Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42]([OH:44])=O)[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[N:48]1([C:54]2[CH:61]=[CH:60][C:57]([C:58]#[N:59])=[CH:56][CH:55]=2)[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1>>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:36][CH2:37][N:38]([CH2:41][C:42]([N:51]4[CH2:50][CH2:49][N:48]([C:54]5[CH:55]=[CH:56][C:57]([C:58]#[N:59])=[CH:60][CH:61]=5)[CH2:53][CH2:52]4)=[O:44])[CH2:39][CH2:40]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:3])([CH3:5])[CH3:4]
Reactant: N#Cc1ccc(N2CCNCC2)cc1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCN(c3ccc(C#N)cc3)CC2)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with 4-piperazin-1-yl-benzonitrile (Fluka) to give the title compound. HR-MS (ES, m/z) calculated for C46H53Cl2N8O3 [(M+H)+] 835.3612, observed 835.3611.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17].[CH3:19][O:20][C:21]1[C:22]([CH3:28])=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24].C(O)(=O)C.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]([NH2:18])=[O:17])=[C:2]2[NH:24][C:23]1[CH:25]=[CH:26][CH:27]=[C:21]([O:20][CH3:19])[C:22]=1[CH3:28]
Reactant: COc1cccc(N)c1C
Reactant: COc1cc2ncc(C(N)=O)c(Cl)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1cc2ncc(C(N)=O)c(Nc3cccc(OC)c3C)c2cc1OC
Temperature: 100 °C
Yield: 72 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-3-quinolinecarboxamide (0.046 g, 0.17 mmol), 3-methoxy-2-methylaniline (0.036 g, 0.26 mmol) and acetic acid (40 μl) in DMF (0.8 ml) was heated at 100° C. for 2.5 h. After cooling, the mixture was diluted with water (15 ml) and made alkaline with saturated NaHCO3. The resulting gummy precipitate was collected and crystallized from methanol-water to give the title compound (45 mg, 70%).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]3=2)[CH:10]=[CH:9]1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=1>CC([O-])=O.CC([O-])=O.[Pd+2].C(O)C>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:9]2[CH2:8][C:16]3[C:11]([CH:10]=2)=[CH:12][CH:13]=[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=32)=[CH:25][CH:24]=1
Reactant: C1=Cc2ccc3ccccc3c2C1
Reactant: COc1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(C2=Cc3ccc4ccccc4c3C2)cc1
Temperature: 25 °C
Yield: 53.2 %

Procedure:
20 mnl of triethylamine, 3.32 g (20 mmole) of benzindene, 4.68 g (20 mmole) of p-methoxy-phenyl-iodide and 0.134 g (0.6 mmole) of Pd(OAc)2 were stirred under reflux for 10 h. After that the mixture was cooled to room temperature and treated with 100 ml of ethanol. The crystalline precipitate was isolated, washed with ethanol and dried under vacuum to obtain 2.9 g (54%) of the mixture of two isomers.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:29])[C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]#[N:28])[CH:13]=2)=[N:8][CH:9]=1)([O-:3])=[O:2].[Cl:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33]Br.O>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:29])[C:12]2[CH:13]=[C:14]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]#[N:28])[CH:15]=[C:16]([O:18][CH2:33][C:32]3[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=3[Cl:30])[CH:17]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Clc1ccccc1CBr
Reactant: N#Cc1ccccc1COc1cc(O)cc(C(=O)Nc2ccc([N+](=O)[O-])cn2)c1
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1COc1cc(OCc2ccccc2Cl)cc(C(=O)Nc2ccc([N+](=O)[O-])cn2)c1
Temperature: 85 °C
Reaction time: 17 h

Procedure:
A solution of N-(5-nitropyridin-2-yl)-3-[(2-cyanobenzyl)oxy]-5-hydroxybenzamide (195 mg) in DMF (3 ml) was treated with Ag2CO3 (165 mg) and 2-Chlorobenzyl bromide (0.073 ml). Heated to 85° C. and stirred for 17 hours under Nitrogen. Allowed to cool to ambient temperature. Water (25 ml) added. Extracted with ethyl acetate (50 ml), washed with brine (25 ml), dried over MgSO4. Volatile material was removed by evaporation to give a solid, which was purified by flash chromatography on silica eluted with 0-5% ethyl acetate in dichloromethane to give the title compound (43 mg) as a solid, 1H NMR δ (d6-DMSO): 5.20 (s, 2H), 5.33 (s, 2H), 6.96 (s, 1H), 7.40 (m, 5H), 7.57 (m, 2H), 7.72 (m, 2H), 7.90 (d, 1H), 8.40 (d, 1H), 8.64 (dd, 1H), 9.22 (s, 1H), 11.50 (s, 1H). LCMS rt=3.27 min (97.4%), ES+ 515.50 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:11]([O-])=O)[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.C(Cl)(Cl)Cl>C(O)(C)C.[Pd]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: O=[N+]([O-])c1cc(Br)c2[nH]ccc2c1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: Nc1cc(Br)c2[nH]ccc2c1
Yield: 71.4 %

Procedure:
A solution of 7-bromo-5-nitroindole (0.68 g, 2.8 mmol) hydrazine (1.0 mL, 31 mmol) and 10% Pd/C (50 mg) in 50 mL of isopropanol was stirred at reflux for 2 h. The reaction mixture was filtered and concentrated in vacuo, yielding oily residue which was subjected to column chromatography (CHCl3, neat) to produce 0.41 g (2.0 mmol, 70%) of the desired product.
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[CH3:8][C@@:9]12[O:19][C@H:18]1[C@@H:17]1[O:20][C@@H:16]1[C:15]1[C:21]([O:23][C@H:13]([CH:14]=1)[C@@H:12]1[C:24]([C:26]([O:28][C@H:11]1[CH2:10]2)=[O:27])=[CH2:25])=[O:22]>CC(C)=O>[CH:1]([N:4]([CH2:25][CH:24]1[CH:12]2[CH:11]([CH2:10][C:9]3([CH3:8])[CH:18]([CH:17]4[CH:16]([C:15]5[C:21](=[O:22])[O:23][CH:13]2[CH:14]=5)[O:20]4)[O:19]3)[O:28][C:26]1=[O:27])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(C)C
Reactant: C=C1C(=O)O[C@H]2C[C@]3(C)O[C@H]3[C@@H]3O[C@@H]3C3=C[C@@H](OC3=O)[C@H]12
Solvent: CC(C)=O
Product: CC(C)N(CC1C(=O)OC2CC3(C)OC3C3OC3C3=CC(OC3=O)C21)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.5 %

Procedure:
Diisopropylamine (500 μmol; 70 μl) is added to a solution of mikanolide (100 μmol; 29 mg) in acetone (1 ml). The reaction mass is stirred for 30 minutes at ambient temperature then the solvent is eliminated by evaporation under reduced pressure. The residue is taken up in ether, filtered and dried under vacuum. 10 mg of product is obtained in the form of a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[N:11]O)[S:5][C:6]=1[N+:7]([O-:9])=[O:8].C(OC(=O)C)(=O)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:10]#[N:11])[S:5][C:6]=1[N+:7]([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1sc(C=NO)cc1Br
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: N#Cc1cc(Br)c([N+](=O)[O-])s1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
A mixture of 4-bromo-5-nitro-thiophene-2-carbaldehyde oxime (216 g, 0.86 mol, Example 286: step b) and acetic anhydride (1 L, 10.6 mol) was heated to reflux for 4 hrs. The reaction mixture was cooled to rt and the solvents were removed in vacuo. The crude reaction mixture was diluted in methylene chloride and washed with water. The organic layer was dried over magnesium sulfate and concentrated in vacuo resulting in a residue, which was stirred in diethyl ether/hexanes and filtered to afford the title compound as a yellow solid (170.2 g, 85%). 1H-NMR (DMSO-d6): δ 8.25 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=2)[CH:16]=[C:15]([C:26]([OH:28])=O)[CH:14]=1)#[N:2].Cl.[O:30]1[CH2:35][CH2:34][N:33]([CH2:36][C@H:37]([NH2:39])[CH3:38])[CH2:32][CH2:31]1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:10])[F:11])=[CH:5][C:4]=1[C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=2)[CH:16]=[C:15]([C:26]([NH:39][C@H:37]([CH3:38])[CH2:36][N:33]2[CH2:34][CH2:35][O:30][CH2:31][CH2:32]2)=[O:28])[CH:14]=1)#[N:2]
Reactant: C[C@@H](N)CN1CCOCC1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-c3cc(C(F)(F)F)ccc3C#N)c2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)CN3CCOCC3)cc(-c3cc(C(F)(F)F)ccc3C#N)c2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round bottom flask was charged with 2′-cyano-5-(5-methylpyridin-2-yl)-5′-(trifluoromethyl)biphenyl-3-carboxylic acid (30 mg, 0.078 mmol), (R)-1-morpholinopropan-2-amine hydrochloride (33 mg, 0.18 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (145 mg, 0.38 mmol), N,N-diisopropylethylamine (106 μL, 0.61 mmol), N,N-dimethylformamide (0.5 mL) and the reaction was stirred overnight at room temperature. The mixture was purified by HPLC to afford the title compound as a light orange solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:16])=[CH:4][C:5]2[CH:6]3[CH2:14][N:13]([CH3:15])[CH2:12][CH2:11][CH:7]3[NH:8][C:9]=2[CH:10]=1.[H-].[Na+].[CH3:19][C:20]1([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH2:22][O:21]1>CN(C=O)C>[Cl:1][C:2]1[C:3]([Cl:16])=[CH:4][C:5]2[C:6]3[CH2:14][N:13]([CH3:15])[CH2:12][CH2:11][C:7]=3[N:8]([CH2:19][C:20]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)([OH:21])[CH3:22])[C:9]=2[CH:10]=1
Reactant: CC1(c2ccncc2)CO1
Reactant: CN1CCC2Nc3cc(Cl)c(Cl)cc3C2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCc2c(c3cc(Cl)c(Cl)cc3n2CC(C)(O)c2ccncc2)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A flask was charged with 7,8-dichloro-2-methyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (1 g, 3.9 mmol) in DMF (10 mL) and stirred for 5 min. To this was added NaH (60% in hexane) (470 mg, 11.7 mmol) and the mixture stirred at RT for 10 min. 4-(2-Methyloxiran-2-yl)pyridine (795 mg, 5.8 mmol) was added and the mixture stirred at RT for 16 h. The progress of reaction was monitored by TLC. The reaction mixture was poured into ice water and filtered. The filtrate was washed with water and concentrated. The residue was recrystallized from ether to get pure product. 1HNMR (CD3OD, Formate salt) d (ppm): 8.38 (d, 2H), 7.56 (s, 1H), 7.48 (d, 2H), 7.30 (s, 1H), 4.60 (m, 2H), 4.30 (m, 2H), 3.58 (m, 1H), 3.50 (m, 1H), 3.35 (m, 1H), 3.10 (m, 1H), 3.0 (s, 3H), 1.70 (s, 3H).
Reaction SMILES: [C:1](O)(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH3:23][O:24][C:25](=[O:52])[CH2:26][CH2:27][C@H:28]([C@@H:30]1[C@:47]2([CH3:48])[C@H:33]([C@H:34]3[C@H:44]([CH2:45][C@@H:46]2[OH:49])[C@:42]2([CH3:43])[C@@H:37]([CH2:38][C@@H:39]([NH2:50])[CH2:40][CH2:41]2)[CH2:36][C@H:35]3[OH:51])[CH2:32][CH2:31]1)[CH3:29]>C1COCC1>[CH3:23][O:24][C:25](=[O:52])[CH2:26][CH2:27][C@H:28]([C@@H:30]1[C@:47]2([CH3:48])[C@H:33]([C@H:34]3[C@H:44]([CH2:45][C@@H:46]2[OH:49])[C@:42]2([CH3:43])[C@@H:37]([CH2:38][C@@H:39]([NH:50][C:1](=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5])[CH2:40][CH2:41]2)[CH2:36][C@H:35]3[OH:51])[CH2:32][CH2:31]1)[CH3:29]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@@H](N)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reactant: C=CCCC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCCC(=O)N[C@H]1CC[C@@]2(C)[C@@H](C1)C[C@@H](O)[C@@H]1[C@@H]2C[C@H](O)[C@]2(C)[C@@H]([C@H](C)CCC(=O)OC)CC[C@@H]12

Procedure:
A solution of 4-pentenoic acid (marketed product) and triethylamine in THF was added drop by drop, under nitrogen and at 5° C., to isobutyl chloroformate and subsequently with a solution of (3β,5β,7α,12α)-3-amino-7,12-dihydroxy-cholan-24-oic acid methyl ester (prepared according to the procedure described in EXAMPLE 5) in THF. When the reaction was over, solvent was evaporated and the residue was taken up with H2O and AcOEt. The organic phase was separated, washed with H2O, dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by flash chromatography to obtain the desired product.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]([NH:15][C:16]3[N:21]=[C:20]([C:22]4[S:23][CH:24]=[CH:25][CH:26]=4)[CH:19]=[CH:18][N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]\[C:30]([OH:32])=[O:31]>C(O)C>[C:27]([OH:34])(=[O:33])[CH:28]=[CH:29][C:30]([OH:32])=[O:31].[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]([NH:15][C:16]3[N:21]=[C:20]([C:22]4[S:23][CH:24]=[CH:25][CH:26]=4)[CH:19]=[CH:18][N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)/C=C\C(=O)O
Agent: c1cc(Nc2nccc(-c3cccs3)n2)cc(OCCn2ccnc2)c1
Solvent: CCO
Product: O=C(O)C=CC(=O)O

Procedure:
To a solution of 1.0 g of N-[3-[2-(1H-imidazol-1-yl)ethoxy]phenyl]-4-(2-thienyl)-2-pyrimidinamine in 10 ml of hot ethyl alcohol is added 5 ml of ethyl alcohol containing 0.32 g of maleic acid. Crystals begin to form and the reaction mixture is cooled. The solid is collected by filtration, washed with ethyl alcohol and dried to afford the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[C:8]([C:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH:14]=3)=[N:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C>O1CCOCC1.[OH-].[Pd+2].[OH-].[Pd]>[NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[C:8]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:15][CH2:14]3)=[N:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2nccnc2Oc2ccc(N)cc2)CC1
Agent: [Pd+2]
Agent: [Pd]
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2nccnc2Oc2ccc(N)cc2)CC1

Procedure:
A solution of tert-butyl 4-(3-(4-aminophenoxy)pyrazin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2.87 g, 7.79 mmol) in 1,4-dioxane (39 mL) was added palladium hydroxide, 20 wt. % Pd (dry basis) on carbon, wet, Degussa type E101 NEW (0.27 g, 0.39 mmol) and hydrogenated (double-walled balloon pressure) at room temperature for 1 day. The reaction was filtered via a pad of Celite, and the filtrate was concentrated in vacuo and chromatographed via flash column chromatography (20% to 60% EtOAc/Hexanes) to provide tert-butyl 4-(3-(4-aminophenoxy)pyrazin-2-yl)piperidine-1-carboxylate as a cream solid. MS (ESI, pos. ion) m/z: 393.0 [M+1+Na].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=O)[NH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21].O>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[S:21])[NH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=c1[nH]cnc2cc(OCc3ccccc3)ccc12
Solvent: O
Solvent: c1ccncc1
Product: S=c1[nH]cnc2cc(OCc3ccccc3)ccc12
Yield: 98.8 %

Procedure:
A suspension of 7-benzyloxy-3,4-dihydroquinazolin-4-one (7 g, 28 mmol), (prepared as described for the starting material in Example 6), in pyridine (350 ml) containing phosphorus pentasulphide (12.5 g, 33 mmol) was heated at reflux for 8 hours. After cooling, the mixture was poured into water (1 liter). The precipitate was collected by filtration, and washed with water. The solid was dissolved in 6M sodium hydroxide and the solution was filtered. The filtrate was acidified to pH2 with 6M hydrochloric acid. The precipitate was collected by filtration, washed with water, and dried under vacuum at 60° C. to give 7-benzyloxy-3,4-dihydroquinazolin-4-thione (7.42 g, 99%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][C:12]([CH2:15]O)=[N:13][CH:14]=2)=[CH:5][CH:4]=1.O=S(Cl)[Cl:21]>C(Cl)Cl>[Cl:21][CH2:15][C:12]1[CH:11]=[N:10][C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:18])([F:17])[F:1])=[CH:4][CH:5]=2)=[CH:14][N:13]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cnc(-c2ccc(C(F)(F)F)cc2)cn1
Solvent: ClCCl
Product: FC(F)(F)c1ccc(-c2cnc(CCl)cn2)cc1
Reaction time: 6 h

Procedure:
0.20 g (0.79 mmol) of the above prepared [5-(4-trifluoromethyl-phenyl)-pyrazin-2-yl]-methanol was dissolved in 8 ml of CH2Cl2 and treated dropwise at 0° C. with 0.11 ml (2 eq.) of SOCl2. The reaction mixture was kept at 0° C. for 1 h, at RT for 18 h and 6 h at 30° C. Evaporation of the solvents and dissolution in ether and heptane with consecutive evaporation afforded 0.21 g of pure title compound as light brown solid.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=2[F:14])=[N:4][C:3]=1[C:15]([NH:17][C:18]1[C:19]([O:24][CH:25]2[CH2:30]CNCC2)=[N:20][CH:21]=[N:22][CH:23]=1)=[O:16].C[Si](C)(C)[O:33][CH2:34][CH2:35]CCO>>[NH2:1][C:2]1[S:6][C:5]([C:7]2[C:8]([F:14])=[CH:9][CH:10]=[CH:11][C:12]=2[F:13])=[N:4][C:3]=1[C:15]([NH:17][C:18]1[C:19]([O:24][CH2:25][CH2:30][CH2:35][CH2:34][OH:33])=[N:20][CH:21]=[N:22][CH:23]=1)=[O:16]
Reactant: C[Si](C)(C)OCCCCO
Reactant: Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cncnc1OC1CCNCC1
Product: Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cncnc1OCCCCO

Procedure:
Following the procedure described in Example 1, and substituting Compound 4 in Step (1) with 4-((trimethylsilyl)oxy)butan-1-ol (30B2) (100 mg, 0.617 mmol), the title compound 30 (32 mg, 0.0760 mmol) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH3:27])[CH2:9][CH2:10][N:11]([CH:19]([CH3:21])[CH3:20])C(=O)OC(C)(C)C)[CH:5]=[CH:6][CH:7]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH3:27])[CH2:9][CH2:10][NH:11][CH:19]([CH3:20])[CH3:21])[CH:5]=[CH:6][CH:7]=1
Reactant: COCCCOC(CCN(C(=O)OC(C)(C)C)C(C)C)c1cccc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCCOC(CCNC(C)C)c1cccc(Cl)c1
Reaction time: 1 h

Procedure:
tert-butyl 3-(3-chlorophenyl)-3-(3-methoxypropoxy)propyl(isopropyl)carbamate was dissolved in a solution of 20% (V/V) TFA/CH2Cl2 (10 mL) and allowed to stir for 1 hour. The solvent and reagent were evaporated before re-dissolving in CH2Cl2 and washing with NaHCO3 saturated solution. The crude 3-(3-chlorophenyl)-N-isopropyl-3-(3-methoxypropoxy)propan-1-amine was isolated (138 mg) and used as is. MS ESI+ve m/z 299 (M+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][CH2:24][C:25]([NH2:27])=[O:26])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[N:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C@:13]2([CH2:23][CH2:24][C:25]([NH2:27])=[O:26])[O:12][C:11](=[O:28])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:34]4[CH:35]=[N:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:17][CH:18]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCC(N)=O)(c2ccc(F)cc2)OC1=O
Reactant: COc1ccc(B(O)O)cn1
Product: COc1ccc(-c2ccc([C@H](C)N3CC[C@](CCC(N)=O)(c4ccc(F)cc4)OC3=O)cc2)cn1

Procedure:
The title compound was prepared from 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propanamide and 6-methoxypyridine-3-boronic acid following a procedure analogous to that described in Example 75 Step 1. LC-MS Method 2 tR=1.254 min, m/z=477.21; 1H NMR (CDCl3) 1.55 (d, 3H), 2.01 (m, 1H), 2.15-2.34 (m, 5H), 2.46 (m, 1H), 2.96 (m, 1H), 4.00 (s, 3H), 5.66 (m, 1H), 5.80 (s, 1H), 6.19 (s, 1H), 6.86 (d, 1H), 7.03 (m, 4H), 7.23 (m, 2H), 7.79 (dd, 1H), 8.36 (s, 1H).
Reaction SMILES: COC(C)(C)C.O.[NH2:8][CH:9]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11].[ClH:22].C(O)C>C1CCCCC1>[ClH:22].[NH2:8][C@H:9]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(N)Cc1ccccc1
Agent: Cl
Solvent: O
Solvent: C1CCCCC1
Solvent: COC(C)(C)C
Product: CCOC(=O)[C@H](N)Cc1ccccc1
Temperature: 30 °C
Reaction time: 168 h

Procedure:
To 80 mL of t-butyl methyl ether saturated with water were added 4.00 g (20.7 mmol) of ethyl 2-amino-3-phenylpropionate (racemic mixture) and 800 mg of a lipase (AMANO LIPASE PS (Trade name); available from ALDRICH CORPORATION) originated from Burkholderia cepacia (Pseudomonas cepacia), and the mixture was reacted with stirring at 30° C. After 168 hours, the reaction mixture was filtered, dried over magnesium sulfate, filtered, concentrated under reduced pressure and 12 mL of cyclohexane was added to the residue. To the resulting cyclohexane solution was added 1.52 g (10.1 mmol of hydrochloric acid) of a hydrochloric acid-ethanol solution (hydrochloric acid content: 24.3% by weight) at 0° C. and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was filtered to obtain 1.90 g (Yield based on ethyl 2-amino-3-phenylpropionate (racemic mixture)=40.0%) of ethyl (R)-2-amino-3-phenylpropionate hydrochloride as white crystals.
Reaction SMILES: [F:1][C:2]1[C:8]([OH:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[OH:4].[C:11]([CH2:30][C:31](OCC)=[O:32])(=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CS(O)(=O)=O>[F:10][C:7]1[CH:6]=[C:5]2[C:3](=[C:2]([F:1])[C:8]=1[OH:9])[O:4][C:31](=[O:32])[CH:30]=[C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCCC(=O)CC(=O)OCC
Reactant: Oc1ccc(F)c(O)c1F
Agent: CS(=O)(=O)O
Product: CCCCCCCCCCCCCCCCCc1cc(=O)oc2c(F)c(O)c(F)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.2 %

Procedure:
A mixture of 2,4-difluororesorcinol (Compound 4, 0.15 g, 1.0 mmol) and ethyl stearoylacetate (354 mg, 1.03 mmol) in methanesulfonic acid (4 mL) is stirred at room temperature overnight. The reaction mixture is partitioned between ethyl acetate and water. The ethyl acetate layer is washed with brine (1×) and dried over sodium sulfate, then concentrated to 0.67 g of a pale brown solid, which is purified by silica gel chromatography to give 49 mg of Compound 30 as a colorless powder: Rf =0.64 (EtOAc/hexanes 3:2). 1H NMR (CDCl3) δ 7.12 (dd, 1H), 6.22 (s, 1H), 1.7-0.7 (m, 70H). 19F NMR (CDCl3) Φ 139.8 (t, 1F), 153.5 (d, 1F).
Reaction SMILES: [CH2:1]([C@H:8]([NH:33]C(=O)OC(C)(C)C)[C@@H:9]([OH:32])[CH2:10][N:11]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:12][C:13](=[O:24])[C@@H:14]([NH:19][C:20]([O:22][CH3:23])=[O:21])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1>[NH2:33][C@@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@@H:9]([OH:32])[CH2:10][N:11]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:12][C:13]([C@@H:14]([NH:19][C:20](=[O:21])[O:22][CH3:23])[C:15]([CH3:18])([CH3:17])[CH3:16])=[O:24]
Reactant: COC(=O)N[C@H](C(=O)NN(Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)NN(Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Temperature: 70 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A solution of Example 5F in THF (4 mL) was treated with 4N HCl, and stirred at 70° C. for 3 hrs. The mixture was cooled to room temperature and quenched with saturated sodium bicarbonate and ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and the solvents were evaporated to give 83 mg (100%) of the title compound.