Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][C:5]2[CH2:11][CH2:10][N:9]([CH2:12][CH3:13])[CH2:8][CH2:7][C:6]=2[N:14]=1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[CH2:12]([N:9]1[CH2:10][CH2:11][C:5]2[N:4]=[CH:3][C:2]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[N:14][C:6]=2[CH2:7][CH2:8]1)[CH3:13]
Reactant: C1CNCCN1
Reactant: CCN1CCc2ncc(Cl)nc2CC1
Product: CCN1CCc2ncc(N3CCNCC3)nc2CC1
Temperature: 145 °C
Yield: 52.6 %

Procedure:
3 g 2-chloro-7-ethyl-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepine are combined with 23.3 g piperazine and heated to 145° C. for 5 hours. Excess piperazine is distilled off and the residue is treated with dichloromethane and methanol. Precipitated product is suction filtered and purified by chromatography (Alox, dioxane/toluene/methanol/NH4OH 50/20/20/2). 1.95 g product are obtained.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[CH2:17]([NH2:23])[C:18]1[O:22][CH:21]=[CH:20][CH:19]=1>>[O:22]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:17][NH:23][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: CCOC(=O)c1cc2c(nc1Cl)CCCC2
Reactant: NCc1ccco1
Product: CCOC(=O)c1cc2c(nc1NCc1ccco1)CCCC2
Temperature: 130 °C
Reaction time: 12 h

Procedure:
A mixture of ethyl 2-chloro-5,6,7,8-tetrahydroquinoline-3-carboxylate (500 mg) and furfurylamine (3.0, ml) was stirred in a sealed tube at 130° C. for 12 hr. The reaction mixture was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (10:90-50:50) was concentrated under reduced pressure to give the object compound (683 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2
Reactant: O=C1CCc2cccc(F)c2N1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C1CCc2cc([N+](=O)[O-])cc(F)c2N1
Temperature: -5 °C
Reaction time: 0.33 h
Yield: 75 %

Procedure:
8-Fluoro-3,4-dihydro-1H-quinolin-2-one [prepared according to the procedure found in EP0524846] (2.62 g, 0.0159 mol) is dissolved in concentrated sulfuric acid (20 ml) and cooled to −5° C. Nitric acid (70%, 1.02 ml, 0.0159 mol) is added dropwise and the reaction stirred at −5° C. for 20 minutes. The mixture is poured onto ice and the resulting precipitate collected by filtration, washed well with water, and dried under vacuum. Purification by flash column chromatography (30% ethyl acetate/hexane) gives the title compound as a light yellow solid (2.50 g, 75%); [M+H]+=211.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][CH:31]=1)[O:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:32]([F:35])([F:34])[F:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:37][C:38](=[O:41])[CH2:39]Br>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][CH:31]=1)[O:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:39][C:38]([OH:41])=[O:37])=[CH:24][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:32]([F:35])([F:33])[F:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(Oc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1
Reactant: COC(=O)CBr
Product: O=C(O)COc1ccc(Oc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from 4-{3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]-phen-oxy}phenol and Bromo-acetic acid methyl ester with subsequent hydrolysis following the procedure of Example 515: MS (ES) m/z 527.9.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)=[CH:9][C:10]=2[F:12])[CH:5]=[CH:4][C:3]=1[OH:21].B(Br)(Br)Br>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:13]3[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=3)=[CH:9][C:10]=2[F:12])[CH:5]=[CH:4][C:3]=1[OH:21]
Reactant: COc1ccc(-c2cc(F)c3c(Cl)c(O)ccc3c2)cc1
Agent: BrB(Br)Br
Product: Oc1ccc(-c2cc(F)c3c(Cl)c(O)ccc3c2)cc1

Procedure:
The title compound was prepared by reacting 1-chloro-8-fluoro-6-(4-methoxyphenyl)-2-naphthol (0.14 g, 0.46 mmol) with boron tribromide (0.69 mL of 1N solution, 0.69 mmol) according to method D to yield 0.050 g (38%) of a white solid mp 174–176° C.; 1H NMR (DMSO-d6): δ 6.88 (2H, d, J=8.62 Hz), 7.33 (1H, d, J=8.92 Hz), 7.60–7.67 (3H, m), 7.86 (1H, dd, J=1.43 Hz, J=9.02 Hz), 7.95 (1H, d, J=1.37 Hz), 9.68 (1H, s), 10.59 (1H, s); MS (ESI) m/z 287/289 (M−H)−.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[C:10]1([C@@H:16]([NH2:18])[CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCOCC1>[Br:8][C:6]1[N:7]=[C:2]([NH:18][CH:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:17])[C:3]([NH2:9])=[N:4][CH:5]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: C[C@H](N)c1ccccc1
Solvent: C1COCCO1
Product: CC(Nc1nc(Br)cnc1N)c1ccccc1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
To a solution of 3,5-dibromopyrazin-2-ylamine (1.0 g; 3.95 mmol) in anhydrous dioxane (10 mL) was added (S)-(−)-1-phenylethylamine (0.51 mL; 3.95 mmol) at room temperature. The solution was heated to 100° C. and stirred for 20 h. After concentration under reduced pressure, the resultant residue was purified by flash chromatography [silica gel, hexanes/ethyl acetate (2:1)] to afford 5-bromo-N3-(1-phenylethyl)pyrazine-2,3-diamine as a brown solid (0.69 g; 60%). 1H NMR (300 MHz, DMSO): δ 7.37-7.29 (m, 5H), 7.14 (s, 1H), 6.84 (d, J=7.2 Hz, 1H), 6.29 (s, 2H), 5.10-5.05 (m, 1H), 1.47 (d, J=6.9 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].C1COCC1.Br[C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=1>C([O-])(O)=O.[Na+]>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[N:15][CH:16]=1
Reactant: COCCO
Reactant: Brc1ccc(Br)nc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.25 mL 2-methoxyethanol (3.17 mmol) are added to a mixture of 80 mg (3.17 mmol) sodium hydride and 5 mL THF. The mixture is stirred at rt for 10 min. Subsequently, 500 mg (2.11 mmol) 2,5-dibromopyridine are added and the mixture is stirred for 5 h at 75° C. After that time, the reaction mixture is diluted with sat. aq. NaHCO3 solution and extracted with EtOAc. The organic layer is dried over magnesium sulphate and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, PE/EtOAc 85/15).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=2)[C:23]([OH:25])=[O:24])[CH:13]=1.O[CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C1COCC1.C(Cl)Cl>[N:32]1([CH2:31][CH2:30][O:24][C:23](=[O:25])[C:22]2[CH:26]=[CH:27][CH:28]=[C:20]([C:14]3[CH:13]=[C:12]([NH:11][CH2:10][CH2:9][C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])[N:17]=[C:16]([O:18][CH3:19])[N:15]=3)[CH:21]=2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(=O)O)c2)n1
Reactant: OCCN1CCOCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(=O)OCCN3CCOCC3)c2)n1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 43.9 %

Procedure:
4-Dimethylaminopyridine (4.4 mg, 0.036 mmol) is added to a stirred solution of 3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-benzoic acid (100 mg, 0.24 mmol), N-(2-hydroxyethyl) morpholine (29.07 μL, 0.24 mmol) and 1,3-dicyclohexylcarbodiimide (0.31 mL, 1 M solution in DCM) in dry THF/DCM (6 mL, 1:1) and the reaction mixture is stirred for 5.5 hours at room temperature under nitrogen atmosphere. The mixture is filtered over a pad of Celite and the filtrate concentrated under reduced pressure. The residue is dissolved EtOAc (30 mL), washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue is purified by chromatography (SiO2 packed column) eluting with ethyl acetate/heptane to afford 3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-benzoic acid 2-morpholin-4-yl-ethyl ester (56 mg, Example 75). LCMS: RT=2.07 minutes, MS: 534 (M+H); 1H NMR, (300 MHz, CDCl3): □8.62 (1H, s), 8.3 (1H, d, J=3.5 Hz), 8.1 (1H, d, J=3.5 Hz), 7.55 (1H, t, J=3.5 Hz), 7.42 (1H, s), 7.2 (2H, s), 6.48 (1H, s), 5.04 (1H, b), 4.5 (2H, t, J=2 Hz), 4.05 (3H, s), 3.72 (6H, t, J=2 Hz), 3.1 (2H, t, J=2 Hz), 2.8 (2H, t, 2 Hz), 2.6 (4H, t, 2 Hz).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([F:14])([F:13])([F:12])([F:11])[F:10].Cl.Cl.[NH:17]1[CH2:22][CH2:21][CH:20](/[CH:23]=[C:24]2/[C:25]([NH:30][CH2:31][C:32]#[CH:33])=[N:26][C:27](=[O:29])[S:28]/2)[CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:10][S:9]([F:14])([F:13])([F:12])([F:11])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][N:17]1[CH2:22][CH2:21][CH:20](/[CH:23]=[C:24]2/[C:25]([NH:30][CH2:31][C:32]#[CH:33])=[N:26][C:27](=[O:29])[S:28]/2)[CH2:19][CH2:18]1
Reactant: FS(F)(F)(F)(F)c1ccccc1CBr
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccccc2S(F)(F)(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
To a solution of 2-(bromomethyl)-1-(pentafluorosulfanyl)benzene (213 mg) in DMF (5 mL) were added (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one dihydrochloride (210 mg) and potassium carbonate (362 mg). The reaction mixture was stirred at room temperature overnight, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (164 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[C@@H:4]([NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)=[O:22])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.[N:40]1[CH:45]=[CH:44][C:43]([CH:46]=O)=[CH:42][CH:41]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][O:2][C:3](=[O:39])[C@@H:4]([NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[CH:31][C:32]([C:35]([F:37])([F:36])[F:38])=[CH:33][CH:34]=2)=[CH:25][CH:24]=1)=[O:22])[CH2:5][N:6]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][CH:13]=1)[CH2:46][C:43]1[CH:44]=[CH:45][N:40]=[CH:41][CH:42]=1
Reactant: COC(=O)[C@H](CNCc1ccc(-c2ccccc2)cc1)NC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: O=Cc1ccncc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COC(=O)[C@H](CN(Cc1ccncc1)Cc1ccc(-c2ccccc2)cc1)NC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
3-[(Biphenyl-4-ylmethyl)-amino]-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester (0.050 g, 0.093 mmol) prepared as per the above listed example 656 was subjected to reductive amination as per procedure E with 4-pyridine carbaldehyde (0.010 ml, 0.093 mmol) and sodium triacetoxyborohydride (0.039 gms, 0.186 mmol) to yield the corresponding 3-(Biphenyl-4-ylmethyl-pyridin-4-ylmethyl-amino)-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester which was then hydrolyzed as per general procedure C to yield the title compound (0.040 g, 80%). 1H-NMR(400 MHz, DMSOd6): 3.3 (m, 2H), 4.001 (s, 4H), 5.18 (m, 1H), 7.62–7.75 (m, 8H), 7.8–7.93 (m, 4H), 8.17 (m, 4H), 8.27 (m, 4H), 8.77 (d, 2H), 9.1 (d, 1H), 8.7 (S, 1H); LC/MS (m/z): 610.4 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]1(C)[O:23]C(=O)C[C:20](=O)[O:19]1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14](=[O:16])[CH2:17][C:18]([O:19][CH3:20])=[O:23])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CC(=O)CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-(Benzyloxycarbonylamino)propanoic acid [N-Cbz-β-alanine] (5.0 g, 22.4 mmoles) is suspended in methylene chloride (100 mL) and 2,2-dimethyl-1,3-dioxane-4,6-dione (3.3 g, 22.9 mmoles), triethylamine (8.5 mL, 61.0 mmoles) and diethyl cyanophosphonate (3.7 mL, 22.8 mmoles) are added. All solids dissolve quickly, and the reaction quickly turns yellow. The solution is stirred for 16 hours at ambient temperature. The reaction mixture is then diluted with methylene chloride (100 mL) and carefully washed three times with aqueous hydrochloric acid (3 M, 50 mL each), three times with water (50 mL each) and once with saturated aqueous sodium chloride (50 mL). The reaction mixture is then dried over anhydrous sodium sulfate, filtered and evaporated to an orange syrup. The syrup is dissolved in anhydrous methanol (200 mL) and heated to reflux for 16 hours. The methanol is evaporated and the crude product purified on silica gel (150 mL bed volume) eluting with methylene chloride (500 mL) then methylene chloride:methanol (99.5:0.5 [v/v], 500 mL then 99:1 [v/v], 1000 mL). Fractions containing pure product by thin layer chromatography are pooled and evaporated to a pale yellow oil. The oil is dried well in vacuo. The yield is 4.5 g (68%).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1.F[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([NH2:33])=[O:32])[N:26]=1.CC(C)([O-])C.[Na+]>C1COCC1>[CH3:1][C:2]1([CH3:23])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19]([O:22][C:25]5[N:26]=[C:27]([C:31]([NH2:33])=[O:32])[CH:28]=[CH:29][CH:30]=5)[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1
Reactant: CC1(C)Cc2nc(N3CCOc4ccc(O)cc43)sc2C(=O)N1
Reactant: NC(=O)c1cccc(F)n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)Cc2nc(N3CCOc4ccc(Oc5cccc(C(N)=O)n5)cc43)sc2C(=O)N1
Temperature: 145 °C
Yield: 11.7 %

Procedure:
To a solution of Example 57 (75 mg, 0.227 mmol) in THF (4 mL) was added 2-fluoro-6-pyridinecarboxamide (64 mg, 0.453 mmol) and sodium tert-butoxide (87 mg, 0.906 mmol). The reaction was heated to 145° C. under microwave irradiation for 50 minutes then cooled to r.t. The mixture was partitioned between DCM (50 mL) and water (50 mL); the organic phase was washed with brine (50 mL), dried (MgSO4), and concentrated in vacuo. The residue was purified by preparative HPLC (Method 6) to give the title compound (12 mg, 12%) as a white solid. δH (CDCl3) 8.02 (1H, d, J 2.6 Hz), 7.91 (1H, dd, J 7.2 and 0.9 Hz), 7.85 (1H, t, J 7.9 Hz), 7.08 (1H, dd, J 7.9 and 0.9 Hz), 6.98 (1H, d, J 8.9 Hz), 6.85 (1H, dd, J 8.9 and 2.6 Hz), 4.27-4.43 (2H, m), 4.05-4.17 (2H, m), 2.83 (2H, s), 1.37 (6H, s). LCMS (ES+) 452.0 (M+H)+, RT 2.85 minutes (Method 1).
Reaction SMILES: [P:1](=[O:9])([N:6]=[C:7]=[O:8])([S:4][CH3:5])[O:2][CH3:3].[NH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>CCOCC>[CH3:3][O:2][P:1]([NH:6][C:7]([NH:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:8])([S:4][CH3:5])=[O:9]
Reactant: COP(=O)(N=C=O)SC
Reactant: CCOC(=O)CN
Solvent: CCOCC
Product: CCOC(=O)CNC(=O)NP(=O)(OC)SC
Yield: 80.7 %

Procedure:
To a solution of 6.1 grams (g) of O,S-dimethyl phosphoroisocyanatidothioate in 100 milliliters (ml) of ether was added dropwise with stirring 3.5 g of ethyl glycinate. A solid soon began to precipitate and after about 1 hour this was collected by filtration. The solid was recrystallized from ethanol to obtain 7.4 g of the title compound (77 percent of theory) as white crystals melting at 143°-145° C.
Reaction SMILES: Br[C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:3]=1.[C:13]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)#[N:14].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>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>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[N:4]1[CH:5]=[N:6][C:2]([C:19]2[CH:20]=[C:15]([CH:16]=[CH:17][CH:18]=2)[C:13]#[N:14])=[N:3]1
Reactant: Brc1ncn(-c2ccccn2)n1
Reactant: N#Cc1cccc(B(O)O)c1
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: CCOC(C)=O
Solvent: Cc1ccccc1
Product: N#Cc1cccc(-c2ncn(-c3ccccn3)n2)c1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
2-(3-Bromo-1H-1,2,4-triazol-1-yl)pyridine (0.25 g, 1.12 mmol) and 3-cyanophenylboronic acid (0.33 g, 2.23 mmol) were dissolved in toluene (20 mL) and methanol (2 mL), then deoxygenated via argon bubbling for 10 min. Potassium carbonate (0.23 g, 1.6 mmol) and tetrakis(triphenylphosphine)palladium (129 mg, 0.11 mmol) were then added to the stirred solution. The reaction flask was fitted with a reflux condenser and the mixture stirred at 90° C. for 16 h, after which time it was cooled to ambient temperature and poured into a separatory funnel containing EtOAc (100 mL). The EtOAc solution was washed with H2O (2×100 mL), then brine (100 mL) and the organic phase was dried (MgSO4), filtered and concentrated in vacuo. The resulting crude residue was chromatographed on silica gel eluting with hexanes:EtOAc (40:60)to afford 3-(1-pyridin-2-yl-1H-1,2,4-triazol-3-yl)benzonitrile as a white solid which was then dissolved in dichloromethane (10 mL) and precipitated as the hydrochloride salt (M.p.=185–188° C.) upon treatment with 1M HCl in diethyl ether (1 mL).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:14])[C:10]=1[C:11](Cl)=[O:12])=[O:5])[CH3:2].[NH2:15][C:16]1[C:21]([C:22]#[N:23])=[CH:20][N:19]2[CH:24]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:26]=[C:18]2[CH:17]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:14])[C:10]=1[C:11](=[O:12])[NH:15][C:16]1[C:21]([C:22]#[N:23])=[CH:20][N:19]2[CH:24]=[C:25]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:26]=[C:18]2[CH:17]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Cl
Reactant: N#Cc1cn2cc(-c3ccccc3)nc2cc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnn(C)c1C(=O)Nc1cc2nc(-c3ccccc3)cn2cc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.6 %

Procedure:
5-Chlorocarbonyl-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (940 mg, 4.33 mmol) was added slowly to a solution of 7-amino-2-phenyl-imidazo[1,2-a]pyridine-6-carbonitrile (410 mg, 1.8 mmol) and triethylamine (363 mg) in dichloromethane (8 ml), and the mixture was stirred at r.t. overnight. The mixture was extracted with dichloromethane, the combined organic layers were dried (Na2SO4), and evaporated. The title compound (310 mg, 42%) was obtained by column chromatography (silica gel, heptane:ethyl acetate=80:20-60:40). MS (m/e)=413.3 [M−H+].
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@H:21]([OH:25])[C:22]([OH:24])=O)=[O:18])[CH2:13][C:14](=[O:16])[NH2:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([N:40]1[CH2:51][C:50](=[O:52])[CH2:49][C@H:41]1[C:42]([NH:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=O)(C)(C)C>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@H:21]([OH:25])[C:22]([N:40]1[CH2:51][C:50](=[O:52])[CH2:49][C@H:41]1[C:42]([NH:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:24])=[O:18])[CH2:13][C:14](=[O:16])[NH2:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)O
Reactant: CC(C)(C)NC(=O)[C@@H]1CC(=O)CN1C(=O)OC(C)(C)C
Product: CC(C)(C)NC(=O)[C@@H]1CC(=O)CN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1

Procedure:
A procedure similar to that described in Example 1 was repeated, except that (2S,3S)-3-(N2 -benzyloxycarbonyl-L-asparaginyl)amino-2-hydroxy-4-phenylbutyric acid (prepared as described in Preparation 1) and 1-t-butoxycarbonyl-N-t-butyl-4-oxo-L-prolinamide (prepared as described in Preparation 3) were used as starting materials, in relative proportions similar to those used in that Example, to obtain the title compound as colorless powdery crystals, melting at 116°-120° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[CH2:11]([O:18][CH2:19][C@@H:20]1[CH2:25][NH:24][CH2:23][CH2:22][N:21]1[C:26]1[N:31]=[CH:30][C:29]([N:32]([CH3:52])[C:33](=[O:51])[C:34]([C:37]2[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[C:39]([C:47]([F:50])([F:49])[F:48])[CH:38]=2)([CH3:36])[CH3:35])=[C:28]([C:53]2[CH:58]=[CH:57][C:56]([F:59])=[CH:55][C:54]=2[CH3:60])[CH:27]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH2:11]([O:18][CH2:19][C@@H:20]1[CH2:25][N:24]([CH:1]=[O:3])[CH2:23][CH2:22][N:21]1[C:26]1[N:31]=[CH:30][C:29]([N:32]([CH3:52])[C:33](=[O:51])[C:34]([C:37]2[CH:42]=[C:41]([C:43]([F:44])([F:45])[F:46])[CH:40]=[C:39]([C:47]([F:50])([F:49])[F:48])[CH:38]=2)([CH3:35])[CH3:36])=[C:28]([C:53]2[CH:58]=[CH:57][C:56]([F:59])=[CH:55][C:54]=2[CH3:60])[CH:27]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(F)ccc1-c1cc(N2CCNC[C@H]2COCc2ccccc2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: O=CO
Product: Cc1cc(F)ccc1-c1cc(N2CCN(C=O)C[C@H]2COCc2ccccc2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 50 °C
Yield: 107.5 %

Procedure:
A mixture of 0.35 ml (3.7 mmol) acetic anhydride and 0.17 ml (4.6 mmol) formic acid was heated at 50° C. for 2 h. After cooling to room temperature a portion of 0.08 ml of this mixture was added to 0.5 ml THF. A solution of 0.10 g (0.14 mmol) (S)-N-[6-(2-benzyloxymethyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide (Example 383a)) in 1 ml THF was added dropwise at 0° C. Conversion was monitored by thin layer chromatography. After complete consumption of the starting material the reaction mixture was diluted with water and extracted with three portions of dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give 0.11 g of crude (S)-N-[6-(2-benzyloxymethyl-4-formyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide as a light yellow solid.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C@H:23]([NH2:28])[CH2:24][N:25]([CH3:27])[CH3:26])=[CH:19][C:18]=1[F:29]>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C@H:23]([NH:28][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:24][N:25]([CH3:27])[CH3:26])=[CH:19][C:18]=1[F:29]
Reactant: CN(C)C[C@@H](N)c1ccc(Cl)c(F)c1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Agent: Cl
Product: CN(C)C[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1ccc(Cl)c(F)c1

Procedure:
Compound 53 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with (S)-1-(4-Chloro-3-fluoro-phenyl)-N2,N2-dimethyl-ethane-1,2-diamine hydrochloride to give the title compound as a white solid. LC/MS [390 (M+H)]; 1H NMR (400 MHz, Acetonitrile-d3) δ 10.34 (s, 1H), 8.96 (d, 1H), 8.49 (d, 2H), 8.35 (s, 1H), 7.46 (t, 1H), 7.35 (d, 1H), 7.28 (d, 1H), 6.62 (s, 1H), 5.26 (d, 1H), 2.93 (t, 1H), 2.60 (dd, 1H), 2.29 (s, 6H).