Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:23])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:19][CH2:20][CH2:21][CH3:22])=[N:14][O:15][C:16]=2[CH:17]=[O:18])[CH:9]=1)=[O:4].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:23])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:19][CH2:20][CH2:21][CH3:22])=[N:14][O:15][C:16]=2[CH2:17][OH:18])[CH:9]=1)=[O:4]
Reactant: CCCCc1noc(C=O)c1COc1cc(C(=O)OC)n(C)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCc1noc(CO)c1COc1cc(C(=O)OC)n(C)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 45.8 %

Procedure:
To a solution of 5-(3-butyl-5-formyl-isoxazol-4-ylmethoxy)-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (80 mg, 0.25 mmol) in methanol (4 mL) was added sodium borohydride (18.8 mg, 0.5 mmol) in portions over 3 min. Upon addition, the reaction became a clear light yellow solution containing a black precipitate. After stirring at room temperature for 1.5 h, the mixture was filtered over Celite® and the filter cake was washed with methanol. The filtrate was concentrated and the residue was portioned between 0.5M aqueous hydrochloric acid and ethyl acetate. The aqueous phase was extracted two times with ethyl acetate and the combined organic phases were washed with brine, dried over sodium sulfate and concentrated to a yellow oil. The crude material was purified by chromatography (silica, heptane:acetone 7.5:2.5) to afford the title compound (37 mg, 46%) as a dark brown oil. MS: m/e=324.3 [M+H]+.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]1[CH:17]=[C:18]([CH:35]=[CH:36][CH:37]=1)[CH2:19][NH:20][CH2:21][C@@:22]12[CH2:34][CH2:33][CH2:32][N:23]1[C@@H:24]([C:28]([Cl:31])([Cl:30])[Cl:29])[O:25][C:26]2=[O:27].C=O.C(O)(=O)C>ClCCCl>[F:15][C:16]1[CH:17]=[C:18]([CH:35]=[CH:36][CH:37]=1)[CH2:19][N:20]([CH2:21][C@@:22]12[CH2:34][CH2:33][CH2:32][N:23]1[C@@H:24]([C:28]([Cl:30])([Cl:31])[Cl:29])[O:25][C:26]2=[O:27])[CH3:1]
Reactant: O=C1O[C@H](C(Cl)(Cl)Cl)N2CCC[C@@]12CNCc1cccc(F)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(Cc1cccc(F)c1)C[C@@]12CCCN1[C@@H](C(Cl)(Cl)Cl)OC2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium triacetoxyborohydride (889 mg, 4.19 mmol) was added to a mixture of (3R,7aR)-7a-[(3-fluoro-benzylamino)-methyl]-3-trichloromethyl-tetrahydro-pyrrolo[1,2-c]oxazol-1-one (Stage K.2, 400 mg, 1.048 mmol), formaldehyde (37% in H2O, 0.102 mL, 1.36 mmol) and acetic acid (0.150 mL, 2.62 mmol) in DCE (4 mL) under an argon atm. After 2 h stirring at rt the RM was partitioned between DCM and water. The combined organic layers were dried over Na2SO4 and evaporated to give the title compound as a pale brown oil which was used without further purification.
Reaction SMILES: [CH:1]1([C:6]2[CH:10]=[C:9]([NH:11][C:12]([NH:14][C:15]3[CH:20]=[C:19]([C:21]4[C:32](=[O:33])[N:31]([CH3:34])[C:24]5[N:25]=[C:26]([NH:29][CH3:30])[N:27]=[CH:28][C:23]=5[CH:22]=4)[C:18]([CH3:35])=[CH:17][C:16]=3[F:36])=[O:13])[N:8]([CH3:37])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:38][N:39]([CH3:43])[CH2:40]CN>C1COCC1.CCOC(C)=O>[CH:1]1([C:6]2[CH:10]=[C:9]([NH:11][C:12]([NH:14][C:15]3[CH:20]=[C:19]([C:21]4[C:32](=[O:33])[N:31]([CH3:34])[C:24]5[N:25]=[C:26]([NH:29][CH2:30][CH2:38][N:39]([CH3:43])[CH3:40])[N:27]=[CH:28][C:23]=5[CH:22]=4)[C:18]([CH3:35])=[CH:17][C:16]=3[F:36])=[O:13])[N:8]([CH3:37])[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CNc1ncc2cc(-c3cc(NC(=O)Nc4cc(C5CCCC5)nn4C)c(F)cc3C)c(=O)n(C)c2n1
Reactant: CN(C)CCN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(F)c(NC(=O)Nc2cc(C3CCCC3)nn2C)cc1-c1cc2cnc(NCCN(C)C)nc2n(C)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.2 %

Procedure:
A solution 1-(3-cyclopentyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea from Example 122 (80 mg, 0.15 mmol) in THF (1 mL) was treated with N,N-dimethylethylenediamine (0.080 mL, 0.74 mmol). The reaction was stirred 1 h at RT, diluted with EtOAc (15 mL) and washed with 2 M aq Na2CO3 (2×10 mL), water (10 mL) and brine (10 mL). The organics were dried (Na2SO4), concentrated in vacuo and chromatographed on reverse phase silica gel to provide 1-(3-cyclopentyl-1-methyl-1H-pyrazol-5-yl)-3-(5-(2-(2-(dimethylamino)ethylamino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluoro-4-methylphenyl)urea (33 mg, 39% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.87 (s, 1H), 8.72 (d, J=2.0 Hz, 1H), 8.65 and 8.60 (br s, 1H), 7.91 (d, J=8.6 Hz, 1H), 7.75 and 7.59 (m, 1H), 7.66 (s, 1H), 7.14 (d, J=8.4 Hz, 1H), 5.98 (s, 1H), 3.59-3.43 (m, 8H), 2.86 (m, 1H), 2.21 (br s, 6H), 2.49 (m, 2H obscured by solvent), 2.06 (s, 3H), 1.87 (m, 2H), 1.66-1.48 (m, 6H); MS (ESI) m/z: 562.3 (M+H+).
Reaction SMILES: CC1(C)CCC2([C:8](=[O:9])[O:7][C:6](=[O:10])[CH2:5]2)C1.[CH3:14][C:15]1([CH3:21])[CH2:19][CH2:18][CH2:17][C:16]1=O>>[CH3:14][C:15]1([CH3:21])[CH2:19][CH2:18][CH2:17][C:16]21[C:8](=[O:9])[O:7][C:6](=[O:10])[CH2:5]2
Reactant: CC1(C)CCCC1=O
Reactant: CC1(C)CCC2(CC(=O)OC2=O)C1
Product: CC1(C)CCCC12CC(=O)OC2=O

Procedure:
The title compound was prepared using methods analogous to 7,7-dimethyl-2-oxaspiro[4.4]nonane-1,3-dione using 2,2-dimethylcyclopentanone in Step A. 1H NMR (500 MHz, DMSO-d6) δ 3.18-2.94 (m, 2H), 2.34-2.18 (m, 1H), 1.98-1.64 (m, 4H), 1.62-1.48 (m, 1H), 0.95 (s, 3H), 0.93 (s, 3H).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.Cl.C[O:15][C:16]([C:18]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:17].ON1C2C=CC=CC=2N=N1.[CH2:35]([O:37][C:38]1[CH:42]=[CH:41][S:40][C:39]=1[C:43](O)=[O:44])[CH3:36].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:35]([O:37][C:38]1[CH:42]=[CH:41][S:40][C:39]=1[C:43]([NH:24][C:18]1([C:16]([OH:15])=[O:17])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:44])[CH3:36]
Reactant: COC(=O)C1(N)CCCCC1
Reactant: CCOc1ccsc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1ccsc1C(=O)NC1(C(=O)O)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
633 mg (3.3 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to a solution of 581 mg (3 mmol) of 1-aminocyclohexanecarboxylic acid methyl ester hydrochloride, 482 mg (3.1 mmol) of 1-hydroxybenzotriazole, 517 mg (3 mmol) of 3-ethoxy-2-thiophenecarboxylic acid and 1.16 g (9 mmol) of diisopropylethylamine in 10 ml of methylene chloride under ice-cooling. After the solution was stirred at room temperature overnight, the reaction solution was concentrated under reduced pressure, ethyl acetate was added thereto, and the mixture was washed with water, a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and then saturated brine, followed by drying with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, diisopropyl ether was added to the residue, followed by stirring overnight and the crystal was collected by filtration. Subsequently, the obtained crystal was dissolved in 3 ml of tetrahydrofuran solution, 2.8 ml of 2N—NaOH aqueous solution was added thereto, and the mixture was refluxed under heating for 3 hours. Ether was added to the reaction solution and the aqueous layer was separated. After the separated aqueous layer was neutralized by concentrated hydrochloric acid, the layer was extracted with ethyl acetate. After the obtained organic layer was washed with saturated brine, it was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 656 mg (73%) of the title compound.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[CH3:5][O:6][C:7]1[C:11](=[O:12])[N:10]([CH3:13])[CH2:9][C:8]=1[C:14]([OH:16])=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:5][O:6][C:7]1[C:11](=[O:12])[N:10]([CH3:13])[CH2:9][C:8]=1[C:14]([NH:4][CH2:1][C:2]#[CH:3])=[O:16]
Reactant: COC1=C(C(=O)O)CN(C)C1=O
Reactant: C#CCN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: C#CCNC(=O)C1=C(OC)C(=O)N(C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
To a solution of prop-2-yn-1-amine (0.43 mL, 7.7 mmol), 4-methoxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (1.2 g, 7.0 mmol) and PyBOP® (4.01 g, 7.71 mmol) in DMF (25 mL) was added diisopropylethylene amine (3.67 mL, 21.0 mmol) and the reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated and purified by ISCO chromatography (ethyl acetate/hexane 1-100%, column 40 g cartridge) to afford Intermediate 21 (1.2 g, 82%) as a white paste. HPLC/MS (Method L) RT=0.99 min, [M+1]+ 209.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C=Cc1ccc(OC)nc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(OC)nc1
Yield: 100.2 %

Procedure:
Ethyl 3-(6-methoxy-3-pyridyl)acrylate (32.33 g) in ethanol (160 ml) was hydrogenated at 344 kPa and 40° using palladium-on-charcoal catalyst (5%, 0.2 g). The mixture was filtered and the filtrate was evaporated to give ethyl 3-(6-methoxy-3-pyridyl)propionate (32.7 g) as an oil.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:24](=[O:25])[N:20]3[CH2:21][CH2:22][CH2:23][N:19]3[C:18]=2[C:26]2[CH:31]=[CH:30][N:29]=[C:28](S(C)(=O)=O)[N:27]=2)=[CH:13][CH:12]=1>C1COCC1.C([O-])(O)=O.[Na+]>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:24](=[O:25])[N:20]3[CH2:21][CH2:22][CH2:23][N:19]3[C:18]=2[C:26]2[CH:31]=[CH:30][N:29]=[C:28]([O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:27]=2)=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)c1nccc(-c2c(-c3ccc(F)cc3)c(=O)n3n2CCC3)n1
Reactant: Oc1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1c(-c2ccc(F)cc2)c(-c2ccnc(Oc3ccccc3)n2)n2n1CCC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38 %

Procedure:
To a solution of phenol (0.66 g, 7.08 mmol) in THF (5 mL) is added NaH (0.24 g, 5.91 mmol) followed by a solution of the crude 2-(4-fluorophenyl)-3-(2-methanesulfonyl-pyrimidin-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazol-1-one, 5, prepared herein above (0.25 g, 0.67 mmol) in THF (2 mL). The reaction mixture is stirred for 1.5 hours at room temperature, diluted with aqueous NaHCO3 and extracted with twice with ethyl acetate. The organic layers are combined, dried over MgSO4, and concentrated in vacuo to afford the crude product which is purified over silica (100% EtOAc, followed by 10% MeOH/EtOAc) to provide 0.35 g (38% yield) of the desired product as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.47 (d, J=5.1 Hz, 1H), 7.49 (dd, J=7.8, 7.8 Hz, 2H), 7.40 (ddd, J=5.4, 5.4 Hz, 2H), 7.35-7.22 (m, 3H), 7.10 (dd, J=8.4, 8.4 Hz, 2H), 6.90 (d, J=6.8 Hz, 1H), 4.05 (t, J=7.2 Hz, 2H), 3.86 (t, J=7.2 Hz, 2H), 2.59 (dt, J=7.2, 7.2 Hz, 2H); HRMS calcd for C22H18FN4O2 (M+H)+ 389.1414; found 389.1407. This compound corresponds to analog 1 from Table I.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[C:15]([NH:19][C:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][N:23]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([NH:19][C:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)[CH:4]=2)=[O:27])=[CH:24][N:23]=1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CC(C)(C)NC(=O)c1ccc(C(=O)O)cn1
Product: CC(C)(C)NC(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cn1

Procedure:
250 mg of 5-(methoxycarbonyl)picolinic acid was coupled to tert-butylamine via Procedure G. Crude methyl 6-(tert-butylcarbamoyl)nicotinate was hydrolyzed via Procedure M to yield 250 mg of 6-(tert-butylcarbamoyl)nicotinic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 6-(tert-butylcarbamoyl)nicotinic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield N2-tert-butyl-N5-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-2,5-dicarboxamide. MS (Q1) 409 (M)+.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[CH:16][CH:17]=[C:18](I)[C:9]=2[C:8]1=[O:20].[F:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[CH:16][CH:17]=[C:18]([C:34]3[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=3)[C:9]=2[C:8]1=[O:20]
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C1c2c(I)ccnc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C1c2c(-c3ccc(F)cc3)ccnc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 100.7 %

Procedure:
In a similar manner to Reference Example 4, 5-[3,5-bis(trifluoromethyl)benzyl]-7-iodo-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (300 mg) was reacted with 4-fluorophenylboronic acid (143 mg) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (284 mg, 100%).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]2[O:7][CH2:8][C:9]([CH3:13])([CH3:12])[CH2:10][O:11][C:5]=2[CH:4]=1)#[CH:2].I[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1>>[CH3:13][C:9]1([CH3:12])[CH2:8][O:7][C:6]2[CH:14]=[CH:15][C:3]([C:1]#[C:2][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[CH:4][C:5]=2[O:11][CH2:10]1
Reactant: Oc1ccc(I)cc1
Reactant: C#Cc1ccc2c(c1)OCC(C)(C)CO2
Product: CC1(C)COc2ccc(C#Cc3ccc(O)cc3)cc2OC1

Procedure:
The title compound is prepared in analogy to example 1 from 7-ethynyl-3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepine (6) (example 1d) and 4-iodo-phenol as a brown solid. MS (ESI) 293.1 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:26])[CH3:25])=[CH:19][CH:18]=1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([F:43])[C:29]=1[OH:44]>>[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]3[NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:25])[CH3:26])=[CH:19][CH:18]=2)[CH:31]=[C:30]([F:43])[C:29]=1[OH:44]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CCC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(CN(C)C)cc1
Product: CCC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1Nc1ccc(CN(C)C)cc1
Yield: 62.1 %

Procedure:
Following general procedure M, 1-(6-bromo-4-((4-((dimethylamino)methyl)phenyl)amino)quinolin-3-yl)propan-1-one (125 mg, 0.30 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (91 mg, 0.33 mmol) to afford the desired product (89 mg, 62%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.02 (s, 1H), 8.09-7.88 (m, 3H), 7.35-7.18 (m, 4H), 7.16-7.09 (m, 2H), 3.42 (s, 2H), 3.09 (q, J=7.1 Hz, 2H), 2.14 (s, 6H), 0.98 (t, J=7.1 Hz, 3H). APCI MS m/z 478 [C27H25ClFN3O2+H]+; HPLC>99% (AUC), tR=8.10 min.
Reaction SMILES: [CH3:1][N:2]([CH:4]=[O:5])[CH3:3].[Br:6][C:7]1C(O)=NC=[C:11]([I:13])[CH:12]=1.CI.C([O-])([O-])=O.[K+].[K+]>O>[Br:6][C:7]1[C:4](=[O:5])[N:2]([CH3:3])[CH:1]=[C:11]([I:13])[CH:12]=1
Reactant: Oc1ncc(I)cc1Br
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: Cn1cc(I)cc(Br)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with DMF (50 mL), 142a (6.0 g, 20.0 mmol), CH3I (4.26 g, 30.0 mmol), and K2CO3 (5.52 g, 40.0 mmol). The mixture was stirred at room temperature for 2 h and diluted with water (200 mL). The resulting white solid was collected by filtration to afford 142b (5.97 g, 95%) as a white solid. MS-ESI: [M+H]+ 314
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Cl:9][CH2:10][CH2:11][C:12](Cl)=[O:13]>>[Cl:9][CH2:10][CH2:11][C:12]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1)=[O:13]
Reactant: Nc1ccc(F)cc1
Reactant: O=C(Cl)CCCl
Product: O=C(CCCl)Nc1ccc(F)cc1

Procedure:
By using 4-fluoroaniline and 3-chloropropionyl chloride, the title compound was obtained by similar procedures to those of Example 42a (yield: 57%).
Reaction SMILES: [BH4-].[Na+].CO.[CH2:5]([N:7]1[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]2[CH:19]=[C:20]([CH2:23][N:24]([CH2:38][C:39]3[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=3[CH:41]=[O:42])[CH2:25][CH2:26][N:27]3[CH:32]=[CH:31][C:30]4[O:33][C:34]([CH3:36])=[CH:35][C:29]=4[C:28]3=[O:37])[CH:21]=[CH:22][C:8]1=2)[CH3:6]>O>[CH2:5]([N:7]1[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]2[CH:19]=[C:20]([CH2:23][N:24]([CH2:38][C:39]3[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=3[CH2:41][OH:42])[CH2:25][CH2:26][N:27]3[CH:32]=[CH:31][C:30]4[O:33][C:34]([CH3:36])=[CH:35][C:29]=4[C:28]3=[O:37])[CH:21]=[CH:22][C:8]1=2)[CH3:6]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCn3ccc4oc(C)cc4c3=O)Cc3ccccc3C=O)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCn3ccc4oc(C)cc4c3=O)Cc3ccccc3CO)ccc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 70.9 %

Procedure:
Sodium borohydride (47 mg) were added to a methanol solution(10 ml) of 2-({N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)benzaldehyde (0.59 g) and the mixture was stirred for 3 hours at 0° C. Water was added to the reaction mixture, followed by extraction by ethyl acetate. The organic layer was dried by anhydrous sodium sulfate, and condensed under reduced pressure. The residue was recrystallized from ethyl acetate-ether mixture to give the title compound(0.42 g) as a pale brown white powder.
Reaction SMILES: [OH-].[Na+].[C:3]1([P:9]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][PH:17](=[O:23])[O:18]CC(C)C)=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>O.C1COCC1>[C:3]1([P:9]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][PH:17](=[O:18])[OH:23])=[CH:12][CH:11]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)CO[PH](=O)Cc1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=[PH](O)Cc1ccc(P(c2ccccc2)c2ccccc2)cc1
Temperature: 23 °C
Reaction time: 0.17 h
Yield: 95.6 %

Procedure:
8.70 g (2127.5 mmol) of NaOH in 40 ml of water were added dropwise at 23° C. to a solution of 34.52 g (87 mmol) of isobutyl (4-diphenylphosphino-phenyl)methylphosphinate in 50 ml of THF. After heating under reflux for 6 hours, 18.1 ml (218 mmol) of concentrated hydrochloric acid were added dropwise at 23° C., the mixture was stirred for 10 minutes at 23° C. and completely evaporated on a rotary evaporator. The residue is taken up in methylene chloride, the solution was dried over Na2SO4 and completely evaporated. Drying under reduced pressure gave 28.3 g of (4-diphenylphosphinophenyl)methylphosphinic acid (90% of theory) in the form of a pale yellow solid having a melting point of 40° C.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:16])O[C:10](C)(C)[O:11][C:12]=2[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=[N:18][C:19]([CH3:29])([C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=1)[CH3:20]>>[CH3:13][C:12]1[O:11][CH2:10][N:18]([C:19]([CH3:29])([C:21]2[CH:22]=[C:23]([Cl:28])[CH:24]=[C:25]([Cl:27])[CH:26]=2)[CH3:20])[C:8](=[O:16])[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=NC(C)(C)c1cc(Cl)cc(Cl)c1
Reactant: CC1=C(c2ccccc2)C(=O)OC(C)(C)O1
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)c2cc(Cl)cc(Cl)c2)CO1
Temperature: 150 °C
Yield: 80.3 %

Procedure:
Then, a mixture of 5-phenyl-2,2,6-trimethyl-2H,4H-1,3-dioxin-4-one (0.65 g) and N-methylene-1-methyl-1-(3,5-dichlorophenyl)ethylamine (0.65 g) said above was refluxed at 150° C. for 30 minutes for reaction. The reaction mixture was subjected to recrystallization from a mixed solvent of hexane and ethyl acetate to obtain the captioned compound (0.90 g).
Reaction SMILES: [Li]CCCC.[CH3:6][C:7]([O-:10])(C)[CH3:8].[K+].[Cl:12][C:13]1[CH:14]=[C:15]([F:20])C=[C:17]([Cl:19])[CH:18]=1.C(=O)C>C1COCC1>[Cl:19][C:17]1[CH:18]=[C:13]([Cl:12])[CH:14]=[C:15]([F:20])[C:6]=1[CH:7]([OH:10])[CH3:8]
Reactant: Fc1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)[O-]
Agent: CC=O
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)c1c(F)cc(Cl)cc1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of n-BuLi (4.8 mL, 12 mmol, 2.5 M solution in hexane) was added to THF (50 mL) at −78° C. under nitrogen, followed by the addition of 1.0 M KOtBu in THF (12 mL, 12 mmol). The mixture was stirred at −78° C. for 30 min, then 3,5-dichlorofluorobenzene (1.65 g, 10.0 mmol) in THF (5 mL) was added slowly, and the resulting mixture was stirred at this temperature for 30 min. Then a solution of acetaldehyde (0.88 g, 20 mmol) in THF (5 mL) was added. The mixture was slowly warmed to rt. The mixture was quenched with water (10 mL), and diluted with EtOAc (50 mL). The organic phase was separated, washed with brine (10 mL), and dried over anhydrous sodium sulfate. The crude material was purified by silica gel chromatography (Hex:EtOAc=95:5→90:10) to give the title compound as a colorless oil. 1H NMR (CDCl3): δ=1.62 (d, J=6.8 Hz, 3H), 2.30 (br s, 1H, —OH), 5.35 (q, J=6.8 Hz, 1H), 7.05 (dd, J=10.6, 2.0 Hz, 1H), 7.20 (m, 1H).
Reaction SMILES: [CH:1]1([N:6]2[CH2:10][CH2:9][CH2:8][CH:7]2[CH2:11][NH2:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:13][O:14][C:15]1[C:23]([CH:24]([CH3:26])[CH3:25])=[CH:22][C:21]([S:27](=[O:30])(=[O:29])[NH2:28])=[C:20]([CH3:31])[C:16]=1[C:17](Cl)=[O:18]>CC(CC)=O>[CH:1]1([N:6]2[CH2:10][CH2:9][CH2:8][CH:7]2[CH2:11][NH:12][C:17](=[O:18])[C:16]2[C:20]([CH3:31])=[C:21]([S:27](=[O:30])(=[O:29])[NH2:28])[CH:22]=[C:23]([CH:24]([CH3:26])[CH3:25])[C:15]=2[O:14][CH3:13])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCC1CCCN1C1CCCC1
Reactant: COc1c(C(C)C)cc(S(N)(=O)=O)c(C)c1C(=O)Cl
Solvent: CCC(C)=O
Product: COc1c(C(C)C)cc(S(N)(=O)=O)c(C)c1C(=O)NCC1CCCN1C1CCCC1
Yield: 16.5 %

Procedure:
3.4 g of 1-cyclopentyl-2-aminomethylpyrrolidine (0.020 mole) and 40 ml of methyl-ethyl-ketone are placed in a 250 flask fitted with an agitator, a thermometer and a dropping funnel. The mixture is cooled to about +10° C., then a solution of 5.5 g of 2-methoxy-3-isopropyl-5-sulphamoyl-6-methylbenzoyl chloride (0.018 mole) in 40 ml of methyl-ethyl-ketone is poured in drop by drop. The mixture is reacted 1 hour at room temperature, then the solvent is evaporated under vacuum and the residue dissolved in 100 ml of hydrochloric acid (density 1.18). An insoluble rubbery product is filtered off, and the filtrate is made alkaline with 15 ml of ammonia (density 0.91). The precipitate formed is filtered, washed with water then re-crystallised in 30 ml of ethyl acetate. The crystals are filtered, washed with a little solvent and dried in an oven at 50°046732772 C. 1.3 g (17%) of product is obtained, melting at 196° C.