated to dryness and trituated with petroleum ether to afford 2.44 g (74%) of ethyl 2-ethoxycarbonylamino-6-bromomethylbenzoate (6) as a pale yellow powder; mp 70°-72° C. IR (KBr) νmax 1740, 1685 cm-1.
Reaction SMILES: [C:1]([NH:9][CH:10]([CH2:33][CH2:34][CH2:35][CH2:36][NH:37]C(OCC1C=CC=CC=1)=O)[CH:11]([OH:32])[CH2:12][N:13]([CH3:31])[C:14]([N:16]1[CH2:30][CH2:29][CH2:28][C@H:17]1[C:18]([O:20]CC1C=CC=CC=1)=[O:19])=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+]>[Pd].C(O)C>[NH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH:10]([NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:11]([OH:32])[CH2:12][N:13]([CH3:31])[C:14]([N:16]1[CH2:30][CH2:29][CH2:28][C@H:17]1[C:18]([OH:20])=[O:19])=[O:15]
Reactant: CN(CC(O)C(CCCCNC(=O)OCc1ccccc1)NC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CN(CC(O)C(CCCCN)NC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 8 h

Procedure:
The ester product from part (d) is taken into 100 ml. of 95% ethanol with stirring. Ammonium chloride (1.45 ml.) and 180 mg. of 10% palladium on carbon catalyst are added. The mixture is stirred overnight under hydrogen, filtered, and concentrated to dryness. The crude product is lyophilized and purified chromatographically to give (±)-1-[[[7-amino-3-(benzoylamino)-2-hydroxyheptyl]methylamino]carbonyl]-L-proline.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[C:15][Si](C)(C)C)[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CO.C(Cl)Cl.C(Cl)Cl>[C:14]([C:10]1[CH:9]=[C:8]([C:7]2[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:12][CH:11]=1)#[CH:15]
Reactant: C[Si](C)(C)C#Cc1cccc(-c2cccnc2F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CO
Product: C#Cc1cccc(-c2cccnc2F)c1
Reaction time: 1 h
Yield: 77 %

Procedure:
To a solution of 2-fluoro-3-{3-[(trimethylsilyl)ethynyl]phenyl}pyridine (2.20 g, 8.1 mmol) in MeOH/CH2Cl2 (1/1, 60 mL) is added Cs2CO3 (3.17 g, 9.7 mmol) at room temperature. After stirring for 1 h, the reaction mixture is diluted with CH2Cl2 and passed through a thin layer of silica gel. The solution is concentrated and the crude material is purified by chromatography (silica gel, EtOAc/hexane:20/80) to give the title compound (1.23 g, 77%) as a solid. mp: 45-47° C. MS (+) EI: 198 M+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:11][CH:10]=2)=[CH:5][C:4]=1[CH2:19][NH:20][CH:21]1[CH2:26][CH2:25][CH:24]([N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:23][CH2:22]1.[Cl:36][C:37]1[C:38]2[C:48]([F:49])=[CH:47][CH:46]=[C:45]([F:50])[C:39]=2[S:40][C:41]=1[C:42](Cl)=[O:43]>>[Cl:36][C:37]1[C:38]2[C:48]([F:49])=[CH:47][CH:46]=[C:45]([F:50])[C:39]=2[S:40][C:41]=1[C:42]([N:20]([CH2:19][C:4]1[CH:5]=[C:6]([C:9]2[CH:10]=[CH:11][C:12]([S:15](=[O:17])(=[O:18])[NH2:16])=[CH:13][CH:14]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH:21]1[CH2:22][CH2:23][CH:24]([N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:25][CH2:26]1)=[O:43]
Reactant: COc1ccc(-c2ccc(S(N)(=O)=O)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Product: COc1ccc(-c2ccc(S(N)(=O)=O)cc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Crude biaryl amine 216 (514 mg) is treated with acid chloride 8 (327 mg, 1.22 mmol) using Method D to give the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Br:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[Br:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]1[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH2:7][CH2:8][N:9]=1
Reactant: O=C(NCCc1ccccc1)c1ccccc1Br
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1C
Product: Brc1ccccc1C1=NCCc2ccccc21
Temperature: 100 °C

Procedure:
A suspension of 50.0 g (164 mmol) of N-phenylethyl-2-bromobenzamide and 27.9 g of phosphorus pentoxide in 200 ml of xylene was heated to 100° C. and admixed dropwise with 45.6 g (492 mmol) of phosphorus oxychloride. Subsequently, the reaction mixture was heated under reflux for 2 h. After cooling to 80° C., the reaction mixture was stirred into 4000 g of ice and adjusted to pH=12 with NaOH (solid). The organic phase was removed, the aqueous phase was extracted three times with 300 ml of toluene, and the combined organic phases were washed with 500 ml of water and subsequently dried over magnesium sulfate. After the desiccant had been filtered off and the solvent had been removed, the product was obtained as a yellow oil. The yield at a purity of approx. 99.0% was 46.9 g (164 mmol), 99.9% of theory.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[CH2:22]([O:28][C:29](Cl)=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C1C=CC=CC=1>[C:29](=[O:30])([O:28][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1
Reactant: CCCCCCOC(=O)Cl
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCCCCOC(=O)Oc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
0.976 G. of 4'-cyano-4-hydroxy-biphenyl are dissolved in 10 ml. of absolute pyridine and reacted with 0.988 g. of chloroformic acid n-hexyl ester as in Example 1. The 1.675 g. of yellowish, turbid, partially crystallized oil obtained according to the procedure described in Example 1 is dissolved in benzene and chromatographed on 80 g. of silica gel. Benzene elutes 1.530 g. of colorless crystals which are recrystallized from ether-hexane up to constant melting point and clearing point. The pure 4'-cyano-4-biphenylyl n-hexyl carbonate obtained melts at 87.1°-87.5° and is liquid crystalline (monotrope) upon cooling to 62.7°. UV (EtOH): ε270 = 26,300.
Reaction SMILES: Br[CH:2]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=[O:4].[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K].C(OCC)(=O)C>O>[CH3:14][CH:13]([CH3:15])[CH2:12][CH:2]([N:20]1[C:16](=[O:26])[C:17]2[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:19]1=[O:21])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=[O:4]
Reactant: Cc1ccc(C(=O)C(Br)CC(C)C)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)C(CC(C)C)N2C(=O)c3ccccc3C2=O)cc1
Temperature: 160 °C
Yield: 72.7 %

Procedure:
2-Bromo-4-methyl-1-(4-methylphenyl)pentane-1-one (13.5 g, 50 mmol) and potassium phthalimide (9.26 g, 50 mmol) were thoroughly mixed and heated at 160° C. for 2 hours. After being cooled, the reaction mixture was added with ethyl acetate (100 ml) and with water (50 ml). The resulting organic layer was separated and washed with brine. The organic solution was then dried over sodium sulfate and evaporated under reduced pressure. The residue was crystallized by treatment with hexane and the resulting crystals were recrystallized from hexane to obtain 12.2 g of the intended compound as white crystals (yield: 73%).
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].[CH2:6](O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15].[OH-].[Na+]>>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)O
Reactant: OCCCCCCCCCO
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OCCCCCCCCCO
Yield: 25.9 %

Procedure:
200 g (2.7 mol) of tert-butanol, 100 g (0.625 mol) of 1,9-nonanediol and 2 g of sulfuric aid were placed in a 500 ml round bottomed flask, and refluxed with heat for 5 hours, followed by neutralizing with an aqueous sodium hydroxide solution. After unreacted tert-butanol was evaporated, hexane was added and stirred. The diol insoluble in hexane was discarded by filtration. The hexane layer was washed with water, and dried with anhydrous sodium sulfate. After filtration, the solvent was evaporated and the residue was purified by silica gel column chromatography (hexane/chloroform) to obtain 35 g of 9-tert-butoxy-1-nonanol as a colorless oil.
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[CH:12]=[C:11](F)[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].Cl>O>[Cl:3][C:4]1[CH:12]=[C:11]([NH:2][CH3:1])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: CN
Agent: Cl
Solvent: O
Product: CNc1cc(Cl)c(C(=O)O)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Methylamine (40% aq solution, 8.25 mL) is added to an ice-cooled mixture of 2-chloro-4-fluoro-5-nitro-benzoic acid (7.00 g, 31 mmol) and 70 mL water. After 2 h additional 0.5 mL methylamine solution is added and it is stirred for additional 3 h. Then 200 mL of water and 47 mL 1N aq HCl are added and the resulting precipitate is filtered off, washed with water and dried.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:7][NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=2)[C:12](Cl)=[N:11][N:10]=1.[CH2:26]([OH:28])[CH3:27]>>[Cl:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[C:12]([O:28][CH2:26][CH3:27])=[N:11][N:10]=[C:9]2[NH:8][CH2:7][C:6]1[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:4]([Cl:3])[CH:5]=1
Reactant: COc1ccc(CNc2nnc(Cl)c3ccc(Cl)cc23)cc1Cl
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Product: CCOc1nnc(NCc2ccc(OC)c(Cl)c2)c2cc(Cl)ccc12
Temperature: 150 °C

Procedure:
A solution of 120 mg of 60% oily sodium hydride in 20 ml of ethanol was added to 1.0 g of 4-(3-chloro-4-methoxybenzyl)amino-1,6-dichlorophthalazine prepared in Example 27. The obtained mixture was heated at 150° C. in a sealed tube overnight, cooled and concentrated in a vacuum. The residue was dissolved in ethyl acetate. The obtained solution was washed with water and a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and concentrated in a vacuum. The obtained residue was subjected to silica gel column chromatography and eluted with dichloromethane/methanol (50:1) to give 0.9 g of the title compound.
Reaction SMILES: [CH3:1][C:2]([S@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[CH2:8]1[CH:10]([CH:11](O)C#N)[CH2:9]1>C1COCC1.[Cl-].[Na+].O>[CH:10]1(/[CH:11]=[N:7]/[S@@:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])[CH2:8][CH2:9]1
Reactant: N#CC(O)C1CC1
Reactant: CC(C)(C)[S@](N)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)/N=C/C1CC1
Yield: 102.8 %

Procedure:
(R)-2-Methylpropane-2-sulfinamide (25) (8.63 g, 71.3 mmol) and Ti(OEt)4 (30 mL, 142.6 mmol) were added to a solution of cyclopropylcarboxaldehyde (24) (5 g, 71.3 mmol) in THF (142 mL). The reaction mixture was stirred at rt for 17 h after which brine (142 mL) was added and the resulting suspension was filtered through a pad of Celite. The filtrate was extracted with EtOAc (200 mL) and the organic phase was dried (Na2SO4), filtered and concentrated under vacuum to give 12.7 g (quant) of (R,E)-N-(cyclopropylmethylene)-2-methylpropane-2-sulfinamide (26). Retention time (min)=1.459 method [1], MS (m/z) 174.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[OH-].[Na+]>O.[Ni]>[OH:1][CH:2]1[CH2:10][CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3]1
Reactant: O=C(O)c1cccc(O)c1
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1CCCC(O)C1
Temperature: 150 °C
Reaction time: 8 h
Yield: 35.1 %

Procedure:
A 1 L pressure tank reactor (60 atm) containing a solution of 3-hydroxybenzoic acid (30 g, 217.20 mmol, 1.00 equiv), Raney Ni (5 g) and sodium hydroxide (6.4 g, 160.00 mmol, 0.74 equiv) in water (500 mL) was introduced H2 (gas, 60 atm) and the resulting solution was stirred overnight at 150° C. After completion of the reaction, the reaction temperature was cooled down to room temperature and the solids were filtered out by filtration. The resulting solution was neutralized with 12 M HCl, extracted with 6×100 mL of tetrahydrofuran. The combined organic layers were dried over sodium sulfate and concentrated under vacuum to provide 3-hydroxycyclohexane-1-carboxylic acid (11 g, crude) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([F:22])=[C:13]([CH:21]=2)[CH2:14][N:15]([CH2:19][CH3:20])[CH2:16][CH2:17][OH:18])[C:5]([Cl:23])=[CH:4][N:3]=1.[CH3:24][O:25][C:26]1[C:31]2[CH2:32][CH2:33][CH:34]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[CH2:35][CH2:36][C:30]=2[CH:29]=[CH:28][C:27]=1[NH2:43]>>[Cl:23][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([F:22])=[C:13]([CH:21]=2)[CH2:14][N:15]([CH2:19][CH3:20])[CH2:16][CH2:17][OH:18])=[N:7][C:2]([NH:43][C:27]2[CH:28]=[CH:29][C:30]3[CH2:36][CH2:35][CH:34]([N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)[CH2:33][CH2:32][C:31]=3[C:26]=2[O:25][CH3:24])=[N:3][CH:4]=1
Reactant: COc1c(N)ccc2c1CCC(N1CCOCC1)CC2
Reactant: CCN(CCO)Cc1cc(Nc2nc(Cl)ncc2Cl)ccc1F
Product: CCN(CCO)Cc1cc(Nc2nc(Nc3ccc4c(c3OC)CCC(N3CCOCC3)CC4)ncc2Cl)ccc1F

Procedure:
The title compound was prepared from 2-{[5-(2,5-Dichloro-pyrimidin-4-ylamino)-2-fluoro-benzyl]-ethyl-amino}-ethanol and 1-Methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine in an analogous manner to example 730 (0.042 g, 34%). Mp 81-83° C.; LCMS (m/e) 599 (M); 1H-NMR (DMSO, 400 MHz) δ 8.88 (s, 1H), 8.10 (s, 1H), 7.87 (s, 1H), 7.61-7.60 (d, 1H, J=5.56 Hz), 7.57-7.55 (d, 2H, J=8.33 Hz), 7.08-7.03 (t, 1H, J=9.09 Hz), 6.76-6.73 (d, 1H, J=8.59 Hz), 4.28 (t, 1H, J=5.00 Hz), 3.59-3.58 (d, 6H, J=4.55 Hz), 3.55-3.41 (s, 2H), 3.46-3.41 (q, 2H, J=6.82 Hz), 3.19-3.13 (m, 1H), 2.76-2.67 (m, 1H), 2.61-2.55 (t, 2H, J=11.37 Hz), 2.46 (s, 6H), 2.36-2.29 (t, 1H, J=12.12 Hz), 2.08-1.97 (m, 2H), 1.31-1.23 (m, 2H), 0.97-0.93 (t, 3H, J=7.07 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=3)[C:12]([F:23])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[CH2:29]([O:28][C:26]([CH:25]=[N:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:22]=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:17]=3)[C:12]([F:23])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1)=[O:27])[CH3:30]
Reactant: CCOC(=O)CBr
Reactant: Nc1cccc(Nc2ncc(F)c(Nc3cccc(N)c3)n2)c1
Product: CCOC(=O)C=Nc1cccc(Nc2ncc(F)c(Nc3cccc(N=CC(=O)OCC)c3)n2)c1

Procedure:
In like manner to the preparation of N2,N4-bis(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine, N2,N4-bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine and ethyl bromoacetate were reacted together to give N2,N4-bis(3-ethoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 23.41 min.; purity: 96.3%; MS (m/e): 483.08 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:12][C:13]([F:24])([F:23])[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[CH:17][CH:16]=1>CCO>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[N:22][NH:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][C:13]([F:12])([F:24])[F:23])=[CH:16][CH:17]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: NNc1ccc(OC(F)(F)F)cc1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(C=NNc2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a magnetically stirred solution of 4-nitrobenzaldehyde (1.57 g, 10.41 mmoL) dissolved in EtOH (21 mL) was added (4-(trifluoromethoxy)phenyl)-hydrazine (2 g, 10.41 mmoL) and the reaction was stirred at room temperature overnight. The solvent was concentrated under reduced pressure and dried under high vacuum to give the title compound as a mixture of E and Z-isomers (3.35 g, 99%): 1H NMR (400 MHz, CDCl3) δ 10.17 (s, 1H), 8.40 (d, J=8.6 Hz, 2H, isomer A), 8.24 (d, J=8.6 Hz, 2H, isomer B), 8.08 (d, J=8.7 Hz, 2H, isomer A), 7.79-7.74 (m, 4H, mixture of isomers A & B), 7.19-7.13 (m, 6H, mixture of isomers A & B); 19F NMR (376 MHz, CDCl3) δ −58.34; ESIMS m/z 325 ([M+H])+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][S:17][CH2:18][C@H:19]([O:35][C:36](=[O:48])[NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]CC)[CH2:20][O:21][C:22](=[O:34])[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]CC)[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:82][CH2:83][CH2:84][O:85][CH2:86][CH2:87][O:88][CH2:89][CH2:90][O:91][CH2:92][CH2:93][P:94](=[O:101])([O:98][CH2:99][CH3:100])[O:95][CH2:96][CH3:97]>C(Cl)Cl>[CH2:99]([O:98][P:94]([CH2:93][CH2:92][O:91][CH2:90][CH2:89][O:88][CH2:87][CH2:86][O:85][CH2:84][CH2:83][NH:82][C:13](=[O:14])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[CH2:16][S:17][CH2:18][C@H:19]([O:35][C:36](=[O:48])[NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:20][O:21][C:22](=[O:34])[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])(=[O:101])[O:95][CH2:96][CH3:97])[CH3:100]
Reactant: CCOP(=O)(CCOCCOCCOCCN)OCC
Reactant: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OC(=O)NCCCCCCCCCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC)OC(=O)NCCCCCCCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-2-(benzyloxycarbonylamino)-3-((R)-2,3-bis(decylcarbamoyloxy)propylthio)propanoic acid (1 eq) and HBTU (1.2 eq) in DCM (0.06 M) was added DIEA (2.4 eq), followed by diethyl 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethylphosphonate (1.2 eq, from example 18, step 4). The reaction was stirred at room temperature for 4 hours. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-10% MeOH/DCM to afford the title compound as an opaque oil.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]1(=[O:10])[O:9][CH2:8][CH2:7][CH2:6]1>CO>[OH:2][CH2:1][CH2:3][NH:4][C:8](=[O:9])[CH2:7][CH2:6][CH2:5][OH:10]
Reactant: NCCO
Reactant: O=C1CCCO1
Solvent: CO
Product: O=C(CCCO)NCCO

Procedure:
A solution of 24.4 gm (0.4 mole) of ethanolamine in 30 ml of methanol were slowly added dropwise with stirring to a solution of 34.4 gm (0.4 mole) of γ - butyrolactone in 50 ml of methanol. The temperature rose to 50° C. The mixture was subsequently heated for 3 hours at boiling and the methanol was distilled off under reduced pressure. A quantitative yield of N-(2-hydroxyethyl)-γ-hydroxybutyramide was obtained in the form of a colorless viscous liquid. The compound became crystalline after standing for a long period of time and melts at 54° to 56° C.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2].[C:25](OC)(OC)(OC)[CH3:26].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:25][C:26]1[N:14]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:9]2=[N:10][C:11]([CH3:13])=[CH:12][C:7]([NH:6][CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[C:8]2[N:24]=1
Reactant: COC(C)(OC)OC
Reactant: CCC(CC)Nc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(CC)Nc1cc(C)nc2c1nc(C)n2-c1c(C)cc(C)cc1C

Procedure:
A mixture of N4-(1-ethyl-propyl)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3,4-triamine (250 mg, 0.77 mmol), trimethyl orthoacetate (0.184 g, 1.532 mmol), p-toluenesulfonic acid monohydrate (0.01 g) in toluene was heated at reflux using Dean-Stark apparatus for 3 hours. The mixture was quenched with water, brine, extracted with ethyl acetate. The organic layer was separated, dried (MgSO4) and concentrated to dryness. After purification, the title compound was obtained as a white crystal, mp 101–103° C. Anal. For C22H30N4 calc. C, 75.39; H, 8.63; N, 15.98; found, C, 75.44; H, 8.95; N, 15.95.