Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]OP(C(=[N+]=[N-])C(=O)C)(=O)OC.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:32])([CH3:31])[CH2:21][C@:22]([OH:30])([C:26]([F:29])([F:28])[F:27])[CH2:23][CH:24]=O)=[C:16]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:32])([CH3:31])[CH2:21][C@@:22]([C:26]([F:29])([F:28])[F:27])([OH:30])[CH2:23][C:24]#[CH:1])=[C:16]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:15]=1
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Reactant: CC(C)(C[C@@](O)(CC=O)C(F)(F)F)c1ccc(Cl)cc1S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#CC[C@](O)(CC(C)(C)c1ccc(Cl)cc1S(C)(=O)=O)C(F)(F)F
Reaction time: 8 h
Yield: 89.5 %

Procedure:
To a stirred solution of (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (12.5 g, 0.065 mol) and (R)-5-(4-chloro-2-methanesulfonylphenyl)-3-hydroxy-5-methyl-3-trifluoromethylhexanal (20.5 g, 0.054 mol) in 150 mL of dry MeOH was added potassium carbonate (13.8 g, 0.100 mol) at room temperature. The reaction was stirred overnight. The reaction was diluted with 200 mL of water and extracted with diethyl ether. The organic layers was washed with brine, dried over sodium sulfate, filtered, and the solvent was evaporated in vacuo. The crude material was eluted through a plug of silica using 20-25% diethyl ether/hexanes to provide (S)-6-(4-chloro-2-methanesulfonylphenyl)-6-methyl-4-trifluoromethylhept-1-yn-4-ol (18.5 g, 89%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O-:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Na+].[CH3:12]N(N=O)C(N)=O>COCCOC>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc([O-])cc1
Reactant: CN(N=O)C(N)=O
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 91.4 %

Procedure:
0.80 grams (5 millimoles) of anhydrous sodium p-nitrophenolate and 0.52 grams (5 millimoles) of N-methyl,N-nitrosourea were added to 25 milliliters of 1,2-dimethoxyethane kept dry with molecular sieves and a drying tube. This mixture was maintained at 0° C. for one hour and then elevated to room temperature for six hours while constant stirring was maintained. Solvent was evaporated and the residue treated simultaneously with ether and water. This mixture was shaken and the aqueous layer was removed. The ether layer was washed with potassium hydroxide (0.1 N, 3× 50 milliliters) to remove any unreacted phenol. The ether layer was washed with water (3×50 milliliters) and dried with magnesium sulfate. Filtration afforded a clear solution which was concentrated under diminished pressure to yield 0.70 grams of p-nitroanisole (about 90 percent, melting point 52°-53°. This was shown to be identical with an authentic sample.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[CH2:14]([O:6][C:1](=[O:7])[CH2:2][CH2:3][CH:4]=[CH2:5])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: C=CCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Product: C=CCCC(=O)OCc1ccccc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To 10.53 g (105 mmol) of pent-4-enoic acid in 150 ml ethanol was added 17.1 g (52.5 mmol) of Cs2CO3 and the reaction mixture was stirred at 40° C. for 2 h. The solvent was removed in vacuo, the residue coevaporated three times with toluene and then dissolved in 150 ml of DMF. 17.96 g (105 mmol) of benzyl bromide were added and the reaction mixture stirred at room temperature for 48 h. The reaction mixture was filtered, diluted with water and extracted three times with heptane. The combined organic phases were dried over MgSO4, filtered and the solvent was removed in vacuo. Yield: 19.92 g.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:20][CH:19]4[CH:15]([CH2:16][NH:17][CH2:18]4)[CH2:14]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[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]=1[C:34](O)=[O:35])[CH3:22]>>[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]=1[C:34]([N:17]1[CH2:16][CH:15]2[CH:19]([CH2:20][N:13]([C:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:12]=[CH:11][N:10]=3)[CH2:14]2)[CH2:18]1)=[O:35])[CH3:22]
Reactant: CCOc1ccc2ccccc2c1C(=O)O
Reactant: c1ccc(-c2ccnc(N3CC4CNCC4C3)n2)cc1
Product: CCOc1ccc2ccccc2c1C(=O)N1CC2CN(c3nccc(-c4ccccc4)n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 26 and 2-ethoxy-naphthalene-1-carboxylic acid. MS (ESI): mass calculated for C29H28N4O2, 464.57; m/z found 465.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.42-8.33 (m, 1H), 8.14-7.98 (m, 2H), 7.89-7.61 (m, 3H), 7.53-7.43 (m, 3H), 7.41-7.18 (m, 3H), 7.01-6.95 (m, 1H), 4.31-2.91 (m, 12H), 1.49-1.23 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[N:18]([C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1)=[C:19]=[O:20]>>[C:25]([C:24]1[CH:23]=[CH:22][C:21]([NH:18][C:19]([NH:13][CH2:12][CH:8]2[O:9][CH2:10][CH2:11][N:6]([CH2:5][C:4]3[CH:14]=[CH:15][C:16]([Cl:17])=[C:2]([Cl:1])[CH:3]=3)[CH2:7]2)=[O:20])=[CH:28][CH:27]=1)#[N:26]
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: N#Cc1ccc(N=C=O)cc1
Product: N#Cc1ccc(NC(=O)NCC2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)cc1
Yield: 85.3 %

Procedure:
Example 25 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and 4-isocyanatobenzonitrile (0.0196 g) to give the title compound (0.0325 g). LC-MS (System A): Rt 2.29 mins, Mass Spectrum m/z 419 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1.[Li]CCCC.[C:22](OCC)(=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C1COCC1>[C:12]([O:11][C:10]([NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:16])([CH3:13])([CH3:15])[CH3:14]
Reactant: COc1cccc(NC(=O)OC(C)(C)C)c1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1c(NC(=O)OC(C)(C)C)cccc1OC
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 3-methoxyphenylcarbamate (25.6 g, 0.11 mol) in THF (300 mL) was added n-BuLi (0.25 mol, 1.6 M solution in pentane) at −78° C. The resulted solution was stirred at 0° C. for 3 hours and re-cooled to −78° C. followed by the addition of diethyl oxalate (20.1 g, 0.14 mol). The mixture was stirred at −78° C. for 45 min and at ambient temperature for one hour, and quenched with 1 N HCl. The mixture was extracted with ether. The organic solution was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography to give 3.70 g (27% based on recovered starting material) of the title compound: MS (ES+) m/z 324.3 (M+1).
Reaction SMILES: [O-:1]O.[CH3:3][C:4]1[CH:8]2[CH2:9][C:7]2([CH:10]([CH3:12])[CH3:11])[CH2:6][CH:5]=1>[Ni]>[CH3:11][CH:10]([C:7]12[CH2:9][CH:8]1[C:4]([OH:1])([CH3:3])[CH2:5][CH2:6]2)[CH3:12]
Reactant: CC1=CCC2(C(C)C)CC12
Reactant: [O-]O
Agent: [Ni]
Product: CC(C)C12CCC(C)(O)C1C2

Procedure:
The hydroperoxide resulting from α-thujene can be reduced to 4-hydroxy-β-thujene and can then be hydrogenated, e.g. in the presence of Raney nickel, to give sabinene hydrate.
Reaction SMILES: [C:1]1([CH3:38])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][C@@H:13](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:12][C@@H:11]2[CH2:26]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:39]([NH2:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C1(C)C=CC=CC=1>[C:1]1([CH3:38])[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH2:14][C@H:13]3[CH2:12][C@@H:11]2[CH2:26][N:46]3[CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@H](OS(=O)(=O)c3ccc(C)cc3)CN2S(=O)(=O)c2ccc(C)cc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)N2C[C@H]3C[C@@H]2CN3Cc2ccccc2)cc1
Reaction time: 3 h
Yield: 90 %

Procedure:
A mixture of 2697 g (4.653 moles) of (2R, 4S)-1-(4-toluenesulfonyl)-2-(4-toluenesulfonyloxymethyl)-4-(4-toluenesulfonyloxy)-pyrrolidine and 1640 g (15.304 moles) of benzylamine in 15 L of toluene was heated under reflux. After 6 hours 100 g of benzylamine were added and the reflux continued for 3 hours. The mixture was cooled, filtered and the residue was washed with 5 L of toluene. The combined organic layers were evaporated to dryness and the resulting solid was taken up with 2 L of isopropanol. After cooling the product was filtered, washed with cold isopropanol and dried under reduced pressure to give 1434 g of the titled compound. (90%). M.P. =124° C. [α]D =-15.72° (c=1.6, acetone)
Reaction SMILES: O[C:2]1[C:14]2[N:13]3[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]3)=[C:7]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:6]=2[N:5]=[C:4]([CH3:24])[N:3]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:2]1[C:14]2[N:13]3[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]3)=[C:7]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:6]=2[N:5]=[C:4]([CH3:24])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(C)c(-c2c3nc(C)nc(O)c3n3ccccc23)c(C)c1
Product: Cc1cc(C)c(-c2c3nc(C)nc(Cl)c3n3ccccc23)c(C)c1
Temperature: 25 °C

Procedure:
A solution of 4-hydroxy-2-methyl-10-(2,4,6-trimethylphenyl)pyrimido-[4,5-b]indolizine (120 mg) in phosphorus oxychloride (2 mL) is heated at 100° C. for 2 hours, cooled to room temperature, and concentrated in vacuo. The residue is partitioned into ice water and dichloromethane. The aqueous phase is separated and extracted twice with dichloromethane. The combined organic extracts are washed with a saturated sodium bicarbonate solution and subsequently dried (Na2SO4), filtered, and concentrated in vacuo. The resulting dark residue is chromatographed on silica gel (10% to 20% ethyl acetate in hexane) to give 54 mg of the title compound as a greenish yellow foam: 1H nmr (400 MHz, CDCl3) d 1.99 (s, 6 H), 2.38 (s, 3 H), 2.79 (s, 3 H), 6.80 (m, 1 H), 7.00 (s, 2 H), 7.19 (m, 2 H), 9.27 (d, 1 H).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[CH2:9](Br)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Na+].[I-]>C(O)C>[CH2:9]([O:2][C:1]1[CH:8]=[CH:7][C:5]([O:6][CH2:7][CH2:8][CH2:1][CH2:3][CH2:4][CH3:5])=[CH:4][CH:3]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: Oc1ccc(O)cc1
Reactant: CCCCCCBr
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCOc1ccc(OCCCCCC)cc1

Procedure:
Under argon atmosphere, 6.90 g (300 mmol) of Na is reacted with 200 ml of absolute ethanol. Then, 16.5 g (150 mmol) of hydroquinone 5 is added, followed by 42.2 ml (300 mmol) of hexylbromide and 200 mg of anhydrous NaI. The mixture is refluxed overnight. Ethanol is evaporated under reduced pressure and water (150 ml) is added. The product is extracted with dichloromethane and dried over MgSO4. After filtration, the solvents are removed and the crude compound is recrystallized from ethanol.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][CH2:8]2)([O-])=O.[CH3:13][C:14](OC(C)=O)=[O:15]>CO.N1C=CC=CC=1.[Pd]>[CH2:8]1[C:9]2[C:5](=[C:4]([NH:1][C:14](=[O:15])[CH3:13])[CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:7]1
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1cccc2c1CCC2
Agent: [Pd]
Solvent: CO
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc2c1CCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of commercially available 4-nitroindane (10 g, 61.3 mmol) and 10% Pd/C (1 g) in MeOH (200 mL) was stirred vigorously under an atmosphere of hydrogen overnight at rt. The reaction was filtered through a pad of Celite® and concentrated, and residual solvent was removed by combining the reaction with toluene followed by evaporation. The crude reaction was taken up in pyridine (100 mL), and Ac2O (20 mL) was added and the reaction stirred for 16 h at rt. The reaction was evaporated and the crude product was purified by flash chromatography (5% MeOH in EtOAc/hexane(1:1) to give the title compound (9.12 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:11]2[CH:12]=[C:13]([N+:17]([O-])=O)[C:14]([F:16])=[CH:15][C:10]=2[S:9][C:8]1=[O:20])=[O:5])[CH3:2]>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:17][C:13]1[C:14]([F:16])=[CH:15][C:10]2[S:9][C:8](=[O:20])[N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:11]=2[CH:12]=1
Reactant: CCOC(=O)Cn1c(=O)sc2cc(F)c([N+](=O)[O-])cc21
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)Cn1c(=O)sc2cc(F)c(N)cc21
Yield: 71.7 %

Procedure:
Electrolytic iron powder (0.29 g) was suspended in 5% acetic acid (2 ml), and a solution of 3-ethoxycarbonylmethyl-6-fluoro-5-nitro-2(3H)-benzothiazolone (0.31 g) in acetic acid (1 ml) and ethyl acetate (1 ml) was dropwise added thereto while heating. The resultant mixture was heated under reflux for 3 hours. The reaction mixture was subjected to filtration with celite, and the filtrate was extracted with ethyl acetate. The extract was washed with water and sodium bicarbonate solution, dried and concentrated to give 0.20 g of 5-amino-3-ethoxycarbonylmethyl-6-fluoro-2(3H)-benzothiazolone. m.p., 172.5°-173.5° C.
Reaction SMILES: [Br:1]N1C(C)(C)C(=O)N(Br)C1=O.[OH:12][C:13]1[CH:18]=[C:17]([CH3:19])[N:16]([C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=2[CH3:30])[C:23]([O:25][CH3:26])=[O:24])[C:15](=[O:31])[CH:14]=1>C(#N)C>[Br:1][C:14]1[C:15](=[O:31])[N:16]([C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=2[CH3:30])[C:23]([O:25][CH3:26])=[O:24])[C:17]([CH3:19])=[CH:18][C:13]=1[OH:12]
Reactant: COC(=O)c1ccc(C)c(-n2c(C)cc(O)cc2=O)c1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: CC#N
Product: COC(=O)c1ccc(C)c(-n2c(C)cc(O)c(Br)c2=O)c1
Yield: 171.2 %

Procedure:
A solution of 1,3-dibromo-5,5-dimethylhydantoin (1.375 kg. 4.81 moles) in acetonitrile (11.5 L) was added to a solution of methyl 3-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-4-methylbenzoate (5) (2.50 kg, 9.15 mol) in acetonitrile (4.8 L). The solution was added at a rate that maintained the temperature less than −10° C. for 90 to 180 minutes. A portion of the acetonitrile (approximately 6 L) was removed after completion of the reaction via distillation. The product was precipitated by the addition of water (7.9 L) and filtered to yield 2.90 kg (90%) of methyl 3-(3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-4-methylbenzoate (4)
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[Cl:8][C:9]1[N:13]2[C:14]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([F:35])=[C:24]([CH:34]=3)[C:25]([N:27]3[CH2:33][CH2:32][CH2:31][NH2+:30][CH2:29][CH2:28]3)=[O:26])=[CH:15][NH:16][C:17](=[O:18])[C:12]2=[CH:11][C:10]=1[Cl:36].[C:37]([OH:41])(=[O:40])[CH:38]=O>>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[C:37]([CH2:38][NH+:30]1[CH2:31][CH2:32][CH2:33][N:27]([C:25](=[O:26])[C:24]2[CH:34]=[C:20]([CH2:19][C:14]3[N:13]4[C:9]([Cl:8])=[C:10]([Cl:36])[CH:11]=[C:12]4[C:17](=[O:18])[NH:16][CH:15]=3)[CH:21]=[CH:22][C:23]=2[F:35])[CH2:28][CH2:29]1)([OH:41])=[O:40]
Reactant: O=CC(=O)O
Reactant: O=C(c1cc(Cc2c[nH]c(=O)c3cc(Cl)c(Cl)n23)ccc1F)N1CCC[NH2+]CC1
Agent: O=C([O-])C(F)(F)F
Product: O=C(O)C[NH+]1CCCN(C(=O)c2cc(Cc3c[nH]c(=O)c4cc(Cl)c(Cl)n34)ccc2F)CC1

Procedure:
The title compound was prepared as described in Example 2 from Example 8, H3 and glyoxylic acid. 1H NMR (300 MHz, DMSO-d6) δ: 10.96 (1H, d, J=5.6 Hz), 7.37-7.19 (4H, m), 6.64-6.61 (1H, m), 4.42 (2H, s), 4.20 (2H, s), 4.05-3.25 (8H, m), 2.17-1.99 (2H, m). MS (ES) C22H21Cl2FN4O4 required: 494, found: 495 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[C:6]([C@@H:12]([NH2:14])[CH3:13])=[N:7]2.Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[NH:25][CH:26]=[N:27]2.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[C:6]([C@@H:12]([NH:14][C:23]1[N:31]=[CH:30][N:29]=[C:28]3[C:24]=1[N:25]=[CH:26][NH:27]3)[CH3:13])=[N:7]2
Reactant: Clc1ncnc2nc[nH]c12
Reactant: C[C@H](N)c1nc2cccc(Cl)c2cc1-c1cccc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2cccc(Cl)c2cc1-c1cccc(F)c1

Procedure:
Prepared according to Procedure H using (1S)-1-(5-chloro-3-(3-fluorophenyl)-quinolin-2-yl)ethanamine (0.050 g, 0.166 mmol), 6-chloropurine (0.031 g, 0.20 mmol, 1.2 eq) and DIEA (0.33 mmol, 2.0 eq) in n-butanol (3 mL). N—((S)-1-(5-chloro-3-(3-fluorophenyl)quinolin-2-yl)ethyl)-9H-purin-6-amine [PI3Kδ C50=5 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 9.22 (s, 1 H), 8.63 (s, 1 H), 8.44-8.47 (m, 3 H), 8.42 (s, 1 H), 8.34 (s, 1 H), 7.87-7.94 (m, 2 H), 7.56 (t, 1 H), 1.79 (d, 3H), Mass Spectrum (ESI) m/e=419 (M+1).
Reaction SMILES: O=S1(=O)[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C@:11]23[CH2:45][CH2:44][C@@H:43]([CH:46]([CH3:48])[CH3:47])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:42])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C@@H:20]([C:33]3[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[CH:35][CH:34]=3)[CH2:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:4][CH2:3]1.ClCCN1CC[O:56]CC1>>[CH:46]([C@H:43]1[C@@H:12]2[C@@H:13]3[C@@:26]([CH3:29])([CH2:27][CH2:28][C@@:11]2([NH:10][CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][O:56][CH2:7][CH2:6]2)[CH2:45][CH2:44]1)[C@@:25]1([CH3:30])[C@@H:16]([C@:17]2([CH3:42])[C@@H:22]([CH2:23][CH2:24]1)[C:21]([CH3:31])([CH3:32])[C@@H:20]([C:33]1[CH:34]=[CH:35][C:36]([C:37]([OH:39])=[O:38])=[CH:40][CH:41]=1)[CH2:19][CH2:18]2)[CH2:15][CH2:14]3)([CH3:47])[CH3:48]
Reactant: CC(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: ClCCN1CCOCC1
Product: CC(C)[C@@H]1CC[C@]2(NCCN3CCOCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-1-isopropyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using 4-(2-chloroethyl)morpholine as the alkylating reagent in Step 3. The product was isolated as a colorless oil (4 mg, 39%). LCMS: m/e 647.58 (M+H)+, 2.35 min (method 11). 1H NMR (500 MHz, Acetic) δ 8.02 (d, J=8.2 Hz, 2H), 7.36 (d, J=8.2 Hz, 2H), 3.94 (d, J=3.7 Hz, 4H), 3.73-3.44 (m, 4H), 3.27 (br. s., 4H), 2.50 (d, J=10.4 Hz, 1H), 2.32-1.01 (m, 26H), 1.21 (s, 3H), 1.12 (s, 3H), 1.08 (s, 3H), 0.93 (d, J=6.7 Hz, 3H), 0.86 (d, J=6.7 Hz, 3H), 0.83 (s, 3H), 0.79 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH:19]1([C:22]2[O:23][C:24]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:25]([C:27](O)=[O:28])[N:26]=2)[CH2:21][CH2:20]1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:27]([C:25]3[N:26]=[C:22]([CH:19]4[CH2:20][CH2:21]4)[O:23][C:24]=3[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:28])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)s2)OCCO1
Reactant: O=C(O)c1nc(C2CC2)oc1-c1ccccc1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3nc(C4CC4)oc3-c3ccccc3)n2)s1

Procedure:
Following general procedure X followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-1H-pyrazol-3-ylamine and 2-cyclopropyl-5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 05c: tR=0.80 min; [M+H]+=433.17.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][CH2:11][C@@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])[CH:5]=[N:6][C:7]=1[C:8]#[N:9].[NH2:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[N:24]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[C:8]([C:7]1[N:6]=[CH:5][C:4]([NH:10][CH2:11][C@@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])=[CH:3][C:2]=1[NH:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[N:24]=1)#[N:9]
Reactant: Cc1cc(C)nc(N)c1
Reactant: C[C@@H](CNc1cnc(C#N)c(Br)c1)NC(=O)OC(C)(C)C
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1cc(C)nc(Nc2cc(NC[C@H](C)NC(=O)OC(C)(C)C)cnc2C#N)c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a flask were added tert-butyl {(2S)-1-[(5-bromo-6-cyanopyridin-3-yl)amino]propan-2-yl}carbamate (200 mg, 0.56 mmol), 2-amino-4,6-dimethylpyridine (103 mg, 0.844 mmol), tris(dibenzylideneacetone)dipalladium(0)-dichloromethane complex (52 mg, 0.051 mmol), Xantphos (65 mg, 0.11 mmol), and cesium carbonate (367 mg, 1.13 mmol). 1,4-Dioxane (3 mL) was then added and nitrogen was bubbled into the reaction for 5 minutes. The reaction mixture was then stirred at 80° C. for 16 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The mixture was washed with saturated aqueous ammonium chloride, and the organics were separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel to afford tert-butyl [(2S)-1-({6-cyano-5-[(4,6-dimethylpyridin-2-yl)-amino]pyridin-3-yl}amino)propan-2-yl]carbamate. MS ESI calc'd. for C21H29N6O2 [M+H]+ 397. found 397.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11](O)[CH3:12])=[CH:3][CH:2]=1.S(Cl)([Cl:16])=O>C(Cl)(Cl)Cl>[Cl:16][CH:11]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[CH:2][CH:3]=1)[CH3:12]
Reactant: CC(O)c1ccnc2ccccc12
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(Cl)c1ccnc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
To 1-Quinolin-4-yl-ethanol (1.4 g, 8.09 mmol) in 15 ml chloroform, thiony-chloride (1.8 ml, 20.2 mmol) was added dropwise over a five minute period at room temperature. Stirring was continued for 30 minutes after which the reaction mixture was cooled to 0° C. and quenched carefully by the addition of saturated aqueous NaHCO3 (20 ml). The chloroform layer was dried over sodium sulfate, filtered and concentrated. Column purification (hexane:ethyl acetate; 1.5:3.5) gave 1.54 g (100%) of the product as a syrup which was used as such for the subsequent step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[C:12](Cl)(=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.C(N(CC)CC)C>C1COCC1>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[CH2:6][CH2:5]3)=[O:21])=[CH:14][CH:15]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Nc1ccc2c(c1)CCC2=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2ccc3c(c2)CCC3=O)cc1
Yield: 76 %

Procedure:
Reaction of 5-amino-indan-1-one (73 mg, 0.50 mmol) in THF (6 mL) with p-anisoyl chloride (88 μL, 0.65 mmol) in presence of triethylamine (90 μL, 0.65 mmol) according to method A gave 4-methoxy-N-(1-oxo-indan-5-yl)-benzamide (107 mg, 0.38 mmol, 76% yield) as a yellow powder after purification by chromatography on silica gel (eluent EtOAc/DCM 0/10 to 2/8).