Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]2[CH3:22])[C:9]2[C:4](=[C:5]([O:23][CH3:24])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1>CN(C)C=O>[ClH:1].[CH3:24][O:23][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([NH:30][C:29]1[CH:31]=[CH:32][C:26]([F:25])=[CH:27][CH:28]=1)[N:11]=[C:10]2[N:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]1[CH3:22]
Reactant: Nc1ccc(F)cc1
Reactant: COc1cccc2c(N3CCc4ccccc4C3C)nc(Cl)nc12
Solvent: CN(C)C=O
Product: COc1cccc2c(N3CCc4ccccc4C3C)nc(Nc3ccc(F)cc3)nc12
Product: Cl
Yield: 49 %

Procedure:
In accordance with the same procedures as in Example 18, except that to a mixture of 1.50 g of the compound (4.41 mM) prepared in Example 5 and 15 ml of dimethyl-formamide, 0.88 ml of 4-fluoroaniline(9.27 mM) was added, 0.97 g of the title compound was prepared.
Reaction SMILES: P(Br)(Br)[Br:2].[F:5][C:6]1[C:13]([F:14])=[C:12]2[CH:15]=[CH:16][C:7]=1[CH:8](O)[O:9][CH2:10][O:11]2.CO.O>C(OCC)C>[F:5][C:6]1[C:13]([F:14])=[C:12]2[CH:15]=[CH:16][C:7]=1[CH:8]([Br:2])[O:9][CH2:10][O:11]2
Reactant: BrP(Br)Br
Reactant: OC1OCOc2ccc1c(F)c2F
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: Fc1c2ccc(c1F)C(Br)OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
Phosphorus tribromide (47 g) was added to a solution of 2,3difluoromethylenedioxybenzyl alcohol (32 g) in diethyl ether at 0° C. After 0.5 hours the reaction mixture was allowed to warm to ambient temperature and was stirred at ambient temperature for 3 hours. The reaction mixture was then cooled to 0° C., methanol was added followed by water, the mixture was extracted with diethyl ether, separated and the organic layer washed with saturated sodium bicarbonate (until neutral), dried and the solvent removed to yield the product as a pale yellow oil, (40.4 g), NMR (CDCl3): 4.50(s,2H), 7.10(m,3H).
Reaction SMILES: [CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([OH:51])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.Cl[CH2:53][CH2:54][O:55][CH:56]1[CH2:58][CH2:57]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOCC>[CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([O:51][CH2:53][CH2:54][O:55][CH:56]3[CH2:58][CH2:57]3)[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:17][CH:18]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: ClCCOC1CC1
Reactant: COCCCc1cc(O)cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCOC2CC2)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (3R,4S)-3-({cyclopropyl[3-hydroxy-5-(3-methoxy-propyl)benzyl]-amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-phenyl}piperidine-1-carboxylate (1 eq.) from Example 1/Step 2 in DMF (0.1 M) was added (2-chloroethoxy)cyclopropane (3 eq.) and cesium carbonate (2 eq.). The reaction was heated to 100° C. and stirred for 3 h. After cooling to rt, the reaction was diluted with ether. The organic extract was washed with water, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 35% EtOAc in Hex) to afford the title compound as an oil.
Reaction SMILES: N1C=CC=CC=1.[O:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)[CH2:9][CH2:8]1.[ClH:23].[C:24]([C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33]([CH2:37][C:38](=[O:40])[NH2:39])=[C:32](O)[CH:31]=[CH:30]2)(=[NH:26])[NH2:25].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.O>[ClH:23].[ClH:23].[O:7]1[CH2:8][CH2:9][N:10]([CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([O:20][C:32]3[CH:31]=[CH:30][C:29]4[C:34](=[CH:35][CH:36]=[C:27]([C:24](=[NH:25])[NH2:26])[CH:28]=4)[C:33]=3[CH2:37][C:38](=[O:40])[NH2:39])=[O:19])=[CH:16][CH:15]=2)[CH2:11][CH2:12]1
Reactant: O=C(O)c1ccc(CN2CCOCC2)cc1
Reactant: N=C(N)c1ccc2c(CC(N)=O)c(O)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: N=C(N)c1ccc2c(CC(N)=O)c(OC(=O)c3ccc(CN4CCOCC4)cc3)ccc2c1
Reaction time: 2 h
Yield: 67.4 %

Procedure:
15 Milliliters of anhydrous pyridine was added to 612.2 mg of 4-morpholinomethylbenzoic acid, 703.9 mg of 6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 622.6 mg of DCC and 30.7 mg of DMAP, followed by stirring for 2 hours under cooling with ice and then 3 days under cooling with water. Thereafter, the same procedure as in Example 1 was carried out to obtain 440.7 mg of the desired product.
Reaction SMILES: I[C:2]1[N:3]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[CH:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][CH:15]([CH3:17])[CH3:16].[C:29]([OH:35])(=[O:34])[CH2:30][CH2:31][C:32]#[CH:33].C[Si](N([Si](C)(C)C)C(=O)C(F)(F)F)(C)C>>[CH3:12][N:8]1[C:9](=[O:11])[C:10]2=[C:2]([C:33]#[C:32][CH2:31][CH2:30][C:29]([OH:35])=[O:34])[N:3]([CH2:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=[CH:21][CH:20]=3)[CH:4]=[C:5]2[N:6]([CH2:14][CH:15]([CH3:16])[CH3:17])[C:7]1=[O:13]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(I)n(Cc3cccc4ccccc34)cc21
Reactant: C#CCCC(=O)O
Agent: C[Si](C)(C)N(C(=O)C(F)(F)F)[Si](C)(C)C
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C#CCCC(=O)O)n(Cc3cccc4ccccc34)cc21

Procedure:
The sub-title compound was prepared from 5-iodo-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione, and 4-pentynoic acid in the presence of bistrimethylsilyltrifluoroacetamide in a manner analogous to the method of Example 13 above.
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C@@H:6]1[C@H:11]([CH2:12][CH2:13][CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9][N:8]([CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:7]1.O>CS(C)=O>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][CH:16]=[C:15]2[CH2:14][CH2:13][CH2:12][C@@H:11]1[CH2:10][CH2:9][N:8]([CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:7][C@@H:6]1[CH2:5][C:1]#[N:2]
Reactant: [C-]#N
Reactant: COc1ccc2nccc(CCC[C@@H]3CCN(CCCc4ccccc4)C[C@@H]3CCl)c2c1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc2nccc(CCC[C@@H]3CCN(CCCc4ccccc4)C[C@@H]3CC#N)c2c1
Temperature: 60 °C
Yield: 26.7 %

Procedure:
0.565 g of sodium cyanide was added to a stirred solution of 1.3 g of (3R,4R)-3-chloromethyl-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-(3-phenylpropyl)piperidine in 50 cm3 of dimethyl sulfoxide and then the mixture was heated at a temperature in the region of 60° C. for 20 hours. After cooling, the reaction mixture was poured onto 500 cm3 of water and then extracted with 2 times 200 cm3 of diethyl ether. The combined extracts were dried over magnesium sulfate, filtered, and then evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography at atmospheric pressure on a column of silica gel (particle size 20-45 μm, diameter 2 cm; 32 g), elution was carried out with ethyl acetate, and 15-cm3 fractions were collected. Fractions 12 to 19 were combined and then evaporated (5 kPa) at a temperature in the region of 40° C. 0.34 g of (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-[3-phenylpropyl]piperidine-3-acetonitrile was obtained in the form of an oil with a yellow color.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N:11]2[C:16](=[O:17])[N:15]([CH3:18])[CH:14]([N:19]([CH3:21])[CH3:20])[NH:13][C:12]2=[O:22])=[C:4]([F:23])[CH:3]=1>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:23])=[C:5]([N:11]2[C:16](=[O:17])[N:15]([CH3:18])[CH:14]([N:19]([CH3:20])[CH3:21])[NH:13][C:12]2=[O:22])[CH:6]=1
Reactant: CN(C)C1NC(=O)N(c2cc([N+](=O)[O-])c(Cl)cc2F)C(=O)N1C
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CN(C)C1NC(=O)N(c2cc(N)c(Cl)cc2F)C(=O)N1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a slurry of iron powder (5.3 g) in 5% aqueous acetic acid (30 mL) was added dropwise a solution of the title compound of step B (2.8 g, 8.1 mmol) in a mixture of concentrated acetic acid (25 mL) and ethyl acetate (25 mL) at room temperature. The reaction was stirred at room temperature for 30 minutes, diluted with excess ethyl acetate, filtered through Celite®, and washed with water. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with saturated aqueous sodium bicarbonate solution and water. The organic layers were then dried over magnesium sulfate and concentrated under reduced pressure. The title compound of Step C was isolated by flash chromatography as a foam (1.59 g). 1H NMR (CDCl3) δ 7.15 (d, 1H), 6.65 (d, 1H), 3.95 (br s, 2H), 3.4 (s, 3H), 3.1 (s, 6H).
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@H:20]([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.[CH2:21]([O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36](O)=[O:37])=[CH:30][CH:29]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C1(N=C=NC2CCCCC2)CCCCC1.C(O)(=O)C>CN(C)C1C=CN=CC=1.C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([O:11][C@@H:10]2[C@@:2]3([CH3:1])[CH2:3][CH2:4][C@@H:5]4[C@@H:20]5[C:14](=[CH:15][C:16]([CH2:18][CH2:19]5)=[O:17])[CH2:13][CH2:12][C@H:6]4[C@@H:7]3[CH2:8][CH2:9]2)=[O:37])=[CH:30][CH:29]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Reactant: CCCCCCOc1ccc(CCC(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCCCCOc1ccc(CCC(=O)O[C@H]2CC[C@H]3[C@@H]4CCC5=CC(=O)CC[C@@H]5[C@H]4CC[C@]23C)cc1
Reaction time: 4 h
Yield: 92.8 %

Procedure:
To a stirred solution of 5.48 g 19-nortestosterone (20 mmol), 5.5 g 3-(4-hexyloxyphenyl)propionic acid (22 mmol), 0.24 g 4-dimethylaminopyridine (DMAP, 2 mmol) and 0.19 g p-toluenesulfonic acid (pTSA, 1 mmol) in 50 ml CH2Cl2 is slowly added at about 15° C. a solution of 5.2 g N,N'-dicyclohexylcarbodiimide (DCC, 25 mmol) in 30 ml CH2CL2. After 4 h at room temperature (no discolouration of the reaction mixture is seen) 1 ml of acetic acid is added to destroy the excess of DCC. Precipitated urea is then filtered off and the filtrate evaporated in vacuo. To the residue 50 ml ethyl acetate is added and, after stirring for 1 h, undissolved urea is filtered off and the filtrate evaporated in vacuo. The residue is crystallized from methanol/water. There is obtained 9.4 g of Anadur® (93% yield) as white crystals having a m.p. of 53°-55° C. and being pure in TLC.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[CH3:31][C:32]1[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O>COCCOC>[CH3:31][C:32]1[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][C:33]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11]
Reactant: Cc1cccc(B(O)O)c1C
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cccc(-c2ccccc2CCC(=O)N(NC(=O)c2ccccc2)C(C)C)c1C
Yield: 26 %

Procedure:
A solution of benzoic acid N′-[3-(2-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (50 mg, 0.13 mmol) in DME (4 ml)/2M Na2CO3 (225 μL, 0.45 mmol) was treated with 2,3-dimethyl-phenylboronic acid (38 mg, 0.26 mmol) and Pd[PPh3]4 (15 mg, 0.013 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient and then by RP HPLC to afford the product as a solid (14 mg, 27%). LC-MS m/e 415.35 (M+H+)
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([CH:7]=[O:8])[CH:3]=1.C(N(CC)CC)C.Cl[C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[CH3:1][C:2]1[N:6]([C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:5]=[C:4]([CH:7]=[O:8])[CH:3]=1
Reactant: Cc1cc(C=O)n[nH]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(C=O)nn1C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
To a solution of 5-methyl-1H-pyrazole-3-carbaldehyde (Werner A. et al., Tetrahedron, 51, 4779 (1995): 1.1 g) in acetonitrile (20 mL), triethylamine (1.5 mL) and chlorotriphenylmethane (3.1 g) were added and mixed for 12 hours. The reaction solution was concentrated, and the residue was dissolved in chloroform. This solution was washed with a saturated aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified with a silica gel column to give the title compound (1.9 g) as a colorless solid.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH2:12][C:13]2[C:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:23])[N:3]=1.[CH3:34][C:35]([OH:39])([C:37]#[CH:38])[CH3:36].C(N(CC)CC)C>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH2:12][C:13]3[C:14]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:31])([F:32])[F:33])=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][C:17]=4[CH3:23])[N:3]=[C:2]([C:38]#[C:37][C:35]([CH3:36])([OH:39])[CH3:34])[C:10]=12
Reactant: Cc1cccc2cc(Cn3nc(I)c4c(N)ncnc43)c(-c3ccccc3C(F)(F)F)nc12
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc2cc(Cn3nc(C#CC(C)(C)O)c4c(N)ncnc43)c(-c3ccccc3C(F)(F)F)nc12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A suspension of 3-iodo-1-((8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.0569 g, 0.102 mmol) and copper(i) iodide (0.00387 g, 0.0203 mmol, 0.2 eq) in DMF (2 mL) was treated with 2-methyl-3-butyn-2-ol (0.0984 mL, 1.02 mmol, 10 eq), triethylamine (0.0282 mL, 0.203 mmol, 2 eq) and tetrakis(triphenylphosphine)palladium(0) (0.0117 g, 0.0102 mmol, 10 mol %) under Ar. The mixture was stirred under Ar at rt for 45 min. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography on a 40 g of Redi-Sep™ column using 0 to 100% gradient of CH2Cl2:MeOH:NH4OH (89:9:1) in CH2Cl2 over 14 min as eluent to provide 4-(4-amino-1-((8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methylbut-3-yn-2-ol [PI3Kδ IC50=116 nM] as a tan solid. 1H NMR (DMSO-d6) δ ppm 8.21 (1 H, s), 8.02 (1H, s), 7.87 (1 H, d, J=7.8 Hz), 7.77-7.82 (1 H, m), 7.65 (1 H, d, J=6.7 Hz), 7.57-7.62 (2 H, m), 7.51-7.57 (1 H, m), 7.26-7.32 (1 H, m), 5.76 (1 H, s), 5.44 (2 H, s), 2.60 (3 H, s), 1.46 (6 H, s). Mass Spectrum (ESI) m/e=517.2 (M+1).
Reaction SMILES: CN(C=O)C.[CH3:6][C@@H:7]1[NH:12][CH2:11][CH2:10][N:9]([C:13]2[N:14]=[N:15][C:16]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[C:17]3[CH:22]=[CH:21][N:20]=[CH:19][C:18]=23)[CH2:8]1.[F:33][C:34]1([F:52])[CH2:39][CH2:38][N:37]([C:40](OC2C=CC([N+]([O-])=O)=CC=2)=[O:41])[CH2:36][CH2:35]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[F:33][C:34]1([F:52])[CH2:39][CH2:38][N:37]([C:40]([N:12]2[CH2:11][CH2:10][N:9]([C:13]3[N:14]=[N:15][C:16]([C:23]4[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=4)=[C:17]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=34)[CH2:8][C@@H:7]2[CH3:6])=[O:41])[CH2:36][CH2:35]1
Reactant: C[C@H]1CN(c2nnc(-c3ccc(C(F)(F)F)cc3)c3ccncc23)CCN1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCC(F)(F)CC1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H]1CN(c2nnc(-c3ccc(C(F)(F)F)cc3)c3ccncc23)CCN1C(=O)N1CCC(F)(F)CC1
Temperature: 75 °C

Procedure:
DMF (3 mL) was added to (S)-4-(3-methylpiperazin-1-yl)-1-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazine 47 (150 mg, 402 μmol), 4-nitrophenyl 4,4-difluoropiperidin-1-carboxylate 41 (230 mg, 803 μmol), potassium carbonate (167 mg, 1.2 mmol), 4-dimethylaminopyridine (9.8 mg, 80 μmol). The reaction was heated to 75° C. for 72 h. The reaction was diluted with ethyl acetate (70 mL) and washed with 1×10 mL water, 1×10 mL NaHCO3, and 1×10 mL brine. The organic layer was dried over MgSO4, filtered, and concentrated. Purification by column chromatography afforded (S)-(4,4-difluoropiperidin-1-yl)(2-methyl-4-(1-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-4-yl)piperazin-1-yl)methanone 48. MS 520.2 (calc'd) 521.2 (M+H, found).
Reaction SMILES: [Br:1][C:2]1[CH:27]=[C:26]([C:28]2[C:37]3[C:38]4[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=4[S:40][C:36]=3[C:35]([Br:45])=[C:34]3[C:29]=2[CH:30]=[CH:31][CH:32]=[CH:33]3)[CH:25]=[C:24]([Br:46])[C:3]=1[O:4][CH:5]([CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)[C:6]([O:8]C(C)(C)C)=[O:7].O.CCOCC>FC(F)(F)C(O)=O>[Br:46][C:24]1[CH:25]=[C:26]([C:28]2[C:37]3[C:38]4[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=4[S:40][C:36]=3[C:35]([Br:45])=[C:34]3[C:29]=2[CH:30]=[CH:31][CH:32]=[CH:33]3)[CH:27]=[C:2]([Br:1])[C:3]=1[O:4][CH:5]([CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)[C:6]([OH:8])=[O:7]
Reactant: CC(C)(C)OC(=O)C(Cc1ccc2ccccc2c1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: O=C(O)C(Cc1ccc2ccccc2c1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Temperature: 25 °C

Procedure:
A solution of 2-[2,6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-phenoxy ]-3-naphthalen-2yl--propionic acid, tert butyl ester (0.221 g, 0.270 mmol) in trifluoroacetic acid (10 mL) was heated to 50° C. for 15 hours. The mixture was cooled to room temperature and combined with water. Ether was added and the resulting organic suspension was separated from the water layer and concentrated. The residue was dried in vacuo at 46 C. to provide the title compound as an off white solid (0.186 g, 90%) mp 270-271° C.; NMR (DMSO-d6); δ13.25 (broad singlet, 1 H), 8.28 (d, J=8 Hz, 1 H,), 8.06 (d, J=8 Hz, 1 H), 7.91(m, 4 H), 7.81(d, J=2 Hz, 1 H), 7.79(d, J =2 Hz, 1 H) 7.82-7.77(m, 1 H), 7.63-7.47(m, 6 H), 7.25 (dd, J=7, 1 Hz,, 1 H), 6.64 (d, J=8 Hz, 1 H) 5.42 (t, J=7 Hz, 1 H), 3.59 (d, J=7 Hz, 2 H); MS (FAB+): [M+], 3 bromine pattern, 757.8 (21%) 759.8 (100%) 761.8 (100%) 763.8 (50%); Anal. Calcd. for C31H19Br3O3S: C, 55.07; H,3.04, N, 0.00. Found: C, 55.36; H, 2.89, N, 0.06.
Reaction SMILES: C([O:5][C:6]([NH:8][CH2:9][CH2:10][C@@H:11]1[C:15]2[C:16]3[N:17]([N:20]=[C:21]([CH3:28])[C:22]=3C(OCC)=O)[CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12]1)=O)(C)(C)C.[CH2:29](N(CC)CC)C.C(OC(=O)C)(=O)C.O>Cl.O1CCCC1>[CH3:28][C:21]1[CH:22]=[C:16]2[C:15]3[C@@H:11]([CH2:10][CH2:9][NH:8][C:6](=[O:5])[CH3:29])[CH2:12][CH2:13][C:14]=3[CH:19]=[CH:18][N:17]2[N:20]=1
Reactant: CCOC(=O)c1c(C)nn2ccc3c(c12)[C@@H](CCNC(=O)OC(C)(C)C)CC3
Reactant: CCN(CC)CC
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)NCC[C@H]1CCc2ccn3nc(C)cc3c21
Temperature: 100 °C
Reaction time: 72 h
Yield: 96 %

Procedure:
A mixture of ethyl (9R)-9-{2-[(tert-butoxycarbonyl)amino]ethyl}-2-methyl-8,9-dihydro-7H-cyclopenta[c]pyrazolo[1,5-a]pyridine-1-carboxylate (135 mg, 0.348 mmol) in 12M hydrochloric acid (4 mL) was stirred at 100° C. for 3 days, and concentrated under reduced pressure. To a mixture of the residue and triethylamine (485 μL, 3.48 mmol) in tetrahydrofuran (3.5 mL) was added acetic anhydride (98.7 μL, 1.04 mmol) under ice-cooling, and the mixture was stirred at room temperature for 10 min. Water (50 μL) was added, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→5/95) to give the title compound (86.0 mg, yield 96%, 99.9% ee). The enantiomer excess (ee) was measured by high performance liquid chromatography (column: CHIRALPAK AD-H mm ID×250 mm L, manufactured by Dicel Chemical Industries, Ltd.), mobile phase: hexane/ethanol=95/5, flow rate: 1.0 mL/min, column temperature: 30° C., sample concentration: 0.5 mg/mL (hexane/ethanol=95/5), injection volume: 10 μL).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]N2C(=O)CCC2=O)=O)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39]>CN(C=O)C>[C:1]([O:5][C:6](=[O:33])[C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=[O:25])[NH:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[CH:11][CH:12]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: NCCCC(=O)O
Reactant: CC(C)(C)OC(=O)c1ccc(CCCCCCCCCCC(=O)ON2C(=O)CCC2=O)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(CCCCCCCCCCC(=O)NCCCC(=O)O)cc1
Reaction time: 16 h
Yield: 75.6 %

Procedure:
4-[10-(2,5-Dioxopyrrolidin-1-yloxycarbonyl)decyl]benzoic acid tert-butyl ester (300 mg, 0.65 mmol) was dissolved in DMF (3 ml) and 4-amino butyric acid (67 mg, 0.65 mmol). The mixture was stirred for 16 h under nitrogen. The solvent was removed under vacuum and AcOEt (35 ml) was added. The solution was washed with 0.2 N HCl and water (15 ml each). Sat. NaHCO3 was added (not intended) to the organic phase. DCM (50 ml) was added. Some of the organic phase was removed and DCM (100 ml) was added to the aqueous phase and allowed to stand overnight. The mixture was cooled on ice and the pH was adjusted to 1.9 with 4N HCl. The organic phase was isolated, dried over MgSO4 and concentrated under vacuum to yield on oil (220 mg, 76% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.Cl[CH2:12][CH:13]=O.C(=O)(O)[O-].[Na+].C>O.C1C=CC=CC=1>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[N:3]2[CH:12]=[CH:13][N:1]=[C:2]2[CH:7]=1
Reactant: O=CCCl
Reactant: COc1nc(N)cc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: COc1nc(Cl)cc2nccn12
Temperature: 80 °C

Procedure:
A mixture of 1.7 g (0.011 mole) of 4-amino-6-chloro-2-methoxypyrimidine and 3.0 g (0.015 mole) of 50% aqueous chloroacetaldehyde in 20 ml of water was heated at 80° C. for one hour, and was then cooled in an ice bath with concomitant neutralization with sodium bicarbonate. The mixture was extracted with three 50 ml portions of chloroform which were then dried over magnesium sulfate and evaporated. The residue obtained was dissolved in boiling benzene, treated with decolorizing charcoal, and filtered. The residue which was obtained by evaporation of the filtrate was triturated with diethyl ether to provide a yellow solid. The solid was purified on a preparative scale high pressure liquid chromatograph, using a mixture of 75% ethyl acetate/25% hexanes as the eluent. Recrystallization from cyclohexane gave white solid 7-chloro-5-methoxyimidazo[1,2-c]pyrimidine, m.p. 115°-118° C. Analysis: Calculated for C7H6H3OCl: %C,45.8; %H, 3.3; %N, 22.9; Found: %C, 45.4; %H, 3.1; %N, 23.4.