Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:27]([N:34]1[CH2:39][CH2:38][CH:37](O)[CH2:36][CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1.CCOC(C)=O>[CH2:27]([N:34]1[CH2:39][CH2:38][CH:37]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:36][CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Oc1ccccc1
Reactant: OC1CCN(Cc2ccccc2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: c1ccc(CN2CCC(Oc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a cold (0° C.) mixture of phenol (190 mg, 2.02 mmol) and triphenylphosphine (680 mg, 2.6 mmol) in dry THF (6.4 mL) is added dropwise over 30 min a solution of 1-benzyl-piperidin-4-ol (490 mg, 2.6 mmol) and diethylazadicarboxylate (0.41 mL, 2.6 mmol) in dry THF (4.8 mL). The mixture is stirred at room temperature under nitrogen for 20 h. The mixture is dissolved in EtOAc, washed with sat. NaHCO3 (2×20 mL), dried (MgSO4), filtered and concentrated to provide a crude oil. Flash chromatography (EtOAc/Hex: 3/7) provides the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][C:15]=3[N:17]3[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23]C(=O)O)[CH2:18]3)N(C)[C:9]2=[O:28])=[CH:5][CH:4]=1)#[N:2].[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[NH2:23][CH:19]1[CH2:20][CH2:21][CH2:22][N:17]([C:15]2[CH:14]=[CH:13][N:12]=[C:11]3[C@@H:32]([CH3:33])[C:9](=[O:28])[N:8]([CH2:7][C:6]4[CH:29]=[CH:30][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[C:16]=23)[CH2:18]1
Reactant: Cn1c(=O)n(Cc2ccc(C#N)cc2)c2c(N3CCC[C@@H](NC(=O)O)C3)ccnc21
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1C(=O)N(Cc2ccc(C#N)cc2)c2c(N3CCCC(N)C3)ccnc21
Yield: 99 %

Procedure:
The operation referred to the step (6) described in Example 1. 348 mg (R)-1-[1-(4-cyanobenzyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl]piperidin-3-yl carbamic acid ter.-butyl ester (0.75 mmol) and 2.0 mL trifluoroacetic acid were charged to afford 270 mg titled product with a yield of 99%.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:5]=1[CH:6]=O.[C:14]([O:17][CH2:18][CH3:19])(=[O:16])[CH3:15]>C1COCC1>[F:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:5]=1[CH2:6][CH2:15][C:14]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(C)=O
Reactant: COc1ccc(C=O)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(OC)cc1F
Temperature: 0 °C
Reaction time: 4 h

Procedure:
An oven dried flask was charged with sodium hydride (60%) (389 mg, 9.73 mmol) and THF (25 mL) and cooled to 0° C. Triethyl phosphonoacetate (1.948 mL, 9.73 mmol) was added dropwise and the reaction was heated to 50° C. for 1 hr. The reaction was then cooled to 0° C., and 2-fluoro-4-methoxy-benzaldehyde (1000 mg, 6.49 mmol) was added via cannula in THF (4×5 mL). The reaction was then heated at reflux for 16 hours. Next, the reaction was cooled to room temperature and diluted with ethyl acetate (75 mL). The organic layer was washed with water (2×75 mL) and brine (75 mL), dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in ethanol (20 mL) and 10% palladium on carbon (100 mg) was added. The reaction was placed under an atmosphere of H2 (balloon) and stirred for 4 hours. The reaction was then filtered and concentrated. Purification of the residue via flash chromatography on silica gel (0 to 40% ethyl acetate/hexanes) afforded ethyl 3-(2-fluoro-4-methoxyphenyl)propanoate. 1H NMR (CDCl3, 500 MHz) δ 7.09 (t, J=8.5 Hz, 1H), 6.60 (m, 2H), 4.12 (q, J=7.2 Hz, 2H), 3.77 (s, 3H), 2.90 (t, J=7.6 Hz, 2H), 2.58 (t, J=7.7 Hz, 2H), 1.23 (t, J=7.2 Hz, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][CH:6]=[N:5][C:4]=1[CH3:8].[CH3:9][C:10]1[N:15]=[C:14]([SH:16])[N:13]=[C:12]([OH:17])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:9][C:10]1[N:15]=[C:14]([S:16][CH2:2][C:3]2[S:7][CH:6]=[N:5][C:4]=2[CH3:8])[N:13]=[C:12]([OH:17])[CH:11]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Cc1ncsc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(O)nc(SCc2scnc2C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
A mixture of 5-(chloromethyl)-4-methyl-1,3-thiazole (887 mg, 4.9 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (600 mg, 4.2 mmol), and potassium carbonate (2.1 g, 15 mmol) in acetone (30 mL) was stirred at room temperature overnight. The solid material was removed by filtration. The filtrate was recovered and evaporated, co-evaporated with EtOAc (20 mL) and dried in vacuo. The solid residue was treated with diethyl ether (30 mL). The solid product was recovered by filtration, washed with diethyl ether (2×15 mL) and hexanes (1×15 mL), and dried in vacuo, affording 6-methyl-2-{[(4-methyl-1,3-thiazol-5-yl)methyl]sulfanyl}pyrimidin-4-ol (1.0 g, 93% yield); 1H NMR (400 MHz, DMSO-d6): δ 1.91 (s, 3H), 2.34 (s, 3H), 4.31 (s, 2H), 5.32 (s, 1H), 8.73 (s, 1H); M+ 254. The product was used without further purification.
Reaction SMILES: [C:1]1([CH:7]([CH2:11][CH3:12])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(=O)(O)[O-].[Na+]>[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:8](=[O:10])[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11][CH3:12])=[CH:21][CH:20]=1
Reactant: CCC(C(=O)O)c1ccccc1
Reactant: ClCCCCOc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCC(C(=O)c1ccc(OCCCCCl)cc1)c1ccccc1
Reaction time: 16 h
Yield: 94.2 %

Procedure:
To a stirred solution of 2-phenylbutyric acid (5.6 g, 34 mmol) in trifluoroacetic anhydrlde (20 ml) was added 4-chlorobutoxybenzene (7.5 g, 41 mmol). After 16 h, the mixture was poured into saturated sodium bicarbonate solution (250 ml), and extracted with ether (2×100 ml). The combined organic layers were dried (MgSO4), and concentrated in vacuo. The residues were purified by flash chromatography (silica; eluant:10-30% ethyl acetate in petrol) to give the title compound as an orange oil (10.6 g, 94% ).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][N:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O>>[CH3:19][O:18][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([C:21]3[S:20][CH:24]=[CH:23][N:22]=3)[CH:26]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCC(N)c1c(OC)cncc1OC
Reactant: O=Cc1cccc(-c2nccs2)c1
Product: COc1cncc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2nccs2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(3,5-dimethoxypyridin-4-yl)pentanoate with commercially available 3-(thiazol-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.52 min.; [M+H]+: 409.72 g/mol.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)#[N:23]>C1(C)C=CC=CC=1>[C:22]([C:24]1[CH:32]=[CH:31][C:27]([C:28]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)=[O:29])=[CH:26][CH:25]=1)#[N:23]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: OC1CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: N#Cc1ccc(C(=O)OC2CCN(Cc3ccccc3)CC2)cc1
Yield: 61.4 %

Procedure:
2.0 g (0.01 mol) of 1-benzyl-4-hydroxypiperidine and 1.4 ml (0.01 mol) of triethylamine were dissolved in 100 ml of toluene and treated with 1.6 g (0.00966 mol) of 4-cyanobenzoyl chloride. The mixture was boiled at reflux for 2 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetatelhexane (1:1). 1.9 g (61%) of 1-benzyl-piperidin-4-yl 4-cyano-benzoate were obtained as brownish crystals; m.p. 110°-111°.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].C([O-])([O-])=O.[Cs+].[Cs+].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1OCCOC1>[CH3:8][C:7]1[C:2]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[C:3]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: Cc1cc([N+](=O)[O-])cc(CNC(=O)OC(C)(C)C)c1Br
Reactant: C1COCCN1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc([N+](=O)[O-])cc(CNC(=O)OC(C)(C)C)c1N1CCOCC1
Temperature: 90 °C
Reaction time: 24 h
Yield: 70.7 %

Procedure:
In a oven-dried flask and under a nitrogen atmosphere, were placed tert-butyl N-[(2-bromo-3-methyl-5-nitrophenyl)methyl]carbamate prepared in step C of example 5 (500 mg, 1.45 mmol), (+/−) BINAP (45 mg, 0.07 mmol), Cs2CO3 (661 mg, 2.03 mmol), Pd2dba3 (33 mg, 0.07 eq) and 10 mL of dry 1,4-dioxanne. Morpholine (152 μL, 1.74 mmol) was added and the mixture was stirred at 90° C. for 24 h. The solution was filtered through a celite pad and evaporated. The residue was purified by flash chromatography on silica gel (DCM/AcOEt//9/1) to yield expected compound as a pale brown solid (360 mg, 71% yield); m/z (ESI) 352.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]=1[CH:4]=[CH:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C:10]2=[O:22].[C:23](OC(=O)C)(=[O:25])[CH3:24].O>N1C=CC=CC=1>[C:23]([NH:1][C:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]=1[CH:4]=[CH:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C:10]2=[O:22])(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12CCC(=O)C(N)=C1C=C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)NC1=C2C=C[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CCC1=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 2.7 g of 4-aminoandrosta-4,6-dien-3,17-dione in 10.8 ml of dry pyridine are added 5.4 ml of acetic anhydride at room temperature dropwise. After 90 minutes of additional stirring, the reaction mixture is cooled to 0° C. and worked up by the addition of cold water, followed by extraction with ethyl acetate. The organic phase is separated, washed with saturated NaCl aqueous solution, dried over Na2SO4 and evaporated in vacuo to yield a residue which is purified by column chromatography on silica gel. Elution with ethyl acetate:methanol 9:1 yields 2.6 g of the title compound as yellow crystals, m.p. 235°-236° C. (dec.);
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([O:27][CH2:28][CH3:29])=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.C(O)(C)C.[NH3:34]>>[CH2:28]([O:27][C:8]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([NH2:34])[C:3]2=[C:10]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[N:18]3)=[CH:13][CH:12]=2)[N:9]=1)[CH3:29]
Reactant: CCOc1nc(-c2ccc3ccc(-c4ccccc4)nc3c2)c2c(Cl)nccn12
Reactant: N
Solvent: CC(C)O
Product: CCOc1nc(-c2ccc3ccc(-c4ccccc4)nc3c2)c2c(N)nccn12
Temperature: -20 °C

Procedure:
7-(8-Chloro-3-ethoxy-imidazo[1,5-a]pyrazin-1-yl)-2-phenyl-quinoline (20.0 mg, 0.050 mmol) was dissolved into a 80 mL sealed tube with isopropyl alcohol (1.0 mL, 3.0 mmol). The solution was cooled to −20° C. and charged with ammonia gas. The reaction was heated to 110 IC for 72 hours. The reaction was then cooled, concentrated in vacuo and dissolved with CH2Cl2. The crude product was purified via silica gel column chromatography, (Jones, 2.0 gram column; 100% EtOAc) to yield the title compound as a yellow solid; MS (ES+): m/z 382.08 (90) [MH+], 383.09 (30) [MH++]. HPLC: tR=2.26 min (OpenLynx, polar—5 min); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.52 (t, J=7.07 Hz, 3H), 4.66 (q, J=7.07 Hz, 2H), 6.96 (d, J=5.05 Hz, 1H), 7.13 (d, J=5.05 Hz, 1H), 7.34-7.63 (m, 3H), 7.75-8.01 (m, 3H), 8.10-8.32 (m, 3H), 8.40 (s, 1H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N-:5]=[N+:6]=[N-:7].[Na+].[C:9]([C:11](=[CH:17][NH:18][C:19]1[C:28]2[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=2[CH:22]=[CH:21][N:20]=1)[C:12](OCC)=[O:13])#[N:10].Cl>O.O1CCCC1>[NH:5]1[C:9]([C:11]2[C:12](=[O:13])[N:20]3[CH:21]=[CH:22][C:23]4[CH2:24][CH2:25][CH2:26][CH2:27][C:28]=4[C:19]3=[N:18][CH:17]=2)=[N:10][N:7]=[N:6]1
Reactant: CCOC(=O)C(C#N)=CNc1nccc2c1CCCC2
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: O=c1c(-c2nnn[nH]2)cnc2c3c(ccn12)CCCC3
Yield: 19 %

Procedure:
Aluminum chloride (2.05 g., 0.0154 mole) was added to cold (-30° C.) tetrahydrofuran (75 ml.). Sodium azide was added and the mixture heated under reflux for 40 minutes. Ethyl 2-cyano-3-(5,6,7,8-tetrahydro-1-isoquinolylamino)-acrylate (3.33 g., 0.0123 mole) was added and the mixture heated under reflux for 20 hours. The cooled mixture was diluted with water (100 ml.) and acidified with concentrated hydrochloric acid. The precipitate was collected, washed with water, dried and recrystallized from 2-methoxyethanol to give the title compound (0.625 g., 19%), m.p. 290°-292° C. (decomp.).
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:25])([F:24])[C:5]([C:11]1[CH:12]=[N:13][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][C@@H:18]2[CH3:23])=[N:15][CH:16]=1)([OH:10])[C:6]([F:9])([F:8])[F:7].C(N(CC)CC)C.[N+:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[S:42](Cl)(=[O:44])=[O:43])([O-:35])=[O:34].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:25][C:4]([F:3])([F:24])[C:5]([C:11]1[CH:12]=[N:13][C:14]([N:17]2[CH2:22][CH2:21][N:20]([S:42]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[N+:33]([O-:35])=[O:34])(=[O:43])=[O:44])[CH2:19][C@@H:18]2[CH3:23])=[N:15][CH:16]=1)([OH:10])[C:6]([F:9])([F:8])[F:7]
Reactant: C[C@H]1CNCCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1CN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.7 %

Procedure:
To a 15 mL round-bottomed flask was added 1,1,1,3,3,3-hexafluoro-2-(2-((2S)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-2-propanol dihydrochloride (0.28 g, 0.66 mmol, Example 89, Step 2), triethylamine (0.28 mL, 2.0 mmol) and CH2Cl2 (6 mL). To this solution at room temperature was added 2-nitrobenzenesulfonyl chloride (0.15 g, 0.66 mmol, Sigma-Aldrich, St. Louis, Mo.). The mixture was stirred at room temperature for 3 h and then saturated aqueous sodium bicarbonate was added. This was stirred for an additional 5 min and then the solution was transferred onto a phase separation cartridge (Radleys Discovery Technologies, Essex, UK) with the organic phase being collected. The collected solution was purified by silica gel chromatography (0 to 75% EtOAc in hexanes) to afford (S)-1,1,1,3,3,3-hexafluoro-2-(2-(2-methyl-4-(2-nitrophenylsulfonyl)piperazin-1-yl)pyrimidin-5-yl)-2-propanol (0.24 g) as a white solid.
Reaction SMILES: Cl[C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4].[NH2:8][C:9]1[CH:10]=[C:11]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=1.C(=O)([O-])O.[Na+]>ClCCl.O>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][O:15][C:14]2[CH:13]=[CH:12][C:11]([C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:29][CH:28]=3)=[CH:10][C:9]=2[NH:8][C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:18][CH:19]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1ccc(COc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2N)cc1
Reactant: COC(=O)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(=O)Nc1cc(-c2ccc(OC(F)(F)F)cc2)ccc1OCc1ccc(C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
A solution of methyl chloroglyoxylate (184 μl, 2.0 mmol) in dichloromethane (1.5 ml) was added dropwise at a slow speed to a mixture of 3-amino-4-[4-(tert-butyl)benzyloxy]-4′-(trifluoromethoxy)biphenyl (415 mg, 1.0 mmol), sodium hydrogencarbonate (168 mg, 2.0 mmol), water (5 ml) and dichloromethane (7 ml), and the mixture was stirred at 0° C. for 2 hours. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (456 mg, 90.9%) as a white solid.
Reaction SMILES: C(O)C.[CH2:4]([CH:6]1[CH2:15][CH:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([OH:16])[CH2:13]2)[CH2:8][N:7]1[CH2:19][C:20]1[CH:25]=[C:24](OC)[C:23](OC)=[C:22]([O:30][CH3:31])[CH:21]=1)[CH3:5]>C1COCC1.[Pd]>[CH2:4]([CH:6]1[CH2:15][CH:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([OH:16])[CH2:13]2)[CH2:8][N:7]1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:30][CH3:31])[CH:21]=1)[CH3:5]
Reactant: CCC1CC2CC(O)=C(OC)C=C2CN1Cc1cc(OC)c(OC)c(OC)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCC1CC2CC(O)=C(OC)C=C2CN1Cc1cccc(OC)c1

Procedure:
Pd/C (10%, 30.3 mg), THF (2.0 mL) and ethanol (2.0 mL) were reacted with 263 (292, 0.7 mmol) in THF (4.0 mL) as described for the synthesis of 264. The residue was purified by flash column chromatography using Flashmaster (SiO2: 5 g, hexane 100% to hexane/ethyl acetate 60:40). The title compound was obtained as yellow oil (211 mg, 92%). 1H NMR (400 MHz, CDCl3) δ 0.98 (3H, t, J 7.2, CH2CH3), 1.42 (1H, sept, J 7.1, one of CH2CH3), 1.69 (1H, sept, J 6.8, one of CH2CH3), 2.52 (1H, dd, J 16.4, 6.3, one of ArCH2CH), 2.80 (1H, dd, J 16.4, 5.1, one of ArCH2CH), 2.86-2.90 (1H, m, CHN), 3.58-3.73 (4H, m, 2×ArCH2N), 3.80 (6H, s, 2×OCH3), 6.42 (1H, s, CH), 6.64 (1H, s, CH), 6.79 (1H, dd, J 8.0, 2.2, CH), 6.92-6.98 (2H, m, 2×CH), 7.22 (1H, t, J 7.8, CH). 13C NMR (100 MHz, CDCl3) δ 11.1, 23.0, 29.5, 50.9, 55.0, 55.1, 55.9, 58.5, 108.8, 112.3, 114.1, 114.6, 121.1, 125.3, 126.7, 129.1, 141.5, 143.9, 144.9, 159.6. LC/MS (ES+) tr 1.13 min; m/z 328.10 ((M+H)+, 100%); MeOH/H2O 95:5 (1.0 mL/min), HPLC tr 2.86 min (>99%); CH3CN/H2O 90:10 (1.0 mL/min).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]3[CH:18]=[CH:17][O:16][N:15]=3)[N:11]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[N:10]=2)[N:3]=1.C[O-:28].[Na+]>CO>[F:8][C:7]1[C:2]([OH:28])=[N:3][C:4]([C:9]2[CH:13]=[C:12]([C:14]3[CH:18]=[CH:17][O:16][N:15]=3)[N:11]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[N:10]=2)=[N:5][CH:6]=1
Reactant: C[O-]
Reactant: Fc1ccccc1Cn1nc(-c2ncc(F)c(Cl)n2)cc1-c1ccon1
Agent: [Na+]
Solvent: CO
Product: Oc1nc(-c2cc(-c3ccon3)n(Cc3ccccc3F)n2)ncc1F
Temperature: 40 °C
Yield: 55 %

Procedure:
To a solution of 3-(3-(4-chloro-5-fluoropyrimidin-2-yl)-1-(2fluorobenzyl)-1H-pyrazol-5-yl)isoxazole (Compound 30, 0.040 g, 0.107 mmol) in 1 mL methanol was added sodium methoxide (0.024 ml, 0.107 mmol) as a 25% weight solution. The reaction was stirred at 40° C. until judged complete by LC/MS. Once complete, the reaction mixture was directly concentrated in vacuo, and the resulting crude oil was purified using silica gel chromatography employing a 0-100% ethyl acetate in hexane gradient to afford the desired compound as a white solid in 55% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([NH:11][S:12]([C:15]2[C:16]3[N:17]=[CH:18][CH:19]=[N:20][C:21]=3[CH:22]=[CH:23][CH:24]=2)(=[O:14])=[O:13])[CH:3]=1.Cl.[CH3:26][O:27][C:28](=[O:42])[C@@H:29]([NH2:41])[CH2:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1>>[CH3:26][O:27][C:28](=[O:42])[C@@H:29]([NH:41][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=1[NH:11][S:12]([C:15]1[C:16]2[N:17]=[CH:18][CH:19]=[N:20][C:21]=2[CH:22]=[CH:23][CH:24]=1)(=[O:14])=[O:13])[CH2:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc2ccccc2c1
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc2ccccc2c1)NC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12

Procedure:
4-Chloro-2-(quinoxaline-5-sulfonylamino)benzoic acid was coupled with (S)-2-amino-3-naphthalen-2-yl-propionic acid methyl ester hydrochloride as in EXAMPLE 1, Part C.
Reaction SMILES: [F:1][C:2]1[CH:45]=[CH:44][C:5]([CH2:6][C:7]2[CH:43]=[CH:42][CH:41]=[CH:40][C:8]=2[CH2:9][O:10][CH2:11][CH:12]2[CH2:39][CH2:38][C:15]3[N:16](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:17]=[N:18][C:14]=3[CH2:13]2)=[CH:4][CH:3]=1.FC1C=CC(CC2C=CC=CC=2COCC2CCC3N=CN(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)C=3C2)=CC=1.Cl.C(OCC)(=O)C>O.C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:43]=[CH:42][CH:41]=[CH:40][C:8]=2[CH2:9][O:10][CH2:11][CH:12]2[CH2:39][CH2:38][C:15]3[NH:16][CH:17]=[N:18][C:14]=3[CH2:13]2)=[CH:44][CH:45]=1
Reactant: Fc1ccc(Cc2ccccc2COCC2CCc3c(ncn3C(c3ccccc3)(c3ccccc3)c3ccccc3)C2)cc1
Agent: Cl
Agent: Fc1ccc(Cc2ccccc2COCC2CCc3ncn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c3C2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Fc1ccc(Cc2ccccc2COCC2CCc3[nH]cnc3C2)cc1
Temperature: 90 °C

Procedure:
A solution of a mixture of 5-[2-(4-fluorobenzyl)benzyloxymethyl]1-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazole and 5-[2-(4-fluorobenzyl)benzyloxymethyl]-3-triphenylmethyl-4,5,6,7-tetrahydro-3H-benzimidazole (0.62 g, 1.0 mmol) in water (0.6 ml) and glacial acetic acid (5 ml) was heated to 90° C. for 2.5 h. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (50 ml). A 3.5 M solution of hydrogen chloride in ethyl acetate (0.6 ml, 2.1 mmol) was added. The solvent was removed in vauco. The residue was dissolved in ethyl acetate (30 ml). A precipitation appeared, which was isolated to give 235 mg of the hydrochloride salt of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16].[C:21](Cl)(=[O:30])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.P(=O)([O-])[O-]>C(Cl)Cl>[C:21]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][P:13]([O:14][CH2:15][CH3:16])([O:17][CH2:18][CH3:19])=[O:20])(=[O:30])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOP(=O)(CCCCCCCCCCCO)OCC
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: O=[PH]([O-])[O-]
Solvent: ClCCl
Product: CCOP(=O)(CCCCCCCCCCCOC(=O)C=Cc1ccccc1)OCC
Reaction time: 2 h
Yield: 41 %

Procedure:
The diethyl 11-hydroxyundecylphosphonate (1.00 g, 3.24 mmol) was combined with TEA (0.48 mL, 3.40 mmol) in 15 mL dry DCM in a 50 mL round-bottomed flask (rbf) and the mixture was brought down to 0° C. Cinnamoyl chloride (566 mg, 3.40 mmol) was added dropwise. The reaction was stirred for 2 hours and then stopped once most of the starting phosphonate was consumed. TLC in ethyl acetate showed several new spots. The reaction mixture was then washed 3× (20 mL) NaOH followed by sodium thiosulfate and water washes. The organic layer was then dried over magnesium sulfate and the solvent removed. A chromatography column in ethyl acetate was run and the desired product was isolated as a yellow-tinted oil with Rf=0.60 (580 mg, 41% yield). 1H NMR (400.13 MHz, CDCl3) δ 7.68 (d, J=16.02 Hz), 7.53 (m, 2H), 7.38 (m, 3H), 6.44 (d, J=16.02 Hz), 4.20 (t, J=6.74 Hz, 2H), 4.08 (m, 4H), 1.79-1.49 (m, 6H), 1.43-1.22 (m, 20H). 13C{1H} NMR (100.61 MHz, CDCl3) δ 167.02, 144.48, 134.39, 130.14, 128.79 (2C), 127.97 (2C), 118.21, 64.65, 61.28 (d, J=6.54 Hz, 2C), 30.54 (d, J=16.94), 29.42 (2C), 29.28, 29.20, 29.02, 28.65, 25.90, 25.62 (d, J=140.40 Hz), 22.33 (d, J=5.21 Hz), 16.42 (d, J=5.92 Hz, 2C). 31P{1H} NMR (161.98 MHz, CDCl3): δ 33.32. Analysis found (calculated) %: C, 65.39 (65.73); H, 9.05 (8.96). MS (ESI, m/z): 439 ([M+H]+, 100%). Exact mass found (calculated for [M+H]+, m/z): 439.25720 (439.26079).