Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[N:10][C:11]([C:17]2[CH:18]=[C:19]([C:23]4[N:27]=[C:26]([C:28](OC)=[O:29])[O:25][N:24]=4)[CH:20]=[N:21][CH:22]=2)=[N:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:40]([NH:47][CH:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41]>C(O)C>[C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[N:10][C:11]([C:17]2[CH:18]=[C:19]([C:23]4[N:27]=[C:26]([C:28]([N:51]5[CH2:50][CH2:49][CH:48]([NH:47][C:40](=[O:41])[O:42][C:43]([CH3:45])([CH3:44])[CH3:46])[CH2:53][CH2:52]5)=[O:29])[O:25][N:24]=4)[CH:20]=[N:21][CH:22]=2)=[N:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: COC(=O)c1nc(-c2cncc(-c3nc(NCc4ccccn4)c4c(-c5ccccc5)cccc4n3)c2)no1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)c2nc(-c3cncc(-c4nc(NCc5ccccn5)c5c(-c6ccccc6)cccc5n4)c3)no2)CC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 38.5 %

Procedure:
To a solution of methyl 3-(5-(5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl)pyridin-3-yl)-1,2,4-oxadiazole-5-carboxylate (from example 187, 0.2 g, 0.38 mmol) in ethanol (10 mL) was added 4-(Boc-amino)piperidine (0.389 g, 1.90 mmol). Upon completion of addition, the reaction mixture was heated to 80° C. where it stirred for 16 h. At the conclusion of this period, the ethanol was evaporated and the resulting residue was purified by flash silica gel column chromatography (1.6% methanol in DCM) to yield tert-butyl 1-(3-(5-(5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl)pyridin-3-yl)-1,2,4-oxadiazole-5-carbonyl)piperidin-4-ylcarbamate (0.1 g, 38% yield) as yellow solid. LCMS Method T: retention time 2.08 min; [M+1]=684.2.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16]3)=[CH:11][CH:10]=2)[C:5]([F:26])=[CH:4][N:3]=1>FC(F)(F)C(O)=O.ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][NH:15][CH2:16]3)=[CH:11][CH:10]=2)[C:5]([F:26])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Nc3nc(Cl)ncc3F)cc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cnc(Cl)nc1Nc1ccc2c(c1)CNCC2

Procedure:
A solution of 2-chloro-5-fluoro-N4-[2-(t-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-4-pyrimidineamine in 40% trifluoroacetic acid/dichloromethane was stirred at rt for 30 min. Removal of the solvent left an oily residue which was suspended in water, made basic with NaHCO3, and extracted with ethyl acetate. Purification by column chromatography over silica gel provided 2-chloro-5-fluoro-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.04 (d, 1H, J=3.0 Hz), 7.37 (dd, 1H, J=2.4 and 8.4 Hz), 7.27 (d, 1H, J=1.5 Hz), 7.11 (d, 1H, J=8.4 Hz), 6.92 (s, 1H), 4.04 (s, 2H), 3.15 (t, 2H, J=6.0 Hz), 2.79 (t, 2H, J=6.0 Hz); 19F NMR (282 MHz, CDCl3): −44648; LCMS: purity: 97%; MS (m/e): 279 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.Cl[C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1)[NH2:17]>O1CCCC1>[ClH:1].[F:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[CH2:22][O:21][C:20]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:15][CH:14]=1
Reactant: Clc1ncnc2ccc(I)cc12
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Solvent: C1CCOC1
Product: Cl
Product: Fc1cccc(COc2ccc(Nc3ncnc4ccc(I)cc34)cc2)c1
Yield: 100.1 %

Procedure:
In 180 ml of tetrahydrofuran were dissolved 4-chloro-6-iodoquinazoline (6.0 g) and 3-chloro-4-(3-fluorobenzyloxy)aniline (II-1, 5.2 g), followed by heat refluxing for 3 hours. A precipitate was filtered, and washed with tetrahydrofuran to obtain 4-(4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline hydrochloride (III-1, 10.5 g) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9](Cl)=[O:10])=[CH:5][CH:4]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:31]=[C:32]([O:36][CH3:37])[C:33]=1[O:34][CH3:35])[C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH:22]1[C:27]([O:29][CH3:30])=[O:28])=[O:20].C(N(CC)CC)C.O>ClCCl>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([N:24]2[CH2:25][CH2:26][N:21]([C:19](=[O:20])[C:18]3[CH:17]=[C:16]([O:15][CH3:14])[C:33]([O:34][CH3:35])=[C:32]([O:36][CH3:37])[CH:31]=3)[CH:22]([C:27]([O:29][CH3:30])=[O:28])[CH2:23]2)=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=CC(=O)Cl)cc1
Reactant: COC(=O)C1CNCCN1C(=O)c1cc(OC)c(OC)c(OC)c1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)C1CN(C(=O)C=Cc2ccc(OC)cc2)CCN1C(=O)c1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 78.9 %

Procedure:
A solution of 4-methoxy cinnamoyl chloride (0.3 g) in dichloromethane (4 ml) is added dropwise, taking 3 minutes at 0 ° C while stirring, to a mixture of methyl 1-(3,4,5-trimethoxybenzoyl)piperazine-2-carboxylate (0.57 g), triethylamine (0.4 g) and dichloromethane (12 ml). The reaction mixture is stirred for 30 minutes at room temperature, and then poured into water, followed by extraction with dichloromethane. The organic layer is washed with dilute hydrochloric acid, an aqueous solution of sodium hydrogencarbonate and water, successively, then the solvent is distilled off. The residue is purified by means of a silica gel column chromatography to give methyl 4-(4-methoxycinnamoyl)-1(3,4,5-trimethoxybenzoyl)piperazine-2-carboxylate (0.6 g) as a colorless oily product. This product is processed with ethyl ether to give colorless powder
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[C:16]2[C:11](=[C:12]([NH2:17])[CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][CH:8]=1.[Cl:23][C:24]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:29][C:25]=1[C:26](O)=[O:27].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:23][C:24]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:38])([CH3:37])[CH3:39])=[CH:29][C:25]=1[C:26]([NH:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[O:6][C:5]1[CH:18]=[CH:19][CH:20]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=1)=[O:27]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Reactant: Nc1cccc2c(Oc3cccc(C(F)(F)F)c3)ccnc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Oc4cccc(C(F)(F)F)c4)ccnc23)c1
Yield: 20.4 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 4-(3-(trifluoromethyl)phenoxy)quinolin-8-amine (Intermediate-11, 40 mg, 0.132 mmol), 2-chloro-5-(pivalamidomethyl)benzoic acid (Intermediate-5, 200 mg, 0.743 mmol), oxalyl chloride (140 mg, 1.11 mmol), DMF (1 drop) and DIPEA (52 mg, 0.40 mmol) in CH2Cl2 (5 mL) to afford 15 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.5 (s, 1H), 9.01 (d, J=7.8 Hz, 1H), 8.60 (d, J=4.8 Hz, 1H), 8.05 (d, J=8.7 Hz, 1H), 7.71-7.60 (m, 4H), 7.48-7.38 (m, 4H), 6.64 (d, J=5.1 Hz, 1H), 6.05 (br s, 1H), 4.49 (d, J=6.0 Hz, 2H), 1.23 (s, 9H); MS [M+H]+: 556.19.
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14](C=O)=[CH:13][C:12]=2[N+:19]([O-:21])=[O:20])[CH2:4][CH2:3]1.[CH:22]([O:27][CH3:28])([O:25][CH3:26])OC.Cl.C(=O)([O-])[O-].[K+].[K+]>ClCCl.CO>[CH3:28][O:27][CH:22]([O:25][CH3:26])[C:14]1[CH:17]=[CH:18][C:11]([O:10][CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][O:2][CH2:7][CH2:6]2)=[C:12]([N+:19]([O-:21])=[O:20])[CH:13]=1
Reactant: O=Cc1ccc(OCCN2CCOCC2)c([N+](=O)[O-])c1
Reactant: COC(OC)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: COC(OC)c1ccc(OCCN2CCOCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.4 %

Procedure:
A solution of 4-(2-morpholinoethoxy)-3-nitrobenzaldehyde hydrochloride obtained in Step 1 (2.97 g, 9.38 mmol) in dichloromethane (10.0 mL) was added with trimethyl orthoformate (15.0 mL, 13.7 mmol) and a 10% solution of hydrogen chloride in methanol (5.00 mL), followed by stirring at room temperature for 4 hours. The reaction mixture was added with potassium carbonate (10.0 g, 72.4 mmol), then stirred at room temperature for 5 hours, and the solvent was evaporated under reduced pressure. The residue was added with water (50 mL) and was extracted with ethyl acetate (50 mL×3). After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to obtain 4-dimethoxymethyl-1-(2-morpholinoethoxy)-2-nitrobenzene (2.98 g, 97%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:27](OCC)[O:28]CC)=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].Cl>CC(C)=O>[CH3:1][C:2]1[NH:3][C:4]([CH:27]=[O:28])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(C(OCC)OCC)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
To a solution of diethyl 2-methyl-4-(2-nitrophenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.1563 g) in acetone (10 ml) was added 6 N-hydrochloric acid (2.5 ml) and stirred at room temperature for 30 minutes. After removing acetone, water was added to the residue and neutralized with aqueous solution of sodium bicarbonate. The precipitated solid was collected by filtration, washed with water and then dried to give yellowish powder of diethyl 2-methyl-4-(2-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (0.9407 g). The product was recrystallized from a mixture of ethanol and n-hexane to give the pure product, m.p. 101° to 103° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH:13]([NH2:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[NH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:28]1(=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH:13]([NH:20][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:14][CH2:15][CH2:16][CH:17]([CH3:18])[CH3:19])[NH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCCC1
Reactant: CC(C)CCCC(N)c1nc(-c2cccc(Br)c2)c[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)CCCC(NC1CCCCC1)c1nc(-c2cccc(Br)c2)c[nH]1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
A mixture containing 1-(4-(3-bromophenyl)-1H-imidazol-2-yl)-5-methyl-1-hexanamine (obtained at stage 13777.3; 0.8 g; 0.0019 mol), triethylamine (0.4 ml; 0.003 mol) and cyclohexanone (0.32 ml; 0.0023 mol) in 10 ml methanol was agitated for about 30 minutes at about 23° C. Sodium triacetoxyborohydride (630 mg; 0.003 mol) was then added. The reaction mixture was agitated for about 16 hours and then poured into water. After extraction with ethyl acetate, the organic phase was washed with a saturated sodium chloride solution and then dried over magnesium sulfate. The solvent was evaporated and the residue purified over a silica column (eluent: mixture CH2Cl2—MeOH/95-05). A white-colored powder was obtained with a yield of 38%. Melting point: 236-238° C. MH+=418.2.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11]([O:13]C(C)(C)C)=O)[C@H:8]([C:18]([OH:20])=O)[CH2:7]1)[CH:2]=[CH2:3].[CH2:21]([O:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]=1C(Cl)=O)[CH3:22].[CH2:37]([N:39]1[C:51]2[CH:50]=[CH:49][C:48]([NH2:52])=[CH:47][C:46]=2[C:45]2[C:40]1=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH3:38]>>[CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11]([C:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:32]=[CH:33][C:24]=2[O:23][CH2:21][CH3:22])=[O:13])[C@H:8]([C:18]([NH:52][C:48]2[CH:49]=[CH:50][C:51]3[N:39]([CH2:37][CH3:38])[C:40]4[C:45]([C:46]=3[CH:47]=2)=[CH:44][CH:43]=[CH:42][CH:41]=4)=[O:20])[CH2:7]1)[CH:2]=[CH2:3]
Reactant: CCOc1ccc2ccccc2c1C(=O)Cl
Reactant: C=CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Product: C=CCON=C1C[C@@H](C(=O)Nc2ccc3c(c2)c2ccccc2n3CC)N(C(=O)c2c(OCC)ccc3ccccc23)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, 2-ethoxy-1-naphthoyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 60% purity by LC/MS. MS(ESI+): m/z=575.4.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:21]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][C@@:19]2([CH3:28])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:29])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.Cl.C(Cl)(=O)C.[Br:35]Br.C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[Br:35][CH2:13][C:12](=[O:14])[C@@H:11]1[C@:15]2([CH3:29])[C@H:8]([C@H:7]3[C@H:18]([CH2:17][CH2:16]2)[C@:19]2([CH3:28])[C@H:4]([CH2:3][C@H:2]([OH:1])[C@@H:21]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH2:20]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](N5CCOCC5)C[C@]4(C)[C@H]3CC[C@]12C
Reactant: BrBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)Cl
Product: C[C@]12C[C@H](N3CCOCC3)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)CBr)CC[C@@H]12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred suspension of 100 g of (2β,3α,5α)-3-hydroxy-2-(4-morpholinyl)pregnan-20-one, prepared according to British Patent 1,039,441, in 2.5 l of methanol were added 81 ml of 3M methanolic hydrogen chloride and 10 ml of acetyl chloride. Bromine (16.6 ml) in 1 l of methanol was added dropwise over 1.5 h. The mixture was stirred at room temperature for a further 20 min and then poured into 18 l of water. Aqueous sodium carbonate solution was added until the pH exceeded 9.0 and the precipitated solid was filtered, washed with water and dissolved in dichloromethane. The solution was dried over sodium sulfate, the solvent removed, and the residue crystallized from acetone-hexane to give 46 g of (2β,3α,5α)-21-bromo-3-hydroxy-2-(4-morpholinyl)pregnan-20-one. 5.0 g of this 21-bromo compound were dissolved in 50 ml of 1-methyl-2-pyrrolidinone and 2.5 g of lithium chloride were added. The mixture was stirred at 80° C. under nitrogen for 2 h, cooled to room temperature and poured into 500 ml of water. The precipitated solid was filtered off, washed with water and dissolved in dichloromethane. The solution was dried over sodium sulfate, the solvent removed, and the residue crystallized from acetone-hexane to give 2 g of (2β,3α,5α)-21-chloro-3-hydroxy-2-(4-morpholinyl)pregnan-20-one as in Example 1.
Reaction SMILES: [F:1][CH:2]([F:48])[C:3]1[C:11]2[C:10]([F:13])([F:12])[CH2:9][CH2:8][C:7]([F:15])([F:14])[C:6]=2[N:5]([CH2:16][C:17]([NH:19][C@H:20]([C:30]2[C:35]([C:36]3[CH:37]=[CH:38][C:39]([F:45])=[C:40]([CH:44]=3)[C:41]([NH2:43])=[O:42])=[CH:34][N:33]=[C:32]([NH:46][CH3:47])[N:31]=2)[CH2:21][C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=2)=[O:18])[N:4]=1.NC[CH2:51][OH:52].BrC1C([C@@H](NC(=O)CN2C3C(F)(F)CCC(F)(F)C=3C(C(F)F)=N2)CC2C=C(F)C=C(F)C=2)=NC(S(C)(=O)=O)=NC=1>>[F:48][CH:2]([F:1])[C:3]1[C:11]2[C:10]([F:12])([F:13])[CH2:9][CH2:8][C:7]([F:14])([F:15])[C:6]=2[N:5]([CH2:16][C:17]([NH:19][C@H:20]([C:30]2[C:35]([C:36]3[CH:37]=[CH:38][C:39]([F:45])=[C:40]([CH:44]=3)[C:41]([NH2:43])=[O:42])=[CH:34][N:33]=[C:32]([NH:46][CH2:47][CH2:51][OH:52])[N:31]=2)[CH2:21][C:22]2[CH:23]=[C:24]([F:29])[CH:25]=[C:26]([F:28])[CH:27]=2)=[O:18])[N:4]=1
Reactant: NCCO
Reactant: CNc1ncc(-c2ccc(F)c(C(N)=O)c2)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1
Agent: CS(=O)(=O)c1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1
Product: NC(=O)c1cc(-c2cnc(NCCO)nc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)ccc1F

Procedure:
The title compound (26) was prepared according to the method presented for the synthesis of compound 14B of Example 14 starting with 2-aminoethanol and 12C. 1H NMR (400 MHz, CD3OD) δ 8.83 (d, J=7.7 Hz, 1H), 8.06 (s, 2H), 7.49-7.32 (m, 2H), 7.21 (dd, J=10.7, 8.5 Hz, 1H), 7.02-6.58 (m, 2H), 6.45 (d, J=6.1 Hz, 2H), 5.22 (m, 1H), 5.05 (s, 2H), 3.86-3.58 (m, 4H), 3.18-2.85 (m, 2H), 2.66-2.23 (m, 4H). MS (m/z) 716.23 [M+H]+.
Reaction SMILES: [C:1]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=2[F:23])=[CH:12][CH:11]=1)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>O>[CH2:1]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=2[F:23])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC(=O)c1ccc(-c2ccc(Br)cc2F)cc1
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCc1ccc(-c2ccc(Br)cc2F)cc1
Reaction time: 6 h
Yield: 70.9 %

Procedure:
In a reactor were placed 3.75 g of 4-octanoyl-2'-fluoro-4'-bromobiphenyl and 20 ml of trifluroacetic acid, to which was added 2.4 g of triethylsilane at room temperature and stirred for 6 hours. Then, the reaction solution was added into water, extracted into benzene, washed sequentially with water, aqueous sodium hydrogencarbonate, and again water, and dehydrated over Glauber's salt. After the solvent was distilled off, the residue was evaporated in a glass tube oven (GTO) to obtain 2.56 g of 4-octyl-2'-fluoro-4'-bromobiphenyl (71.1%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][S:10][CH:9]1[C:13]([OH:15])=O)=O)(C)(C)C.C1C=CC(/C(/C2C=CC([N+]([O-])=O)=CC=2)=N/O)=CC=1.[C:34]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1.[O:50]1[CH:54]=[CH:53][CH:52]=[C:51]1[CH2:55][NH2:56]>>[C:34]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:39]=[CH:38][C:37]([S:40]([N:8]2[CH2:12][CH2:11][S:10][CH:9]2[C:13]([NH:56][CH2:55][C:51]2[O:50][CH:54]=[CH:53][CH:52]=2)=[O:15])(=[O:42])=[O:41])=[CH:36][CH:35]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCSC1C(=O)O
Reactant: NCc1ccco1
Agent: O=[N+]([O-])c1ccc(/C(=N\O)c2ccccc2)cc1
Product: O=C(NCc1ccco1)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the general solid phase method as outlined Example 33, starting from 3-(tert-butoxycarbonyl)-1,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, 1,1′-biphenyl-4-sulfonyl chloride and 2-furylmethanamine, the title compound was obtained in 92.2% purity by HPLC.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[C@H:11]([CH3:22])[O:10][C:9]1([CH3:24])[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25]1([C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[NH:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:32]=[C:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:17][CH:16]=2)[C@H:11]([CH3:22])[O:10][C:9]1([CH3:24])[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CCc1ccc(Br)cc1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CCc1ccc(N=C(c2ccccc2)c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 20 h
Yield: 81.7 %

Procedure:
To a solution of (4S,5S)-4-[2-(4-bromo-phenyl)-ethyl]-2,2,5-trimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (3.13 g) in toluene (30 ml) were added diphenylmethanimine (1.71 g) and sodium tert-butoxide (1.06 g). The reaction mixture was degassed by bubbling argon through the mixture for several minutes. BINAP (489 mg) and Pd2(dba)3 (216 mg) were then added and the reaction mixture was stirred at 100° C. for 20 h. The reaction mixture was then cooled to room temperature, poured into EtOAc, and extracted with water. The organic layer was separated, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, gradient: 0% to 30% EtOAc in hexane) to afford (4S,5S)-4-{2-[4-(benzhydrylidene-amino)-phenyl]-ethyl}-2,2,5-trimethyl-oxazolidine-3-carboxylic acid tert-butyl ester as a yellow oil (3.2 g, 82%). MS (ISP): 499.3 ([M+H).
Reaction SMILES: [CH2:1]([NH:4][C:5](=[NH:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:2]#[CH:3].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:23]([CH:25]([C:29](Cl)=[O:30])[C:26](Cl)=[O:27])[CH3:24]>C1COCC1>[CH2:23]([C:25]1[C:29](=[O:30])[N:4]([CH2:1][C:2]#[CH:3])[C:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[N:12][C:26]=1[OH:27])[CH3:24]
Reactant: C#CCNC(=N)c1ccccc1
Reactant: CCC(C(=O)Cl)C(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCn1c(-c2ccccc2)nc(O)c(CC)c1=O
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 93.6 %

Procedure:
To a cold (-78° C.) solution of N-propargylbenzamidine (5.50 g, 34.77 mmol) in 150 mL of THF was added sodium bis(trimethylsilyl)amide (36.51 mL, 36.51 mmol, 1.05 equiv, 1M solution in THF) over 20 minutes. The reaction mixture was stirred for 5 minutes at -78° C., followed by the addidion of a cold (-78° C.) solution of ethylmalonyl dichloride (6.46 g, 38.25 mmol, 1.1 equiv.) in 150 mL of THF via a canula over 2 hours. After stirring for 30 minutes, the reaction mixture was quenched with 100 mL of water, warmed to room temperature, and diluted with 300 mL of ethyl acetate and 100 mL of water. The organic layer was successively washed with 200 mL of water and 200 mL of saturated sodium chloride, dried (MgSO4), filtered, and concentrated to give a solid. The crude mixture was azeotropically evaporated with 200 mL of toluene to remove residual hexamethyldisilazane, affording 8.28 g of 5-ethyl-6-hydroxy-2-phenyl-3-propargyl-4(3H)-pyrimidinone which was used without further purification.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[NH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[C:13]([C:17]1[CH:21]=[C:20]([NH:22][C:23]([NH:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][CH:27]=2)=[O:24])[N:19]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([OH:42])[CH:37]=2)[N:18]=1)([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C.Cl.[Na+].[Cl-]>C(Cl)Cl>[C:13]([C:17]1[CH:21]=[C:20]([NH:22][C:23]([NH:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][CH:27]=2)=[O:24])[N:19]([C:36]2[CH:37]=[C:38]([O:42][S:2](=[O:4])(=[O:3])[NH:5][C:6]([N:8]3[CH2:12][CH2:11][CH2:10][CH2:9]3)=[O:7])[CH:39]=[CH:40][CH:41]=2)[N:18]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: C1CCNC1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc3ccccc23)n(-c2cccc(O)c2)n1
Reactant: O=C=NS(=O)(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc3ccccc23)n(-c2cccc(OS(=O)(=O)NC(=O)N3CCCC3)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 1.4 %

Procedure:
To a stirring solution of chlorosulfonyl isocyanate (0.35 g, 5 mmol) in CH2Cl2 (20 mL) at 0° C. was added pyrrolidine (0.18 g, 5 mmol) at such a rate that the reaction temperature did not rise above 5° C. After stirring for 2 h, a solution of Example 41 (1.10 g, 6.5 mmol) and triethylamine (0.46 g, 9 mmol) in CH2Cl2 (20 mL) was added. When the addition was complete, the mixture was allowed to warm to RT and stirred overnight. The reaction mixture was poured into 10% HCl (10 mL) saturated with NaCl, the organic layer was separated and the aqueous layer extracted with ether (20 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo, purified by preparative HPLC to yield (pyrrolidine-1-carbonyl)sulfamic acid 3-[3-tert-butyl-5-(3-naphthalen-1-yl-ureido)-pyrazol-1-yl]phenyl ester (40 mg). 1H NMR (CDCl3): δ 9.12 (brs, 1H), 8.61 (brs, 1H), 7.85-7.80 (m, 3H), 7.65 (d, J=8.0 Hz, 2H), 7.53-7.51 (m, 1H), 7.45-7.25 (m, 5H), 6.89 (s, 4H), 3.36-3.34 (brs, 1H), 3.14-3.13 (brs, 2H), 1.69 (brs, 2H), 1.62 (brs, 2H), 1.39 (s, 9H); MS (ESI) m/z: 577 (M+H+).