Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[CH2:4][C@@H:5]([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7].Cl[C:26](=[O:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28].C(N(CC)CC)C>CN(C=O)C>[C:16]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]=[CH:14][C:13]([CH2:12][C@@H:3]([NH:2][C:26](=[O:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:4][C@@H:5]([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:18][CH:17]=1
Reactant: CCOC(=O)[C@H](C)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)C(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@H](C)C(=O)OCC
Reaction time: 1 h
Yield: 82.1 %

Procedure:
To a solution of (2R,4S)-ethyl 4-amino-5-(biphenyl-4-yl)-2-methylpentanoate hydrochloride salt (1 g, 2.87 mmol) in DMF (10 mL) is added TEA (0.42 mL, 3.02 mmol) followed by ethyl 2-chloro-2-oxoacetate (392 mg, 2.87 mmol). The crude is stirred at it for 1 hr. To the crude is added an additional 0.2 ml of ethyl 2-chloro-2-oxoacetate followed by triethylamine (1.26 mL, 9.06 mmol). The crude is quenched with water and diluted in EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered, and concentrated. The crude is purified via flash chromatography using 30% EtOAc/heptane to 50% EtOAc/heptane to give (2R,4S)-ethyl 5-(biphenyl-4-yl)-4-(2-ethoxy-2-oxoacetamido)-2-methylpentanoate (970 mg).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([CH3:28])([CH3:27])[CH2:21][NH:22][C:23]2=[O:26])=[CH:18][CH:17]=1.[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1.C(O)(=O)C>ClCCl>[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([CH3:28])([CH3:27])[CH2:21][NH:22][C:23]3=[O:26])=[CH:18][CH:17]=2)=[CH:32][CH:31]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC1(C)CNC(=O)c2cc(N)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC1(C)CNC(=O)c2cc(NCc3ccc(Cl)cc3)ccc21
Reaction time: 8 h
Yield: 38.7 %

Procedure:
Sodium triacetoxyborohydride (800 mg, 3.79 mmol) was added to a stirred solution of 7-amino-4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-one (220 mg, 1.15 mmol), 4-chlorobenzaldehyde (324 mg, 2.31 mmol) and acetic acid (69 μl, 1.15 mmol) in anhydrous dichloromethane (10 ml) at room temperature. The reaction was stirred overnight and quenched with the addition of water. The organic phase was separated, washed with brine, then dried (MgSO4) and evaporated in vacuo. The resulting residue was purified by flash column chromatography (20% ethyl acetate in dichloromethane) to afford the title compound as a light brown solid (140 mg, 39%). HPLC retention time 4.40 min. Mass spectrum (ES+) m/z 315 (M+H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=2)[CH2:4][CH2:3]1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[N:19]=1>>[F:32][C:17]([F:16])([F:33])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26]([N:2]2[CH2:3][CH2:4][CH:5]([C:8]3[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=3)[CH2:6][CH2:7]2)=[O:27])[N:19]=1
Reactant: N#Cc1ccc(C2CCNCC2)nc1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Agent: Cl
Product: N#Cc1ccc(C2CCN(C(=O)c3cccc(-c4noc(C(F)(F)F)n4)c3)CC2)nc1
Yield: 30 %

Procedure:
This compound was synthesized from 6-(piperidin-4-yl)nicotinonitrile hydrochloride and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (50 mg, yield 30%). 1H NMR (400 MHz, CDCl3) δ 8.84 (d, J=2.0 Hz, 1H), 8.20-8.19 (m, 2H), 7.95-7.92 (dd, J=8.2 Hz, 2.1 Hz, 1H), 7.67-7.59 (m, 2H), 7.33 (d, J=8.3 Hz, 1H), 4.92 (m, 1H), 3.91 (m, 1H), 3.24 (m, 1H), 3.09 (m, 1H), 2.97 (m, 1H), 2.09 (m, 1H), 1.94-1.83 (m, 3H). MS (ESI) m/z: Calculated for C21H16F3N6O2: 427.13. found: 428.2 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([OH:14])=[O:13])[CH2:6][CH2:5]2.C(Cl)(=O)C(Cl)=O.ClCCl.[N+:24]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)([O-:26])=[O:25]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([O:14][C:30]1[CH:31]=[CH:32][C:27]([N+:24]([O-:26])=[O:25])=[CH:28][CH:29]=1)=[O:13])[CH2:6][CH2:5]2
Reactant: O=C(O)C1CCc2cc(F)ccc2O1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)C1CCc2cc(F)ccc2O1
Temperature: 25 °C
Reaction time: 17 h
Yield: 40.5 %

Procedure:
A 50 ml rbf was charged with 6-fluoro-3,4-dihydro-2H-chromen-2-carboxylic acid (10.0 g, 51.0 mmol), oxalyl chloride (9.71 g, 76.5 mmol) and dichloromethane (24.9 g) under nitrogen atmosphere at room temperature. The mixture was stirred for 17 h at room temperature and then concentrated in vacuo at 30° C. The residue was dissolved in toluene (75 ml) and stirred at rt. 4-nitrophenol (7.05 g, 51.02 mmol) was added to the reaction mixture, followed by pyridine (5 ml) over the period of 5 min. The slurry was heated to 80° C., stirred for 3 h at this temperature and then cooled to 25° C. The solid was separated by filtration and the filtered solution washed with 2M aqueous sodium hydroxide (65 g), with a saturated solution of sodium bicarbonate (2×51 g), and with demi water (53 g). The separated organic phase was concentrated in vacuo and dried via azeotropic distillation to furnish 4-nitrophenyl 6-fluoro-3,4-dihydro-2H-chromen-2-carboxylate as a vetrous oil (7.71 g, 40.5% yield, 85.0 A %).
Reaction SMILES: [C:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:28]=[CH:27][C:18]3[C:19](=[O:26])[CH:20]=[C:21]([C:23]([OH:25])=[O:24])[O:22][C:17]=3[CH:16]=2)=[CH:6][C:5]=1[OH:31])(=[O:3])[CH3:2].C(=O)(O)[O-].[Na+:36]>O>[Na+:36].[C:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:28]=[CH:27][C:18]3[C:19](=[O:26])[CH:20]=[C:21]([C:23]([O-:25])=[O:24])[O:22][C:17]=3[CH:16]=2)=[CH:6][C:5]=1[OH:31])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(OCCCCCOc2ccc3c(=O)cc(C(=O)O)oc3c2)cc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)c1ccc(OCCCCCOc2ccc3c(=O)cc(C(=O)[O-])oc3c2)cc1O

Procedure:
A mixture of 3.35 parts of 7-[5-(4-acetyl-3-hydroxyphenoxy) pentyloxy]-4-oxo-4H-1-benzopyran-2-carboxylic acid and 0.66 parts of sodium bicarbonate in 200 parts of water, was heated to effect solution. The solution was filtered while hot and on cooling a white solid crystallised. This was filtered, washed with ice-cold water and dried under vacuum over phosphorus pentoxide to yield 3.0 parts of 7-[5-(4-acetyl-3-hydroxyphenoxy) pentyloxy]-4-oxo-4H-1-benzopyran-2-carboxylic acid sodium salt, melting point 210° C. (indefinite).
Reaction SMILES: C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:16]([N:20]1[C:24]([C:25]#[N:26])=[C:23]([C:27](O)=[O:28])[N:22]=[C:21]1[N:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1)[C:17]#[C:18][CH3:19]>O1CCCC1>[CH2:16]([N:20]1[C:24]([C:25]#[N:26])=[C:23]([CH2:27][OH:28])[N:22]=[C:21]1[N:30]1[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:35]1)[C:17]#[C:18][CH3:19]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C(=O)O)c1C#N
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(CO)c1C#N
Temperature: -10 °C
Reaction time: 1 h

Procedure:
6.9 g of triethylamine and then 100 ml tetrahydrofuran solution of 10.19 g of isobutyl chloroformate were added dropwise to 600 ml of tetrahydrofuran containing 22.9 g of t-butyl 4-[1-(2-butynyl)-4-carboxy-5-cyano-1H-imidazol-2-yl]piperazine-1-carboxylate at −10° C. After the precipitate had been removed by filtration, the solution was again cooled to −10° C. A 100 ml aqueous solution of 9.45 g of sodium borohydride was added dropwise to the solution. After one hour, 500 ml of ethyl acetate and 500 ml of water were added to the solution. The pH of the solution was adjusted to 5 using 1 N hydrochloric acid, and then adjusted to 10 using a saturated sodium bicarbonate solution. The organic layer was washed successively with 500 ml of water and 500 ml of a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 19.1 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (4:1).
Reaction SMILES: [H-].[Na+].[CH:3](=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:6].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>CN(C)C=O.CCCCCC>[CH2:22]([O:6][C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[CH:3]=[O:11])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CCCCCCCCCCCBr
Reactant: O=Cc1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCCCCCCCCCCOc1ccccc1C=O

Procedure:
To a stirred suspension of sodium hydride (10.0 mmoles), which was prewashed with petroleum ether, in sieve dried dimethylformamide (10 ml) was added dropwise a solution of salicylaldehyde (10.1 mmoles) in dimethylformamide (1 ml). To the reaction mixture was then added undecyl bromide (10.0 mmoles) and the mixture stirred for 16 hours at ambient temperature under nitrogen. The reaction mixture was taken up in hexane (50 ml) and washed with 10 percent sodium hydroxide (2×50 ml) and saturated sodium chloride (50 ml). The organic phase was dried over anhydrous magnesium sulfate and charcoal. Evaporation of the volatiles yielded a colorless liquid which was purified by flash chromatography over silica gel with 2 percent ethyl acetate in hexane as eluant to afford the desired product as an oil.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[C:17]([Zn]C#N)#[N:18]>CN(C=O)C.O.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>[F:14][C:13]([F:16])([F:15])[C:10]1[CH:11]=[CH:12][C:7]([C:6]2[O:5][CH:4]=[N:3][C:2]=2[C:17]#[N:18])=[CH:8][CH:9]=1
Reactant: N#C[Zn]C#N
Reactant: FC(F)(F)c1ccc(-c2ocnc2Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ncoc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 240.6 %

Procedure:
A mixture of Example 56B (500 mg, 1.71 mmol), dicyanozinc (221 mg, 1.88 mmol), and Pd(Ph3P)4 (101 mg, 0.087 mmol) in DMF (3 mL) was heated in a microwave reactor to 160° C. for 6 min. The reaction mixture was cooled to ambient temperature, diluted with water (50 mL) and extracted with EtOAc. The combined organic extracts were filtered through celite, and the filtrate was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. An identical reaction was then performed using Example 56B (1.0 g, 3.4 mmol), dicyanozinc (442 mg, 3.77 mmol), and Pd(Ph3P)4 (198 mg, 0.171 mmol) in DMF (6 mL). The crude product from both reactions was combined and purified by chromatography on silica gel (25% EtOAc/hexanes) to afford 980 mg (80%) of the title compound as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.10 (dd, J=8.9, 0.7, 2H), 8.00 (s, 1H), 7.81 (dd, J=8.7, 0.5, 2H). MS (DCI+) m/z 256 (M+NH4).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[N:35]=[C:36]=[O:37]>O1CCCC1>[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[NH:35][C:36]([N:15]1[CH2:16][CH2:17][N:12]([C:10]2[S:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:11]=2)[CH2:13][CH2:14]1)=[O:37]
Reactant: O=C=Nc1ccc2ccccc2c1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2ccccc2c1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 2-naphthyl isocyanate (206 mg, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 176 mg (52.2%) of the desired product as a solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[CH2:11]=O>C1COCC1>[C:5]1([CH:3]2[O:4][CH2:11][NH:1][CH2:2]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C=O
Reactant: NCC(O)c1ccccc1
Solvent: C1CCOC1
Product: c1ccc(C2CNCO2)cc1
Temperature: 25 °C
Yield: 91 %

Procedure:
A mixture of 2-amino-1-phenylethanol (1.000 g, 0.007 mmol) and formaldehyde (37%, 0.92 mL, 0.012 mmol) in THF (10 mL) was heated to reflux for 3 h and allowed to cool to ambient temperature with stirring over night. The mixture was concentrated and the residue was dissolved in dichloromethane. The resulting solution was washed with water. The organic phase was dried over anhydrous sodium sulphate, concentrated in vacuo. The yellowish residue was purified by column chromatography to obtain the title compound in 91% yield (0.990 g). MS (ES+) m/z 419.2 (M+1).
Reaction SMILES: [C:1]([NH:3][C:4](=[N:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([O:23][CH3:24])[CH:14]=1)OC1C=CC=CC=1)#[N:2].[CH:25]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26]1.C(N(CC)CC)C>C(#N)C>[C:1]([NH:3][C:4]([NH:30][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)=[N:12][C:13]1[CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:16]=[C:15]([O:23][CH3:24])[CH:14]=1)#[N:2]
Reactant: NC1CCCC1
Reactant: COc1cc(N=C(NC#N)Oc2ccccc2)cc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cc(N=C(NC#N)NC2CCCC2)cc(C(F)(F)F)c1
Temperature: 75 °C
Reaction time: 19 h
Yield: 64.8 %

Procedure:
To a solution of N-Cyano-N'-(3-methoxy-5-trifluoromethyl-phenyl)-O-phenylisourea (0.52 mmol, 175 mg) in dry acetonitrile (1 ml), cyclopentylamine (1.04 mmol, 0.113 ml) and triethylamine (0.080 ml) were added. The mixture was stirred for 19 h at 75° C. under nitrogen. After concentration the residue was dissolved in dichloromethane, washed with 1 N aqueous HCl (2×), water, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (ethyl acetate/heptane 1:2) to give a syrup. Crystallisation from ethyl acetate/heptane 1:4 gave grey crystals (110 mg, 65%). Mp 101-102° C.; 1H-NMR (CDCl3): δ 1.40 (m, 2H), 1.65 (m, 4H), 2.02 (m, 2H), 4.13 (sextet, 1H), 5.05 (br, 1H), 6.96 (s, 1H), 7.00 (s, 1H), 7.03 (s, 1H), 8.15 ppm (br, 1H); EI SP/MS: 326 (M+).
Reaction SMILES: [ClH:1].Cl.Br[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH:12][C@@H:13]2[CH2:18][CH2:17][C@H:16]([NH:19][C:20]3[N:29]=[C:28]([N:30]([CH3:32])[CH3:31])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)[CH2:15][CH2:14]2)=[C:6]([O:33][C:34]([F:37])([F:36])[F:35])[CH:5]=1.Cl>CCO.CCOC(C)=O.[Pd]>[ClH:1].[ClH:1].[CH3:32][N:30]([CH3:31])[C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]([NH:19][C@H:16]2[CH2:17][CH2:18][C@@H:13]([NH:12][CH2:11][CH2:10][C:7]3[CH:8]=[CH:9][CH:4]=[CH:5][C:6]=3[O:33][C:34]([F:37])([F:36])[F:35])[CH2:14][CH2:15]2)[N:29]=1
Reactant: CN(C)c1nc(N[C@H]2CC[C@@H](NCCc3ccc(Br)cc3OC(F)(F)F)CC2)nc2ccccc12
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(C)c1nc(N[C@H]2CC[C@@H](NCCc3ccccc3OC(F)(F)F)CC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of cis-N2-{4-[2-(4-bromo-2-trifluoromethoxy-phenyl)-ethylamino]-cyclohexyl}-N4,N4-dimethyl-quinazoline-2,4-diamine dihydrochloride obtained in step B of example 37 (250 mg, 0.4 mmol) in EtOH (5 mL) was added 10% Pd/C (75 mg). The mixture was stirred at ambient temperature under hydrogen atmosphere for 17 hr, filtered, poured into saturated aqueous NaHCO3. The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (NH-silica gel, 50% EtOAc in hexane) to give a colorless oil. To a solution of above oil in EtOAc (4 mL) was added 4 M hydrogen chloride in EtOAc (0.25 mL). The mixture was stirred at ambient temperature for 1 hr and concentrated. The residue was suspended with Et2O (15 mL) and stirred at ambient tempareture for 1 hr. The solid was collected by filtration, washed with Et20, and dried under reduced pressure to give cis-N4,N4-dimethyl-N2-{4-[2-(2-trifluoromethoxy-phenyl)-ethylamino]-cyclohexyl}-quinazoline-2,4-diamine dihydrochloride (104 mg, 48%) as a white solid.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][O:8][C:9]([C:11]1C=[CH:18][CH:17]=[CH:16][C:12]=1C(O)=O)=[O:10]>CN(C=O)C.ClCCl>[Cl:4][C:2]([C:1]1[CH:18]=[CH:17][CH:16]=[CH:12][C:11]=1[C:9]([O:8][CH3:7])=[O:10])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)c1ccccc1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccccc1C(=O)Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (0.86 ml, 9.8 mml) and two drops of DMF were added to a solution of 2-(methoxycarbonyl)benzoic acid (590 mg, 3.27 mmol) in dichloromethane (10 ml) and cooled to 0° C. and stirred at RT for 30 min. After 30 min, the solvent was removed to obtain methyl 2-(chloroformyl)benzoate (quantitative). A solution of this intermediate (401 mg, 2.03 mmol) in dichloromethane was added to a solution of intermediate 10 (540 mg, 2.03 mmol) and pyridine (0.19 ml, 2.43 mmol) in dichloromethane (5 ml) at 0° C. and stirred at RT for 30 min. Work-up (CH2Cl2/H2O) and purification gave methyl 2-(3-chloro-3′-ethoxy-5-fluorobiphenyl-4-ylcarbamoyl)benzoate (250 mg) as an off-white solid. Lithium borohydride (20 mg, 0.94 mmol) was added to a solution of this product (200 mg, 0.47 mmol) in THF (5 ml) at 0° C. and the mixture stirred at RT for 2 hrs. Work-up (EtOAc/aq. 10% NH4Cl then H2O) and purification afforded the title compound (30 mg) as a white solid. M.P.: 139.2-141.5° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 10.22 (s, 1H), 7.76 (s, 1H), 7.73-7.60 (m, 3H), 7.54 (t, J 6.7, 1H), 7.43-7.36 (m, 2H), 7.33-7.26 (m, 2H), 6.97 (dd, J 1.8, 8.1, 1H), 5.32 (t, J 5.6, 1H), 4.72 (d, J 5.6, 2H), 4.12 (q, J 7, 2H), 1.35 (t, J 7, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13](OC)=[O:14])=[CH:11][CH:10]=2)[CH:5]=[C:4]([NH2:19])[N:3]=1.[NH2:20][NH2:21]>CO>[NH2:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([NH:20][NH2:21])=[O:14])=[CH:11][CH:10]=2)[CH:5]=[C:4]([NH2:19])[N:3]=1
Reactant: COC(=O)c1ccc(Oc2cc(N)nc(N)n2)cc1
Reactant: NN
Solvent: CO
Product: NNC(=O)c1ccc(Oc2cc(N)nc(N)n2)cc1
Reaction time: 48 h
Yield: 73.8 %

Procedure:
Methyl 4-[(2,6-diaminopyrimidin-4-yl)oxy]benzoate (2.74 g, 10.52 mmol) was suspended in ca. 180 mL of anhydrous methanol and anhydrous hydrazine (1.021 g, 1.0 mL, 31.85 mmol, 3.03 eq) was added to this suspension. The reaction mixture was refluxed for 3 hours, then MeOH was very slowly distilled off till the total volume reached ca. 30 mL. This solution was allowed to stand at ambient temperature for 48 hrs. A white precipitate slowly crystallized out. It was collected, washed with 40 mL of EtOAc, 40 mL of anhydrous Et2O and dried in vacuo to give the title product as a fine white powder (2.02 g). Yield 73.7%.
Reaction SMILES: C[C@@H]1CC2C(=CC=C([C@@H:12]3[CH2:17][N:16]4[CH2:18][CH2:19][NH:20][CH2:21][C@H:15]4[CH2:14][N:13]3[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])C=2)C(=O)O1.Br[C:31]1[CH:32]=[CH:33][C:34]([F:39])=[C:35]([CH:38]=1)[C:36]#[N:37]>>[C:36]([C:35]1[CH:38]=[C:31]([C@@H:12]2[CH2:17][N:16]3[CH2:18][CH2:19][NH:20][CH2:21][C@H:15]3[CH2:14][N:13]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:32]=[CH:33][C:34]=1[F:39])#[N:37]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: C[C@@H]1Cc2cc([C@@H]3CN4CCNC[C@H]4CN3C(=O)OC(C)(C)C)ccc2C(=O)O1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CNCCN2C[C@H]1c1ccc(F)c(C#N)c1

Procedure:
(3R,9aS)-tert-butyl 3-(3-cyano-4-fluorophenyl)hexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate was synthesized following the procedure of (3R,9aS)-tert-butyl 3-((R)-3-methyl-1-oxoisochroman-6-yl)hexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate starting from 5-bromo-2-fluorobenzonitrile: LC/MS: (M+1)+: 361.17.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:28])[N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23](O)[CH:22]=2)[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:14]=1)#[N:2].[CH2:29]([N:31](CC)CC)[CH3:30].CS(Cl)(=O)=O>O1CCCC1.C(=O)(O)[O-].[Na+]>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:28])[N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH2:30][C:29]#[N:31])[CH:22]=2)[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:14]=1)#[N:2]
Reactant: CCN(CC)CC
Reactant: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(-c2cccc(O)c2)c1=O
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCc1cccc(-n2cc(-c3ccccn3)cc(-c3ccccc3C#N)c2=O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-(2-Cyanophenyl)-5-(2-pyridyl)-1-(3-hydroxyphenyl)-1,2-dihydropyridin-2-one (53 mg) was dissolved in 2 ml of tetrahydrofuran, then 60 ml of triethylamine and 20 ml of methanesulfonyl chloride were added thereto with ice cooling and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with an aqueous solution of sodium bicarbonate and extracted with ethyl acetate and the extract was dried over anhydrous magnesium sulfate. The drying agent was filtered off, the filtrate was concentrated in vacuo, the resulting residue was dissolved in 1 ml of dimethyl sulfoxide, 3 mg of sodium cyanide were added and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed with an aqueous solution of sodium bicarbonate and a saturated saline solution and dried over anhydrous magnesium sulfate. The drying agent was filtered off, the filtrate was concentrated in vacuo and the resulting crude crystals were recrystallized from ethyl acetate-diethyl ether-hexane to give 12 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([CH2:13][CH2:14]Br)[CH2:10][C@@H:9]1[C:16]([O:18][CH3:19])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[P:20]([O:27]CC)([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([CH2:13][CH2:14][P:20]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:27])[CH2:10][C@@H:9]1[C:16]([O:18][CH3:19])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H]1C[C@@H](CCBr)CN1C(=O)OC(C)(C)C
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CC[C@@H]1C[C@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1)OCC

Procedure:
A mixture of 0.60 g of cis methyl N-t-butoxycarbonyl-4-(2-bromoethyl)pyrrolidine-2-carboxylate and 3 ml triethyl phosphite is refluxed for 2 hours. The excess triethyl phosphite is distilled off under vacuum and the residue is flash chromatographed with methylene chloride/methanol (95:5) to afford cis methyl N-t-butoxycarbonyl-4-(2-diethylphosphonoethyl)pyrrolidine-2-carboxylate.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]1(=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>CCCCCC>[CH2:10]1[CH2:9][CH:8]=[C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH2:12][CH2:11]1
Reactant: O=C1CCCCC1
Reactant: C1COCCN1
Solvent: CCCCCC
Product: C1=C(N2CCOCC2)CCCC1

Procedure:
A mixture of morpholine (697 ml.), cyclohexanone (820 ml.) and hexane (800 ml.) is heated to reflux under nitrogen with a Dean-Stark trap for 18 hours. The aqueous phase (206 ml.) is collected in the distillate trap. The mixture is distilled under vacuum increasing the vacuum to 29 inches and 90°-100° to give the title compound as an oily residue.