Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C:15](=O)[CH:14]([NH:19][C:20](=[O:22])[CH3:21])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>O1CCCC1>[CH3:21][C:20]1[O:22][C:15]2[CH2:16][CH2:17][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:12][CH2:13][C:14]=2[N:19]=1
Reactant: CC(=O)NC1CCN(C(=O)OCc2ccccc2)CCC1=O
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nc2c(o1)CCN(C(=O)OCc1ccccc1)CC2
Yield: 814.9 %

Procedure:
3 g 4-acetylamino-5-oxo-azepane-1-carboxylic acid benzyl ester in 100 mL tetrahydrofuran and 3.8 g (methoxycarbonylsulfamoyl)triethylammonium hydroxide were heated in a sealed tube at 75° C. for 1 h. The solvent was evaporated and the residue was purified by chromatographie on silica gel (ethyl acetate/hexane 1:2) to yield 23 g of the desired product. (M+H)+: 287
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:19][C:20]3[CH:21]=[C:22]([CH:26]=[C:27]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[CH:28]=3)[C:23](O)=[O:24])=[C:7]([CH3:18])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1.C(Cl)CCl.[CH2:39]([NH2:41])[CH3:40].C1COCC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:39]([NH:41][C:23](=[O:24])[C:22]1[CH:26]=[C:27]([N:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)[CH:28]=[C:20]([NH:19][C:6]2[C:5]3[C:10](=[CH:11][C:2]([F:1])=[CH:3][CH:4]=3)[N:9]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:7]=2[CH3:18])[CH:21]=1)[CH3:40]
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Nc1cc(C(=O)O)cc(N2CCOCC2)c1
Reactant: CCN
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: ClCCCl
Product: CCNC(=O)c1cc(Nc2c(C)c(-c3ccccn3)nc3cc(F)ccc23)cc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure U by stirring 3-(7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-ylamino)-5-morpholinobenzoic acid (0.025 g, 0.055 mmol), DMAP (0.013 g, 0.109 mmol), EDC (0.021 g, 0.109 mmol), 2M ethanamine THF (0.035 mL, 0.071 mmol), and DCM (0.6 mL) at 23° C. for 1 hour. Purification by reverse-phase HPLC afforded N-ethyl-3-((7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)amino)-5-(4-morpholinyl)benzamide as a yellow amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.67-8.71 (1H, m), 8.61 (1H, s), 8.27 (1H, m), 8.09 (1H, dd, J=9.3, 6.2 Hz), 7.97-8.02 (1H, m), 7.84-7.91 (1H, m), 7.71-7.77 (1H, m), 7.45-7.52 (2H, m), 6.86-6.89 (1H, m), 6.59-6.62 (1H, m), 6.44-6.48 (1H, m), 3.69-3.75 (4H, m), 3.17-3.25 (2H, m), 3.05-3.11 (4H, m), 2.16-2.20 (3H, m), 1.04-1.10 (3H, m). Mass Spectrum (ESI) m/e=486.2 (M+1).
Reaction SMILES: [C:1](=[S:4])([SH:3])[NH2:2].[CH2:5]([O:7][C:8](=[O:14])[CH2:9][C:10](=O)[CH2:11]Cl)[CH3:6]>C(O)C>[CH2:5]([O:7][C:8](=[O:14])[CH2:9][C:10]1[N:2]=[C:1]([SH:3])[S:4][CH:11]=1)[CH3:6]
Reactant: NC(=S)S
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CCO
Product: CCOC(=O)Cc1csc(S)n1

Procedure:
An ammonium salt (102 g) of dithiocarbamic acid was dissolved in ethanol (700 mL), and a solution of 4-chloro-3-oxobutanoic acid ethyl ester (152 g) in ethanol (200 mL) was added dropwise under ice-cooling over 30 min. The temperature was gradually raised, and the mixture was heated under reflux for 2 hr. The reaction solution was concentrated under reduced pressure, water (1 L) was added thereto, and the precipitated solid was collected by filtration. This solid was dissolved in ethyl acetate (4 L), and the mixture was washed with water (2 L) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (500 mL) was added to the obtained solid, and the solid was washed by suspending and collected by filtration to give the title compound (165 g) as a slightly yellow solid.
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]1[C:18]2[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=2[Cl:19])[NH:12][C@@H:11]([C:21]([O:23]C)=[O:22])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CS(C)=O>[CH2:1]([NH:8][C@@H:9]1[C:18]2[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=2[Cl:19])[NH:12][C@@H:11]([C:21]([OH:23])=[O:22])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H]1C[C@H](NCc2ccccc2)c2c(Cl)cc(Cl)cc2N1
Solvent: CS(C)=O
Product: O=C(O)[C@H]1C[C@H](NCc2ccccc2)c2c(Cl)cc(Cl)cc2N1

Procedure:
This compound was prepared by the method given in Example 37 step b) using trans-4-benzylamino-5,7-dichloro-2-methoxycarbonyl-1,2,3,4-tetrahydroquinoline in place of trans-5,7-dichloro-2-methoxycarbonyl-4-phenylmethylcarbonylamino-1,2,3,4-tetrahydroquinoline to give the title compound as colourless crystals, m.p. 140°-143° C. δ (360 MHz, DMSO) 1.85 (1H, ddd, J=13.3, 12.4 and 3.0 Hz, CHACHBHCCHD), 2.73 (1H, dm, J=13.3 Hz, CHACHBHCCHD), 4.32 (2H, 2d, J=13.4 Hz, CH2C6H5), 4.46 (1H, m, CHACHBHCCHD), 4.48 (1H, m, CHACHBHCCHD), 6.70 (1H, d, J=2.1 Hz, 6-H or 8-H), 6.90 (1H, d, J=2.1 Hz, 6-H or 8-H), 7.12 (1H, s, ArNH), 7.43 (3H, m, ArH), 7.63 (2H, m, ArH); m/e (FAB-) 349 (M-1); Found C, 50.17; H, 6.22; N, 5.01. C17H16Cl2N2O2.1.8HCl.0.2 C6H14 requires C, 50.06; H, 4.78; N, 6.45%.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:11]=2[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C.N>C1(C)C=CC=CC=1>[C:1]1([C@@H:7]([NH:9][C@H:10]2[C@@H:11]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12][CH2:13][N:14]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:15]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C1=C(N[C@@H](C)c2ccccc2)CN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: N
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1N[C@@H](C)c1ccccc1
Reaction time: 20 h
Yield: 94 %

Procedure:
The product of Example 61A (62.3 g, 0.167 mol), NaBH(OAc)3 (150.0 g, 0.708 mol), and powdered 4A molecular sieves (133.0 g) in toluene (730 mL) in a 3-neck round bottom flask equipped with a mechanical stirrer, thermometer and addition funnel at 0° C. was treated with acetic acid (191 mL, 3.30 mol) dropwise. After the addition was complete, the ice-bath was removed and the mixture was stirred for 20 hours, filtered and the filtrate concentrated under reduced pressure. The residue was dissolved in ethyl acetate (1000 mL) and quenched by slow addition of saturated aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organics were dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure to provide the product as a ˜1:1.5 mixture of the two (cis) isomers (60.0 g, 0.159 mol, 94% yield). MS (DCI/NH3) m/z 377 (M+H)+.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Br[CH2:13][CH2:14][F:15].C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:15][CH2:14][CH2:13][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: FCCBr
Reactant: Oc1ccc2c(c1)NCCC2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Oc1ccc2c(c1)N(CCF)CCC2
Yield: 44 %

Procedure:
500 mg (3.35 mmol) 1,2,3,4-Tetrahydro-quinolin-7-ol are dissolved in 8 mL DMF and stirred at 60° C. overnight with 0.325 mL (1.3 eq) 1-bromo-2-fluoroethane, in the presence of 0.63 mL (1.1 eq) diisopropylethylamine. The reaction mixture is extracted with 0.1 N aqu. HCl and ethyl acetate. The combined organic extracts are washed with brine, dried over sodium acetate and evaporated. The residue is column chromatographed (silica gel, ethyl acetate/petroleum ether 1:2 to 1:1) to yield 290 mg (44%) desired product as a brown oil.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH2:14])=[O:7])([CH3:4])[CH3:3].C(OC(N1CCC(CN[C:30]([N:32]=[CH:33][N:34]([CH3:36])[CH3:35])=[S:31])CC1)=O)(C)(C)C>>[CH3:4][C:2]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:30]([N:32]=[CH:33][N:34]([CH3:36])[CH3:35])=[S:31])=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Reactant: CN(C)C=NC(=S)NCC1CCN(C(=O)OC(C)(C)C)CC1
Product: CN(C)C=NC(=S)NC[C@@H]1CCCN1C(=O)OC(C)(C)C

Procedure:
2-(S)-(3-dimethylaminomethylene-thioureidomethyl)-pyrrolidine-1-carboxylic acid 1,1-dimethylethyl ester was prepared from (S)-2-(aminomethyl)-1-pyrrolidinecarboxylic acid 1,1-dimethylethyl ester according to the procedure described in Example A (4-(3-dimethylaminomethylene -thioureidomethyl)-piperidine-1-carboxylic acid tert-butyl ester). Purified by column chromatography on silica gel (2:1 to 3:1 ethyl acetate/hexane eluant). Yellow solid. MS: 315.4 (M+H)+
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:10]=2[C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)=[O:12])[CH2:4][CH2:3]1.[CH:32](OCC)=[O:33]>CN(C)C=O>[CH3:24][O:23][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH3:22])[CH2:14][NH:13][C:11](=[O:12])[C:10]1[CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[CH:27]=[CH:28][C:9]=1[NH:8][C@H:5]1[CH2:6][CH2:7][C@H:2]([NH:1][CH:32]=[O:33])[CH2:3][CH2:4]1
Reactant: CCOC=O
Reactant: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2N[C@H]2CC[C@H](N)CC2)cc1OC
Solvent: CN(C)C=O
Product: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2N[C@H]2CC[C@H](NC=O)CC2)cc1OC

Procedure:
To a solution of 2-[(trans-4-aminocyclohexyl)amino]-N-(3,4-dimethoxybenzyl)-5nitrobenzamide (10 g) in dimethylformamide (60 mL) was added ethyl formate (200 mL), and the mixture was heated for 8 hours under reflux. The mixture was partitioned between ethyl acetate and water. The separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with a mixture of chloroform and methanol (20: 1). The obtained product was recrystallized from ethanol to give N-(3,4-dimethoxybenzyl)-2-[(trans-4-formamidocyclohexyl)amino]-5-nitrobenzamide as yellow crystals (7.21 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]([CH3:25])[C:12]([C:18]1[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=1)([OH:17])[C:13]([F:16])([F:15])[F:14])[C:5](O)=[O:6].Cl.[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][NH2:37])=[CH:32][CH:31]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][NH:37][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][C:10]([CH:11]([CH3:25])[C:12]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=3)([OH:17])[C:13]([F:16])([F:14])[F:15])=[C:2]([Cl:1])[CH:3]=2)=[CH:32][CH:31]=1
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: CC(c1ccc(C(=O)O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: COC(=O)c1ccc(CNC(=O)c2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)cc1

Procedure:
In analogy to Example 26, step 4, 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-benzoic acid, Example 26, step 3, was reacted with methyl-4-(aminomethyl)benzoate hydrochloride and HBTU at 80° C., 2 h to give the title compound as a white solid. MS (m/e)=541.2 [M+H+].
Reaction SMILES: [CH:1]1([N:4]([CH:20]([C:22]2[CH:23]=[N:24][C:25]([O:36][CH3:37])=[C:26]([C:28]#[C:29][CH2:30][NH:31][C:32]([O:34][CH3:35])=[O:33])[CH:27]=2)[CH3:21])[C:5]([C@@H:7]2[O:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.O1CCCC1>C(OCC)(=O)C.[Pd]>[CH:1]1([N:4]([CH:20]([C:22]2[CH:23]=[N:24][C:25]([O:36][CH3:37])=[C:26]([CH2:28][CH2:29][CH2:30][NH:31][C:32]([O:34][CH3:35])=[O:33])[CH:27]=2)[CH3:21])[C:5]([C@@H:7]2[O:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:8]2)=[O:6])[CH2:2][CH2:3]1
Reactant: COC(=O)NCC#Cc1cc(C(C)N(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CCO2)C2CC2)cnc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)NCCCc1cc(C(C)N(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CCO2)C2CC2)cnc1OC
Reaction time: 0.75 h
Yield: 105.2 %

Procedure:
to a solution of tert-butyl (2R)-2-({cyclopropyl[1-(6-methoxy-5-{3-[(methoxycarbonyl)-amino]prop-1-yn-1-yl}pyridin-3-yl)ethyl]amino}carbonyl)morpholin-4-carboxylate (150 mg) in ethyl acetate (2.5 mL)-tetrahydrofuran (2.5 mL) was added 10% palladium on carbon (30 mg), and the mixture was stirred under hydrogen for 45 minutes. An insoluble was filtered off, and then the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH-silica gel column chromatography (eluent: ethyl acetate) to give tert-butyl (2R)-2-({cyclopropyl[1-(6-methoxy-5-{3-[(methoxycarbonyl)amino]propyl}pyridin-3-yl)ethyl]amino}carbonyl)morpholine-4-carboxylate [Ex(296-5)] (159 mg) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]=[CH:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][CH:7]=1.[Cl:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1>O.O1CCOCC1>[CH3:1][O:2][C:3](=[O:15])[CH2:4][CH:5]([C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][CH:7]=1)[C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:16])[CH:22]=1
Reactant: COC(=O)C=Cc1ccc2cc[nH]c2c1
Reactant: OB(O)c1cccc(Cl)c1
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)CC(c1cccc(Cl)c1)c1ccc2cc[nH]c2c1
Temperature: 95 °C
Reaction time: 18 h
Yield: 62 %

Procedure:
A mixture of 3-(1H-indol-6-yl)-acrylic acid methyl ester XXX (0.4 g, 2.0 mmol), 3-chlorophenyl boronic acid (0.62 g, 4.0 mmol), [RhCl(cod)]2 (49 mg, 0.10 mmol) and TEA (0.42 ml, 3.0 mmol) in water (6 ml) and 1,4-dioxane (1 ml) was stirred at 95° C. for 18 hours. The reaction mixture was cooled to room temperature, and partitioned between H2O and EtOAc. The aqueous layer was extracted with EtOAc. The organic layers were combined, dried over MgSO4, filtered, concentrated, and purified via flash chromatography (hexane/EtOAc) to provide 3-(1H-indol-6-yl)-3-(3-chloro-phenyl)-propionic acid methyl ester XL (90 mg, 62% yield) as a white foam.
Reaction SMILES: [ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:7][CH2:6]1)(=[NH:4])[NH2:3].O[C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1.C1(N=C=NC2CCCCC2)CCCCC1.CN(C)C=O>CO.N1C=CC=CC=1>[ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([O:15][C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[O:14])[CH2:7][CH2:6]1)(=[NH:3])[NH2:4]
Reactant: NS(=O)(=O)c1ccc(O)cc1
Reactant: N=C(N)N1CCC(CCC(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CO
Product: N=C(N)N1CCC(CCC(=O)Oc2ccc(S(N)(=O)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.7 %

Procedure:
A mixture of 4.7 g of 1-amidino-4-piperidinepropionic acid hydrochloride, 3.5 g of p-hydroxybenzene sulfonamide, 4.1 g of dicyclohexylcarbodiimide, 10 ml of dry dimethylformamide and 20 ml of dry pyridine was stirred at room temperature for 24 hours. After removal of any insoluble materials, the solvent was removed. The residue was treated with ethyl acetate and then with ether to give crystals. The crystals were dissolved in methanol, and any insoluble materials were removed by filtration. Ether was added to the filtrate to obtain 4.5 g (yield: 57.7%) of p-aminosulfonylphenyl 1-amidino-4-piperidinepropionate hydrochloride as yellow crystals having a melting point of 206° to 209° C.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.N1C=CC=CC=1>C(O)C.[Pd]>[F:18][C:15]([F:16])([F:17])[C:11]1[CH:10]=[C:9]([CH2:8][C:7]2[CH:19]=[CH:20][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH:14]=[CH:13][N:12]=1
Reactant: O=[N+]([O-])c1ccc(Cc2ccnc(C(F)(F)F)c2)cc1
Agent: [Pd]
Solvent: c1ccncc1
Solvent: CCO
Product: Nc1ccc(Cc2ccnc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
10% Degussa Pd on carbon (15 mg, 0.14 mmol) was flushed with nitrogen then diluted in ethanol (2 mL). A solution of 4-(4-nitrobenzyl)-2-(trifluoromethyl)pyridine (100 mg, 0.35 mmol) in ethanol (2 mL) and pyridine (14 mg, 0.18 mmol) was subsequently added, and the mixture was flushed again with nitrogen prior to placing a hydrogen balloon on the flask. The mixture was stirred at rt overnight then filtered through Celite® and concentrated. The residue was dissolved in ethyl acetate and filtered through a silica gel plug, eluting with 50-100% ethyl acetate in hexanes, to give 4-(2-trifluoromethyl-pyridin-4-ylmethyl)-phenylamine as a clear colorless oil (76 mg, 85%). 1H NMR (CHCl3-d) δ 8.57 (d, J=5.0 Hz, 1H), 7.47 (s, 1H), 7.26 (m, 1H), 6.93 (m, 2H), 6.65 (m, 2H), 3.92 (s, 2H), 3.57 (br s, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:28])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[N:26][N:25]=[N:24]3)=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1[S:39](Cl)(=[O:41])=[O:40].O>C(Cl)Cl>[N:23]1([C:20]2[CH:19]=[CH:18][C:17]([O:16][CH2:15][C:14]([N:11]3[CH2:10][CH2:9][N:8]([S:39]([C:30]4[CH:31]=[CH:32][C:33]5[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=5)[CH:29]=4)(=[O:41])=[O:40])[CH2:13][CH2:12]3)=[O:28])=[CH:22][CH:21]=2)[CH:27]=[N:26][N:25]=[N:24]1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)COc2ccc(-n3cnnn3)cc2)CC1
Solvent: O
Solvent: ClCCl
Product: O=C(COc1ccc(-n2cnnn2)cc1)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
In a two neck round bottom flask 2-(4-(1H-tetrazol-1-yl)phenoxy)-1-(piperazine-1-yl)ethanone hydrochloride (compound 3, 0.882 mmoles, 0.286 g, 1 eq) and 2-naphthalene sulfonylchloride (0.882 mmoles, 0.2 g, 1 eq) were charged in DCM (20 mL). TEA (2.646 moles, 0.267 g, 3 eq) was added drop wise to the reaction mixture over a period of 10 min at 0° C. The resulting mixture was stirred for 3 h at room temperature and monitored by TLC. After completion of the reaction, water (10 mL) was added and extracted with DCM (2×20 mL). The combined organic layers were washed with brine (1×20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (Silica gel 60-120, 3:7, Ethyl acetate/Hexane) to obtain the title compound (0.300 g, 71.09%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH2:18][NH2:19])=[CH:16][C:15]2[C:10](=[C:11]([CH3:20])[CH:12]=[CH:13][CH:14]=2)[N:9]=1.Cl[C:22]1[C:27]([Cl:28])=[CH:26][N:25]=[C:24]([NH2:29])[N:23]=1>C(O)CCCC>[Cl:28][C:27]1[C:22]([NH:19][CH2:18][C:17]2[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[CH3:20])=[N:23][C:24]([NH2:29])=[N:25][CH:26]=1
Reactant: Nc1ncc(Cl)c(Cl)n1
Reactant: Cc1cccc2cc(CN)c(-c3ccccc3Cl)nc12
Solvent: CCCCCO
Product: Cc1cccc2cc(CNc3nc(N)ncc3Cl)c(-c3ccccc3Cl)nc12

Procedure:
A mixture of (2-(2-chlorophenyl)-8-methylquinolin-3-yl)methanamine (0.050 g, 0.18 mmol), and 4,5-dichloro-2-aminopyrimidine (0.029 g, 0.18 mmol, 1 eq) were stirred in 1-pentanol (0.9 mL) at 80° C. for 4 days. After purification, 5-chloro-N4-((2-(2-chlorophenyl)-8-methylquinolin-3-yl)methyl)pyrimidine-2,4-diamine [PI3Kδ IC50=165 nM] was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.18 (1H, s), 7.86 (1H, d, J=7.8 Hz), 7.72 (1H, s), 7.45-7.64 (7H, m), 7.28 (1H, t, J=5.9 Hz), 6.02 (2H, s), 4.46 (2H, d, J=18.8 Hz), 2.65 (3 H, s) Mass Spectrum (ESI) m/e=410.0 and 412.1 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13]([CH3:14])=[CH:12][C:11]([OH:15])=[CH:10][C:9]1=[O:16].[OH-].[Na+].C(Cl)(Cl)Cl.O.[CH2:24]([OH:26])C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13]([CH3:14])=[CH:12][C:11]([OH:15])=[C:10]([CH:24]=[O:26])[C:9]1=[O:16]
Reactant: Cc1cc(O)cc(=O)n1-c1ccccc1Cl
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc(O)c(C=O)c(=O)n1-c1ccccc1Cl
Temperature: 70 °C
Reaction time: 2 h

Procedure:
1-(2-Chlorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one obtained in Step A (9.25 g) was added to a solution of sodium hydroxide′ (54.9 g) in water/ethanol (1:2, 157 mL) at room temperature, and the mixture was heated at 70° C. Chloroform (34.8 mL) was slowly added to the reaction mixture at 70° C., and the mixture was stirred for 2 hr, and cooled to room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was suspended in dichloromethane, the solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and recrystallized from diethyl ether to give the title compound (3.95 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2[CH:27]=[CH:28][CH:29]=[N:30][C:25]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1CCCC1.CCN(CC)CC>C(Cl)Cl>[CH3:14][CH:13]([CH3:15])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10](=[O:12])[N:30]1[CH2:29][CH2:28][CH2:27][CH2:25]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: C1CCNC1
Solvent: CCN(CC)CC
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.9 %

Procedure:
To a mixture of (R)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (1.0 g, 4.60 mmol), HATU (2.1 g, 5.52 mmol) and pyrrolidine (0.812 mL, 9.21 mmol) in DCM (30 mL) was added Et3N (1.28 mL, 9.21 mmol). The reaction mixture was stirred at room temperature for 5 h and then washed with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4 and concentrated. Purification by silica column chromatography (MeOH/DCM, 0-10%) afforded the title compound as a light yellow oil (1.18 g, 95%). 1H NMR (400 MHz, CDCl3) δ 0.95 (d, J=18.95 Hz, 3 H) 0.95 (d, J=5.31 Hz, 3 H) 1.30-1.53 (m, 9 H) 1.77-2.07 (m, 5 H) 3.33-3.59 (m, 3 H) 3.59-3.80 (m, 1 H) 4.25 (dd, J=9.35, 6.57 Hz, 1 H) 5.30 (d, J=9.09 Hz, 1 H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[C:11]1([CH:17]2[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BH4-].[Na+].Cl>CC(O)C.C1COCC1>[C:11]1([C@H:17]2[CH2:22][CH2:21][C@H:20]([NH:1][CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=3)[CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CCC(c2ccccc2)CC1
Reactant: NCCc1ccc(O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Oc1ccc(CCN[C@H]2CC[C@H](c3ccccc3)CC2)cc1
Reaction time: 2 h

Procedure:
To a stirred solution of tyramine (3.0 g, 22 mmol) in 2-propanol (100 mL) and THF (50 mL) was added 4-phenylcyclohexanone 1 (3.8 g, 22 mmol) and 3 Å molecular sieves. After 2 hours, sodium borohydride (1.2 g, 31 mmol) was added, and the reaction mixture was stirred overnight. The reaction mixture was quenched with MeOH, filtered through Celite, and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (silica, 9:1 CH2Cl2:MeOH) gave the free base which was converted to an HCl salt. Recrystallization from MeOH/Et2O gave the trans-isomer trans-4-[2-(4-phenylcyclohexylamino)ethyl]phenol (0.98 g, 14%): mp 238-241° C.; IR (KBr): 2940, 1517, cm−1; 1H NMR (500 MHz, DMSO-d6) δ 9.30 (s, 1H), 8.99 (br d, 1H), 7.30-7.15 (m, 5H), 7.07 (d, J=8 Hz, 2H), 6.73 (d, J=8 Hz, 2H), 3.10-3.07 (m, 3H), 2.89-2.86 (m, 2H), 2.53-2.50 (m, 1H), 2.20 (d, J=20 Hz, 2H), 1.88 (d, J=20 Hz, 2H), 1.59-1.46 (m, 4H); CI—MS (methane) (m/z): 296 [M+H]+; HRMS-API (m/z): [M+H]+ calcd for C20H25NO, 296.2014; found, 296.2015; HPLC: method A, 5.83 minutes (100%); method B, 10.56 minutes (96.5%); Analysis Calcd for C20H25NO.HCl.0.25H2O: C, 71.41; H, 7.94; N, 4.16. Found: C, 71.29; H, 7.66; N, 4.12.