Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[C@H:30]([CH3:31])[C@@H:29]2[C@@:5]([C:33]([OH:35])=[O:34])([CH2:6][CH2:7][C@@:8]3([CH3:32])[C@:13]4([CH3:28])[CH2:14][CH2:15][C@H:16]5[C@@:21]([CH2:23][OH:24])([CH3:22])[C@@H:20]([OH:25])[C@H:19]([OH:26])[CH2:18][C@:17]5([CH3:27])[C@H:12]4[CH2:11][CH:10]=[C:9]32)[CH2:4][CH2:3]1.[N+](=[CH2:38])=[N-].CCOCC>CO>[CH3:1][C@H:2]1[C@H:30]([CH3:31])[C@@H:29]2[C@@:5]([C:33]([O:35][CH3:38])=[O:34])([CH2:6][CH2:7][C@@:8]3([CH3:32])[C@:13]4([CH3:28])[CH2:14][CH2:15][C@H:16]5[C@@:21]([CH2:23][OH:24])([CH3:22])[C@@H:20]([OH:25])[C@H:19]([OH:26])[CH2:18][C@:17]5([CH3:27])[C@H:12]4[CH2:11][CH:10]=[C:9]32)[CH2:4][CH2:3]1
Reactant: C[C@H]1[C@H](C)CC[C@]2(C(=O)O)CC[C@]3(C)C(=CC[C@@H]4[C@@]5(C)C[C@@H](O)[C@H](O)[C@@](C)(CO)[C@@H]5CC[C@]43C)[C@H]12
Reactant: C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)[C@]12CC[C@@H](C)[C@H](C)[C@H]1C1=CC[C@@H]3[C@@]4(C)C[C@@H](O)[C@H](O)[C@@](C)(CO)[C@@H]4CC[C@@]3(C)[C@]1(C)CC2
Temperature: 0 °C
Yield: 95 %

Procedure:
Asiatic acid (500 mg) was dissolved in methanol (25 ml), and the solution was cooled to 0° C. An excess amount of diazomethane/ether solution was added, and the resultant mixture was stirred at room temperature for 1 hour. The solvent was removed by evaporation under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane/methanol=30:1) to give 490 mg of white solid(yield: 95%). The product was recrystallized from ethyl acetate to obtain needle-like crystals.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[C:11]1[C:16]([CH2:17][CH3:18])=[C:15]([Cl:19])[N:14]=[CH:13][N:12]=1.[CH3:20][C:21]([O:24][C:25](=[O:40])[C@H:26]([CH2:38][NH2:39])[NH:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])([CH3:23])[CH3:22].C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C.O>[Cl:19][C:15]1[N:14]=[CH:13][N:12]=[C:11]([NH:39][CH2:38][C@@H:26]([C:25]([O:24][C:21]([CH3:23])([CH3:22])[CH3:20])=[O:40])[NH:27][C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[C:16]=1[CH2:17][CH3:18]
Reactant: CCc1c(Cl)ncnc1Cl
Reactant: CC(C)(C)OC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1c(Cl)ncnc1NC[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 120 °C
Yield: 72 %

Procedure:
10 ml of diisopropylethylamine is added to a mixture of 3.8 g (21 mmoles) of 4,6-dichloro-5-ethyl-pyrimidine and 4.4 g (15 mmoles) of (1,1-dimethylethyl)-3-amino-N-[(phenylmethoxy)carbonyl]alaninate (prepared according to J. Med. Chem. (2001), 44(8), 1158-1176) in 50 ml of dimethylformamide, then this mixture is heated at 120° C. for 6 hours. Then the dimethylformamide is eliminated under vacuum and the residue is taken up in a mixture of ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is decanted then dried over magnesium sulphate and the solvent is eliminated by evaporation under vacuum. The residue is chromatographed on silicagel eluting with a gradient of 100% heptane to heptane-ethyl acetate 50-50. 4.7 g (Yield=70%) of expected product is obtained in the form of an oil.
Reaction SMILES: [CH:1]12[O:6][CH:5]1[CH2:4][O:3][CH2:2]2.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O1CCOCC1.C(OCC)(=O)C>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C@@H:5]2[CH2:4][O:3][CH2:2][C@H:1]2[OH:6])=[CH:10][CH:9]=1
Reactant: Oc1ccc(Br)cc1
Reactant: C1OCC2OC12
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O[C@@H]1COC[C@H]1Oc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
3,6-Dioxabicyclo[3.1.0]hexane (100 g, 1.16 mol), 4-bromophenol (241.1 g, 1.39 mol), cesium carbonate (492 g, 1.51 mol) and benzyltriethylammonium chloride (52.9 g, 0.23 mol) were suspended in dioxane (1 L) and heated at reflux for 18 hours. The reaction was cooled to room temperature and diluted with ethyl acetate, then washed with saturated aqueous sodium carbonate solution. The aqueous layer was extracted with ethyl acetate, and the combined organic portions were dried over sodium sulfate, filtered and concentrated in vacuo, to provide crude product, which solidified on standing. This was used without purification in the next step. Yield: 354 g, >100%, assumed quantitative. Material from a smaller-scale experiment carried out in similar fashion was purified by silica gel chromatography for characterization (Gradient: 10% to 35% ethyl acetate in heptane), to afford trans-4-(4-bromophenoxy)tetrahydrofuran-3-ol as a solid. 1H NMR (400 MHz, CDCl3) δ 2.09 (br d, J=4.5 Hz, 1H), 3.83 (m, 1H), 3.91 (dd, J=10.3, 2.1 Hz, 1H), 4.05 (dd, J=10.1, 4.0 Hz, 1H), 4.26 (dd, J=10.4, 4.9 Hz, 1H), 4.41 (br s, 1H), 4.67 (m, 1H), 6.81 (d, J=9.0 Hz, 2H), 7.40 (d, J=9.1 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.O[C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C@@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1)[N:6]=[CH:5]2
Reactant: Brc1ccc2[nH]ncc2c1
Reactant: CCOC(=O)[C@H]1CC[C@H](O)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CC[C@@H](n2ncc3cc(Br)ccc32)CC1
Temperature: 50 °C
Reaction time: 13 h

Procedure:
A solution of 5-bromoindazole (5.00 g), ethyl trans-4-hydroxycyclohexanecarboxylate (8.73 g), triphenylphosphine (13.3 g) in THF (150 mL) was stirred at 0° C. for 15 minutes. To the reaction solution was added dropwise diethylazodicarboxylate (9.03 g) under nitrogen atmosphere at 0° C., and the mixture was stirred at 50° C. for 13 hours. Then, the solvent was removed out, and ethyl acetate (100 mL) and petroleum ether (30 mL) were added thereto. The mixture was stirred at room temperature for 2 hours. The reaction solution was filtered, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:80-1:15 as the eluting solvent) to give Compound Q14 (3.50 g).
Reaction SMILES: S([O:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([O:15][CH3:16])=[CH:8][C:7]=1[CH3:17])(=O)(=O)C.[OH-].[Na+].Cl>CO.O>[CH3:17][C:7]1[CH:8]=[C:9]([O:15][CH3:16])[C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:6]=1[OH:5]
Reactant: COc1cc(C)c(OS(C)(=O)=O)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(C)c(O)cc1[N+](=O)[O-]
Yield: 100 %

Procedure:
In 110 ml of methanol was dissolved 15.5 g (59.4 mmol) of 2-methyl-4-methoxy-5-nitrophenyl mesylate. Then 6.5 g of sodium hydroxide dissolved in 20 ml of water was added thereto. The obtained mixture was heated under reflux for 1 hour. After cooling, concentrated hydrochloric acid was added to thereby acidify the mixture. Then 400 ml of water was added and crystals were precipitated. The crystals were collected by filtration and washed with water. Thus 10.9 g (59.4 mmol) of 2-methyl-4-methoxy-5-nitrophenol was obtained. The yield was 100%.
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[OH:17])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:30]Br>C(Cl)(Cl)(Cl)Cl>[N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH2:16][Br:30])[CH:13]=[CH:12][C:11]=2[OH:17])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: Cc1ccc(O)c(-n2nc3ccccc3n2)c1
Reactant: BrBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Oc1ccc(CBr)cc1-n1nc2ccccc2n1
Temperature: 25 °C

Procedure:
2-(2H-Benzotriazole-2-yl)-4-bromomethylphenol was prepared from the bromination of 2-(2H-Benzotriazole-2-yl)-4-methylphenol using azobis isobutyronitrile (AIBN) as an initiator. In a 500 ml three-necked round bottomed flask, 5 g (0.0223 mol) of 2-(2H-Benzotriazole-2-yl)-4-methylphenol and 100 mg of AIBN were taken and dissolved in 150 ml of dry carbon tetrachloride. In a separate conical flask 4.18 g (1.5 ml, 0.03 mol) of bromine was dissolved in 75 ml of dry carbon tetrachloride and solution was transferred to a cylindrical funnel with pressure equalizing tube. Three-necked round-bottomed flask containing solution of 2-(2H-Benzotriazole-2-yl)-4-methylphenol was kept in oil-bath with temperature 47° C. Nitrogen was bubbled through the solution for creating inert atmosphere. Cylindrical funnel containing bromine solution was mounted on the three-necked round-bottomed flask. Solution in the flask was continuously stirred with the help of magnetic stirrer. Bromine solution was added, drop-by-drop, from funnel to the flask for a span of 4-5 hours till all the solution was poured out. After that heating was stopped and the final reaction mixture was allowed to cool at room temperature. Product was separated by solvent evaporation. Finally the product was purified by recrystallization from acetone. The yield of 2-(2H-Benzotriazole-2-yl)-4-bromomethylphenol was 5.5 g (80%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:10][CH2:11][OH:12])[C:5]([C:17]#[C:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:4]([CH3:28])[N:3]=1>CCO.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:10][CH2:11][OH:12])[C:5]([CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:4]([CH3:28])[N:3]=1
Reactant: CCCC[C@@H](CCO)Nc1nc(N)nc(C)c1C#CCNC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCCC[C@@H](CCO)Nc1nc(N)nc(C)c1CCCNC(=O)OC(C)(C)C
Yield: 75.2 %

Procedure:
The product from step (vii) (100 mg) and Pd/C (30 mg) in EtOH (5 mL) were hydrogenated under 3 bar at rt for 16 h. The catalyst was filtered off and the solvent evaporated to give the subtitle compound 76 mg.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1B1OC(C)(C)C(C)(C)O1>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccnc(Cl)c1
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Product: COc1ccnc(-c2cc([N+](=O)[O-])ccc2F)c1

Procedure:
2-Chloro-4-methoxypyridine (2.0 g, 13.9 mmol) was coupled to 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (4.75 g, 17.8 mmol) using the method in Example 47. Purification by chromatography on silica gel eluting with dichloromethane containing 20% isohexane then recrystallisation from toluene/isohexane gave 2-(2-fluoro-5-nitrophenyl)-4-methoxypyridine as a white solid: δH (400 MHz, CDCl3) 3.93 (3H, s), 6.88 (1H, dd, J 6 and 2), 7.31 (1H, t, J 10), 7.35-7.37 (1H, m), 8.24-8.29 (1H, m), 8.59 (1H, d, J 6), 8.98 (1H, dd, J 7 and 3).
Reaction SMILES: [CH3:1][C:2](=[CH2:33])[CH2:3][O:4][C@@H:5]1[CH2:9][N:8]([CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH2:7][C@H:6]1[NH:16][C:17](=[O:32])[CH2:18][NH:19][C:20](=[O:31])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1>CO>[CH2:3]([O:4][C@@H:5]1[CH2:9][N:8]([CH:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[CH2:7][C@H:6]1[NH:16][C:17](=[O:32])[CH2:18][NH:19][C:20](=[O:31])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=1)[CH:2]([CH3:33])[CH3:1]
Reactant: C=C(C)CO[C@@H]1CN(C2CCOCC2)C[C@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Solvent: CO
Product: CC(C)CO[C@@H]1CN(C2CCOCC2)C[C@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1

Procedure:
To a solution of rel-N-(2-{[(3R,4R)-4-[(2-methylprop-2-en-1-yl)oxy]-1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide in methanol (400 μL) was added and Palladium (10%) on Carbon (50 mg) the was purged with hydrogen gas for two minutes; the reaction was then subjected to 1 atmosphere of hydrogen gas overnight. The flask was purged with Argon; the mixture was filtered, then purified by preparative HPLC to afford the title compound as a white solid. 1H-NMR (MeOD) δ: 0.893 (d, J=1.63 Hz, 3H), 0.915 (d, J=1.63 Hz, 3H), 1.51 (m, 2H), 1.77-1.87 (m, 3H), 2.44 (m, 1H), 2.64 (m, 1H), 2.71 (m, 1H), 3.10 (m, 2H), 3.21 (m, 1H), 3.38 (m, 2H), 3.87 (m, 1H), 3.95 (m, 3H), 4.04 (s, 2H), 4.29 (m, 1H), 7.70 (t, J=7.7 Hz, 1H), 7.87 (d, J=7.7 Hz, 1H), 8.15 (d, J=7.7 Hz, 1H), 8.22 (s, 1H) MS m/z: 472 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1)[CH2:5][NH:6][CH3:7].CCN(C(C)C)C(C)C.[C:25]([C:27]1[CH:28]=[C:29]([C:37](Cl)=[O:38])[C:30]2[C:35]([CH:36]=1)=[CH:34][CH:33]=[CH:32][CH:31]=2)#[N:26]>C(Cl)Cl>[C:25]([C:27]1[CH:28]=[C:29]([C:37]([N:6]([CH2:5][CH:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:3][CH2:2][OH:1])[CH3:7])=[O:38])[C:30]2[C:35]([CH:36]=1)=[CH:34][CH:33]=[CH:32][CH:31]=2)#[N:26]
Reactant: CNCC(CCO)c1ccc(C#N)cc1
Reactant: N#Cc1cc(C(=O)Cl)c2ccccc2c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC(CCO)c1ccc(C#N)cc1)C(=O)c1cc(C#N)cc2ccccc12
Yield: 67.9 %

Procedure:
4-{3-Hydroxy-1-[(methylamino)methyl]propyl}benzonitrile (0.55 g, 2.69 mmol) and DIPEA (0.77 g, 5.9 mmol) were dissolved in CH2Cl2 (5 mL). 3-Cyano-1-naphthoyl chloride (sse Method 11; 0.58 g, 2.69 mmol) was added in portions with stirring and cooling (external ice-bath). The mixture was stirred for 2 h with cooling and then diluted with CH2Cl2 (10 mL). The solution was washed twice with water, twice with a saturated aqueous KHSO4 solution and then with brine. The solvent was removed by evaporation and the residue flash chromatographed on silica gel (CH2Cl2-MeOH, 9:1). There was obtained 0.70 g (67%) of 3-cyano-N-[2-(4-cyanophenyl)-4-hydroxybutyl]-N-methyl-1-naphthamide as a white solid. 1H NMR (400 MHz, CDCl3): 1.4-2.5 (cm, 2H), 2.6 (s, 3H), 3.1-4.6 (cm, 6H), 6.4-7.8 (cm, 8H), 7.9 (d, 1H), 8.2 (s, 1H); LCMS: m/z 384 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[CH:10][C:9]=1[N+:13]([O-:15])=[O:14].[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)([O-:18])=[O:17]>>[N+:13]([C:9]1[CH:10]=[N:11][N:12]2[C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH:23]2[C:22]1[CH:25]=[CH:26][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=1)([O-:15])=[O:14]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccccc1-c1[nH]ncc1[N+](=O)[O-]
Product: O=[N+]([O-])c1ccc(C2Nc3ccccc3-c3c([N+](=O)[O-])cnn32)cc1
Yield: 90 %

Procedure:
5-(o-Aminophenyl)-4-nitropyrazole is reacted with p-nitrobenzaldehyde as described in Example 11. 1-Nitro-5-(p-nitrophenyl)-5,6-dihydropyrazolo[1,5-c]quinazoline is obtained. M.p.: 190°-191° C. Yield: 90%.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][S:6][C:7]1[S:8][C:9]([NH:12][C:13]([N:15]([CH:23]2[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]2)[CH:16]2[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH2:17]2)=[O:14])=[N:10][N:11]=1)C.CC1CCC(NC2CCC(C)CC2)CC1.C(OC(=O)CSC1SC(N)=NN=1)C>>[CH3:29][CH:26]1[CH2:25][CH2:24][CH:23]([N:15]([CH:16]2[CH2:17][CH2:18][CH:19]([CH3:22])[CH2:20][CH2:21]2)[C:13](=[O:14])[NH:12][C:9]2[S:8][C:7]([S:6][CH2:5][C:4]([OH:30])=[O:3])=[N:11][N:10]=2)[CH2:28][CH2:27]1
Reactant: CCOC(=O)CSc1nnc(NC(=O)N(C2CCC(C)CC2)C2CCC(C)CC2)s1
Agent: CC1CCC(NC2CCC(C)CC2)CC1
Agent: CCOC(=O)CSc1nnc(N)s1
Product: CC1CCC(N(C(=O)Nc2nnc(SCC(=O)O)s2)C2CCC(C)CC2)CC1

Procedure:
{5-[3,3-Bis-(4-methyl-cyclohexyl)-ureido]-[1,3,4]thiadiazol-2-ylsulfanyl}-acetic acid ethyl ester prepared from bis-(4-methyl-cyclohexyl)-amine and ethyl-2-[5-amino-1,3,4-thiadiazol-2-yl-thio]acetate as described in general procedures (A) and (B). Hydrolysis using general procedure (F) gave the title compound.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:9])([F:8])[C@H:5]([OH:7])[CH3:6].F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1>CN(C=O)C>[F:3][C:4]([F:9])([F:8])[C@@H:5]([CH3:6])[O:7][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1
Reactant: C[C@@H](O)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](Oc1ccc(N)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
Sodium hydride (55%, 3.22 g) was added to DMF (20 mL) and the mixture was cooled to 0° C. Then, (R)-1,1,1-trifluoro-2-propanol (8.5 g) [CAS 17628-73-8] was added over a period of 1 h and stirring was continued for 30 minutes at 0° C. A solution of 1-fluoro-4-nitro-benzene [CAS 350-46-9] (10 g) in DMF (15 mL) was added over a period of 1.5 h while the internal temperature was kept between 5 to 15° C. Following addition, the mixture was allowed to warm to RT and stirring was continued for another 12 h. The reaction mixture was acidified and partitioned between ethyl acetate and water. The organic layer was separated, dried over Na2SO4 and evaporated to dryness. The residue was dissolved in methanol (150 ml) and Pd on carbon (10% Pd, 1 g) was added. The mixture was then hydrogenated at RT for 12 hours. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to provide crude 4-((R)-2,2,2-trifluoro-1-methyl-ethoxy)-phenylamine as a dark liquid (14.5 g). MS (m/e): 206.1 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3C(OC(C)(C)C)=O)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.FC(F)(F)C(O)=O>ClCCl>[F:24][C:12]1[CH:13]=[C:14]([O:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:15]=[CH:16][C:11]=1[C:10]1[C:3]2[C:4](=[N:5][CH:6]=[N:7][C:2]=2[NH2:1])[N:8]([CH2:25][C@H:26]2[CH2:30][CH2:29][CH2:28][NH:27]2)[N:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1F)nn2C[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
Into a 100 mL, round-bottom flask, was placed a solution of tert-butyl (2R)-2-[[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidine-1-carboxylate (347 mg, 0.69 mmol, 1.00 equiv) in dichloromethane (50 mL). Trifluoroacetic acid (10 mL) dropwise with stirring over 10 min and the resulting solution was stirred for 3 h at 25° C. The resulting mixture was concentrated under vacuum to give 0.278 g (crude) of 3-(2-fluoro-4-phenoxyphenyl)-1-[(2R)-pyrrolidin-2-ylmethyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as brown oil.
Reaction SMILES: FC(F)(F)C(O)=O.C([NH:12][C:13](=[O:26])[C@@H:14]1[CH2:18][C@H:17](OC2C=CC=CC=2)[CH2:16][NH:15]1)(C)(C)C.[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[OH:37].C1(O)C=CC=CC=1>>[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[O:37][N:15]1[CH2:16][CH2:17][CH2:18][C@H:14]1[C:13]([NH2:12])=[O:26]
Reactant: Oc1ccc2ccccc2c1
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@H](Oc2ccccc2)CN1
Solvent: Oc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)[C@@H]1CCCN1Oc1ccc2ccccc2c1

Procedure:
Following substantially the same procedure for synthesizing N-t-butyl-4(S)-phenoxy-L-prolineamide trifluoroacetic acid salt as outlined in Example 1, Steps 6 through 8, but substituting 2-naphthol for the phenol used therein, the 2-naphthyloxy proline amide was produced.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=2[N:7]=1.[N+:20]([C:23]1[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=1)([O-:22])=[O:21].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([O:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([N+:20]([O-:22])=[O:21])[CH:24]=2)[C:5]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=2[N:7]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)nc(Cl)nc21
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(Oc3cccc([N+](=O)[O-])c3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.7 %

Procedure:
To a mixture of Compound 6-B (200 mg, 0.628 mmol) and 3-nitrophenol (96.2 g, 0.691 mmol) in dimethylformamide (2 mL) was added K2CO3 (173.7 mg, 1.26 mmol). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was then filtered. The filtrate was diluted with water, then extracted with ethyl acetate. The organic layer was washed with water, brine, and dried over Na2SO4. After filtration and removal of the volatiles in vacuo, the crude product was purified by flash column chromatography (PE/EA=20/1) affording Compound 6-C (200 mg, yield 75.6%, M+H+=421.92) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH2:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[C:17]([NH2:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].CCN(C(C)C)C(C)C.[N:40]1([CH2:46][CH:47]=[CH:48][C:49](Cl)=[O:50])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH2:22][CH2:23][CH2:24][N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[C:17]([NH:20][C:49](=[O:50])[CH:48]=[CH:47][CH2:46][N:40]4[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCCCN1CCOCC1
Reactant: O=C(Cl)C=CCN1CCCCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C=CCN1CCCCC1)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCCCN1CCOCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 2.9 %

Procedure:
N*4*-(3-Chloro-4-fluoro-phenyl)-7-(3-morpholin-4-yl-propoxy)-quinazoline-4,6-diamine (510 mg, 1.18 mmol) and DIPEA (620 μL, 3.55 mmol) were combined in tetrahydrofuran (10 mL) and cooled to 0° C. 4-Piperidin-1-yl-but-2-enoyl chloride (278 mg, 1.48 mmol) was added and the reaction stirred at 0° C. for 2 hours. The mixture was quenched with ethyl acetate, dried with MgSO4 and concentrated. The residue was purified using chromatography on silica eluting with 15%-20% MeOH in CH2Cl2 to yield the desired product (20 mg). 400 MHz 1H NMR (DMSO-d6) δ 8.82 (s, 1H), 8.50 (s, 1H), 8.11 (dd, 1H, J=6.9, 2.6 Hz), 7.77 (m, 1H), 7.40 (t, 1H, J=9.0 Hz), 7.25 (s, 1H), 6.76 (m, 1H), 6.53 (m, 1H), 4.23 (t, 2H, J=6.0 Hz), 3.55 (m, 4H), 3.08 (m, 2H), 2.40 (m, 10H), 1.96 (m, 2H), 1.29 (m, 6H). MS m/z 584 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([NH2:22])[CH:18]=4)[N:13]=3)[CH2:9][CH2:10][C:4]=2[CH:3]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>N1C=CC=CC=1>[CH3:25][S:26]([NH:1][C:2]1[CH:24]=[CH:23][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([NH:22][S:26]([CH3:25])(=[O:28])=[O:27])[CH:18]=4)[N:13]=3)[CH2:9][CH2:10][C:4]=2[CH:3]=1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)CCN(Cc1ccc3cc(N)ccc3n1)CC2
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc2c(c1)CCN(Cc1ccc3cc(NS(C)(=O)=O)ccc3n1)CC2

Procedure:
The title compound, m.p. 207°-210°, was prepared similarly to the procedure of Example 1 starting from 7-amino-3-(6-aminoquinol-2-ylmethyl)-1,2,4,5-tetrahydro-3H-3-benzazepine and methanesulphonyl chloride in pyridine.