Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](/[C:3](=[C:5]1/[C:6]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:7]=2[O:8][CH2:9][C:10]2[CH:15]=[C:14]([CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[C:25]([C:26]([OH:28])=O)[C:20]=4[N:19]=[C:18]3[CH2:29][CH2:30][CH3:31])[CH:13]=[CH:12][C:11]/1=2)/[CH3:4])#[N:2].C(N1C=CN=C1)([N:39]1C=CN=C1)=O.N.Cl>C1COCC1.O>[C:1](/[C:3](=[C:5]1/[C:6]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:7]=2[O:8][CH2:9][C:12]2[CH:13]=[C:14]([CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[C:25]([C:26]([NH2:39])=[O:28])[C:20]=4[N:19]=[C:18]3[CH2:29][CH2:30][CH3:31])[CH:15]=[CH:10][C:11]/1=2)/[CH3:4])#[N:2]
Reactant: CCCc1nc2c(C(=O)O)cccc2n1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: CCCc1nc2c(C(N)=O)cccc2n1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Temperature: 50 °C
Reaction time: 4 h
Yield: 100.9 %

Procedure:
[step 5] (E)-1-{[11-(1-cyanoethylidene)-3-fluoro-6,11-dihydrodibenzo[b,e]oxepin-8-yl]methyl}-2-propyl-1H-benzo[d]imidazole-4-carboxylic acid (97 mg, 0.20 mmol) obtained in step 4 was dissolved in THF (1.0 mL), 1,1′-carbonyldiimidazole (130 mg, 0.80 mmol) was added, and the mixture was stirred at 50° C. for 4 hr. After cooling to room temperature, 25% aqueous ammonia solution (55 μL, 0.80 mmol) was added, and the mixture was stirred at room temperature for 17 hr. To the mixture were added 1 mol/L hydrochloric acid and water, and the mixture was extracted 3 times with chloroform. The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=100/0 v/v-93/7 v/v) to give the title compound (97 mg, 100%).
Reaction SMILES: Cl.[CH3:2][NH2:3].C[Al](C)C.[Cl:8][CH2:9][CH2:10][S:11][CH:12]([S:17][CH2:18][CH2:19][Cl:20])[C:13](OC)=[O:14]>C1C=CC=CC=1>[CH3:2][NH:3][C:13](=[O:14])[CH:12]([S:17][CH2:18][CH2:19][Cl:20])[S:11][CH2:10][CH2:9][Cl:8]
Reactant: CN
Reactant: COC(=O)C(SCCCl)SCCCl
Agent: C[Al](C)C
Agent: Cl
Solvent: c1ccccc1
Product: CNC(=O)C(SCCCl)SCCCl
Temperature: 50 °C
Reaction time: 21 h
Yield: 64 %

Procedure:
To a stirred suspension of methylamine hydrochloride (3.464 g; 0.051 mol) in 60 mL of dry benzene under nitrogen at room temperature was added trimethylaluminum (Aldrich, 25.65 mL of 2.0M solution in toluene). After gas evolution ceased (30 min) a solution of the ester 4b (4.500 g; 0.017 mol in 10 mL of dry benzene was added and the mixture was warmed to 50° C. After 21 h, the mixture was allowed to cool to room temperature and was then quenched by dropwise addition of 60 mL of 1.0 N HCl. The mixture was extracted several times with ethyl acetate and the combined extracts were dried (MgSO4) and concentrated under vacuum. Flash chromatography on silica gel (eluent: 2/3 ethyl acetate/hexanes) gave 2.849 g (64%) of 4c, mp 82°-84° C.
Reaction SMILES: [CH2:1]([NH:7][C:8](=[S:10])[S-:9])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[CH2:11]([NH+](CC)CC)C.C(Br)Br.C(N(CC)CC)C.S1CCS1>CN(C)C=O>[CH2:1]([N:7]=[C:8]1[S:9][CH2:11][S:10]1)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C([S-])NCc1ccco1
Reactant: CC[NH+](CC)CC
Agent: C1CSS1
Solvent: CN(C)C=O
Solvent: BrCBr
Solvent: CCN(CC)CC
Product: c1coc(CN=C2SCS2)c1
Temperature: 0 °C

Procedure:
A mixture of 13.7 g. of triethylammonium furfuryldithiocarbamate, 10.5 ml. of methylene bromide, and 7.0 ml. of triethylamine in 100 ml. of dimethylformamide was stirred for several hours and then poured into ice-water. The oily product was partitioned into ether and the ether mixture was extracted with 3N hydrochloric acid. After extracting the acidic solution with methylene chloride, it was made basic with potassium hydroxide solution and re-extracted with methylene chloride. The methylene chloride mixture, after water washing, drying, and concentrating in vacuo afforded 4.9 g. of the desired dithietane as a yellow oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[Mg]Br.[C:13]1(=[O:17])[CH2:16][CH2:15][CH2:14]1>>[CH:13]1([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH2:16][CH2:15][CH2:14]1.[OH:17][C:13]1([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: Br[Mg]c1ccc2ccccc2c1
Reactant: O=C1CCC1
Product: OC1(c2ccc3ccccc3c2)CCC1
Product: c1ccc2cc(C3CCC3)ccc2c1

Procedure:
2-Cyclobutylnaphthalene is prepared from 2-naphthylmagnesium bromide by treating the latter with cyclobutanone to furnish 2-(1'-hydroxycyclobutyl)-naphthalene, which is hydrogenolyzed with hydrogen in the presence of Raney nickel to furnish 2-cyclobutylnaphthalene.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:26](CC)C(C)C)(C)C.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(OCC)(=O)C.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:14]([NH2:26])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(N)=O)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1-tert-Butoxycarbonyl-4-phenyl-piperidine-4-carboxylic acid (1.22 g, 4 mmol) was combined with dichloromethane (40 mL). N,N-diisopropylethylamine (0.77 mL, 4.4 mmol, 1.1 eq.), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (0.8435 g, 4.4 mmol, 1.1 eq.), and 1-hydroxybenzotriazole hydrate (HOBT) (0.5946 g, 4.4 mmol, 1.1 eq.) were added. The mixture was allowed to stir at ambient temperature for 15 h. The solution was sparged with NH3 (gas) for 0.5 h and then allowed to stir at ambient temperature for 15 h. The mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was dissolved in ethyl acetate and extracted with saturated NaHCO3 (6X). The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to give a residue. The residue was recrystallized from diethyl ether to give the title compound:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:19]([O:22][CH:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36]Br)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:21])[CH3:20]>CN(C)C=O>[C:19]([O:22][CH:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][O:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[NH:3][C:2](=[O:1])[CH:11]=[CH:10]2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:21])[CH3:20]
Reactant: CCCCCCC(OC(C)=O)c1ccccc1CBr
Reactant: Oc1ccc2cccc(O)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCC(OC(C)=O)c1ccccc1COc1cccc2ccc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
6.5 g of 2,8-dihydroxyquinoline, 5.5 g of anhydrous ground potassium carbonate are stirred in 100 ml of dimethylformamide at 25° C. for 1 hour. After addition of 13.1 g of 1-(2-bromomethylphenyl)heptyl acetate in 50 ml of dimethylformamide, the mixture is stirred at 25° C. for 20 hours. The solvent is removed in vacuo, the residue is taken up in 100 ml of water and the mixture is extracted 3 times with 50 ml of ethyl acetate each time. The organic phases are washed once with 50 ml of water each time, dried over Na2SO4 and concentrated in vacuo. The oil which remains is chromatographed over silica gel 60 with CH2Cl2 /ethyl acetate 10:1. The resulting product slowly crystallizes out.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[CH2:12]([O:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)C(C)(C)CO
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)COCc1ccccc1
Temperature: 25 °C

Procedure:
To a stirred solution of methyl 3-hydroxy-2,2-dimethylpropanoate (600. mg, 4.54 mmol) in DMF (9.0 mL), cooled to 0° C., was added NaH (120. mg, 4.99 mmol). After warming to ambient temperature for 30 minutes, the reaction was cooled to 0° C., prior to the introduction of benzyl bromide (854 mg, 4.99 mmol). After warming to ambient temperature, the reaction was heated to 50° C. for 4 hours, before being allowed to return to ambient temperature. The bulk of the DMF was removed in vacuo, and the residue was diluted with water and EtOAc. The organic layer was washed several times with water and then once with saturated brine. The organics were then dried over sodium sulfate, filtered and concentrated in vacuo, to yield a residue which was applied to a silica gel column for purification, eluting with 100% DCM. The resulting impure material was applied again to silica gel and eluted with a gradient of CH2Cl2:hexanes—85:15 to 100:0. Clean product-containing fractions were pooled and concentrated in vacuo to give the title compound. MS: m/z=223 (M+1).
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[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[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cccnc1Cl
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Product: N#Cc1cccnc1-c1cc([N+](=O)[O-])ccc1F

Procedure:
2-Chloronicotinonitrile (0.80 g, 5.8 mmol) was coupled to 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (2 g, 7.49 mmol) using the method in Example 14 part a). Purification by chromatography on silica gel eluting with dichloromethane gave 2-(2-fluoro-5-nitrophenyl)nicotinonitrile as a yellow solid: δH (360 MHz, CDCl3) 8.97 (1H, dd, J 5 and 2), 8.56 (1H, dd, J 6 and 3), 8.40-8.45 (1H, m), 8.15 (1H, dd, J 8 and 2), 7.55 (1H, dd, J 8 and 5), 7.43 (1H, dd, J 9 and 9); m/z (ES+) 244 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][C:4]=1[CH3:12].Br[C:14]1[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)=[CH:5][C:4]=1[CH3:12]
Reactant: Cn1cc(Br)cn1
Reactant: COc1ccc(B(O)O)cc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2cnn(C)c2)cc1C
Yield: 65.9 %

Procedure:
Under nitrogen atmosphere, a mixture of 4-methoxy-3-methyl-phenylboronic acid 1.62 g, 4-bromo-1-methyl-1H-pyrazole 1.57 g, 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex 0.79 g, sodium carbonate 3.51 g, dioxane 100 ml and water 30 ml was stirred with heating under reflux for four hours. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, and was dried over anhydrous magnesium sulfate and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 4-(4-methoxy-3-methyl-phenyl)-1-methyl-1H-pyrazole 1.3 g.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]2[CH2:30][CH2:29][C@H:28]([NH:31][C:32](=[O:34])[CH3:33])[CH2:27][C:26](=[O:35])[C:25]=2[C:36]=1[O:37][CH3:38]>>[ClH:1].[C:32]([NH:31][C@@H:28]1[CH2:27][C:26](=[O:35])[C:25]2[C:36]([O:37][CH3:38])=[C:21]([NH:20][C:2]3[N:7]=[C:6]([NH:8][C@@H:9]4[C@@H:14]5[CH2:15][C@@H:11]([CH:12]=[CH:13]5)[C@@H:10]4[C:16]([NH2:18])=[O:17])[C:5]([Cl:19])=[CH:4][N:3]=3)[CH:22]=[CH:23][C:24]=2[CH2:30][CH2:29]1)(=[O:34])[CH3:33]
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Reactant: COc1c(N)ccc2c1C(=O)C[C@@H](NC(C)=O)CC2
Product: COc1c(Nc2ncc(Cl)c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)n2)ccc2c1C(=O)C[C@@H](NC(C)=O)CC2
Product: Cl

Procedure:
632 h) (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide was reacted with N—((S)-2-Amino-1-methoxy-9-oxo-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-acetamide; hydrochloride, in a similar manner as Example 601b, to yield desired product (1S,2S,3R,4R)-3-[2-((S)-7-Acetylamino-1-methoxy-9-oxo-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino)-5-chloro-pyrimidin-4-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide as a lyophylate (28%); 1H NMR (400 MHz, DMSO-d6) δ 9.07 (bs, 1H), 8.83 (bs, 1H), 8.16 (s, 1H), 8.09 (d, J=8.33 Hz, 1H), 8.00 (d, J=7.58 Hz, 1H), 7.93 (s, 1H), 7.38 (s, 1H), 7.08 (d, J=8.34 Hz, 1H), 6.36 (bs, 1H), 6.26 (bs, 1H), 3.98-3.94 (m, 2H), 3.69 (s, 3H), 2.93-2.68 (m, 7H), 2.1-1.9 (m, 2H), 1.80 (s, 3H), 1.75-1.70 (m, 1H), 1.42 (d, J=9.10 Hz, 1H); MS (m/e) 525.15 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][CH2:11][N:10]3[C:14](=[O:24])[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:17]=[C:9]23)[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:31]([NH2:39])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C.O.CCOC(C)=O>[CH2:31]([NH:39][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][CH2:11][N:10]3[C:14](=[O:24])[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:17]=[C:9]23)[CH:3]=1)[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NCCc1ccccc1
Reactant: O=c1cc(-c2ccccc2)cc2n1CCCN2c1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1cc(-c2ccccc2)cc2n1CCCN2c1cc(NCCc2ccccc2)ncn1

Procedure:
To a stirred mixture of 1-(6-chloro-pyrimidin-4-yl)-8-phenyl -1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one (0.158 mg, 0.47 mmol) and excess of K2CO3 in DMF (3 mL) was added phenethylamine (0.15 mL, 1.2 mmol). The overall reaction vessel was irradiated under microwave conditions at 150° C. for 10 min. After diluted with water and EtOAc, the organic layer was taken and the aqueous layer was extracted with EtOAc. The overall organic layers were washed with water, brine, and dried (Na2SO4). Filtration followed by evaporation gave the crude residue, which was washed with EtOAc/ether to provide the title compound as a light yellow solid. MS m/e 424 (M+H)+.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[CH:28][CH:27]=1.[NH2:35][CH2:36][C:37]([NH2:39])=[O:38]>>[NH2:39][C:37](=[O:38])[CH2:36][NH:35][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:29]1[CH:28]=[CH:27][C:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH3:19])=[CH:31][CH:30]=1)=[O:7])=[O:18]
Reactant: NCC(N)=O
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1
Product: CON=C1C[C@@H](C(=O)NCC(N)=O)N(C(=O)c2ccc(-c3ccccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and 2-aminoacetamide, the title compound was obtained in 92% purity by HPLC. MS(ESI+): m/z=409.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([N:23](C)[C:24](=O)OC(C)(C)C)[CH2:18]2)=[C:4]2[C:10]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[C:3]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][CH3:24])[CH2:18]2)=[C:4]2[C:10]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1c[nH]c2ncc(Cl)c(N3CCC[C@@H](N(C)C(=O)OC(C)(C)C)C3)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@@H]1CCCN(c2c(Cl)cnc3[nH]cc(NC(=O)C(C)C)c23)C1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 194.1 %

Procedure:
(R)-tert-Butyl 1-(5-chloro-3-isobutyramido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-yl(methyl)carbamate (0.180 g, 0.400 mmol) was placed in DCM (3 mL) at room temperature. TFA (1 mL) was then added, and the reaction was stirred at room temperature for 1 hour and concentrated to dryness. The resulting residue was then purified by reverse phase chromatography (Biotage SP4, C-18 12M+, 0-50% CH3CN/water). The resulting product was next dissolved in minimal DCM (with MeOH to aid solubility) and added to a stirred solution of 1M HCl in ether. The resulting solid was filtered, washed with ether and dried to give (R)—N-(5-chloro-4-(3-(methylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide hydrochloride (0.150 g, 89% yield) as a solid. 1H NMR (400 MHz, D2O) δ 8.16 (s, 1H), 7.28 (s, 1H), 4.01-3.98 (m, 1H), 3.49-3.37 (m, 2H), 3.21-3.11 (m, 2H), 2.69-2.65 (m, 1H), 2.60 (s, 3H), 2.19-2.16 (m, 1H), 1.82-1.78 (m, 1H), 1.64-1.51 (m, 2H), 1.12-1.08 (m, 6H). LCMS (APCI+) m/z 350 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH2:9][O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[N:3]=1.[CH2:16](CN)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:25](#[N:27])C>>[CH2:16]([N:27]([CH3:25])[C:6]1[CH:5]=[C:4]([CH2:9][O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[N:3]=[C:2]([Cl:1])[N:7]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NCCc1ccccc1
Reactant: FC(F)(F)COCc1cc(Cl)nc(Cl)n1
Reactant: CC#N
Product: CN(Cc1ccccc1)c1cc(COCC(F)(F)F)nc(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,4-dichloro-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine (200 mg, 0.77 mmol) in acetonitrile (3 mL) was benzylmethylamine (0.296 mL, 2.30 mmol) added. The reaction was stirred at ambient temperature for 30 minutes. The solvent was evaporated. The mixture was purified by preparative HPLC the title compound (194 mg, 73%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH3:13])=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][NH:6][CH3:7].CNCC1C=CC2C(=CC=CC=2)C=1CCC.Cl.[N:31]1([CH2:37][CH2:38][N:39]2[CH2:44][C:43]3[CH:45]=[C:46](/[CH:49]=[CH:50]/[C:51]([OH:53])=O)[CH:47]=[N:48][C:42]=3[NH:41][C:40]2=[O:54])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[ClH:1].[Cl:1][C:2]1[C:3]([O:11][CH2:12][CH3:13])=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][N:6]([CH3:7])[C:51](=[O:53])/[CH:50]=[CH:49]/[C:46]1[CH:47]=[N:48][C:42]2[NH:41][C:40](=[O:54])[N:39]([CH2:38][CH2:37][N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)[CH2:44][C:43]=2[CH:45]=1
Reactant: CCOc1c(Cl)cccc1CNC
Reactant: O=C(O)/C=C/c1cnc2c(c1)CN(CCN1CCOCC1)C(=O)N2
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: Cl
Product: CCOc1c(Cl)cccc1CN(C)C(=O)/C=C/c1cnc2c(c1)CN(CCN1CCOCC1)C(=O)N2
Yield: 60 %

Procedure:
According to the procedure of Example 1, except substituting 3-chloro-2-ethoxy-benzyl-methylamine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-[3-(2-morpholin-4-yl-ethyl)-2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-6-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3,-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.15 g, 60%) was prepared as an off-white solid: 1H NMR (500 MHz, DMSO-d6) δ 10.82-10.69 (m, 1H), 10.11-10.09 (m, 1H), 8.41-8.33 (m, 1H), 8.01-7.91 (m, 1H), 7.58-7.48 (m, 1H), 7.47-7.36 (m, 1H), 7.28-7.01 (m, 3H), 4.86-4.68 (m, 2H), 4.60-4.51 (m, 2H), 4.07-3.91 (m, 4H), 3.82-3.71 (m, 4H), 3.59-3.49 (m, 2H), 3.40-3.30 (m, 2H), 3.13-2.88 (m, 4H), 1.38 (t, J=7.0 Hz, 3H); MS (ESI) m/e 514 (M+H)+.
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:35])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27]([NH:29][C@@H:30]([CH3:34])[C:31](O)=[O:32])=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:69]([O:71][C:72]([N:74]1[CH2:79][CH2:78][NH:77][CH2:76][CH2:75]1)=[O:73])[CH3:70]>CN(C=O)C.ClCCl>[CH2:69]([O:71][C:72]([N:74]1[CH2:75][CH2:76][N:77]([C:31](=[O:32])[C@@H:30]([NH:29][C:27]([C:18]2[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@H:8]3[C:6](=[O:7])[NH:5][CH:1]3[CH2:2][CH2:3][CH2:4]3)=[O:35])[N:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:19]=2)=[O:28])[CH3:34])[CH2:78][CH2:79]1)=[O:73])[CH3:70]
Reactant: C[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)O
Reactant: CCOC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](C)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 1 h

Procedure:
To a solution of 225 mg (S)-2-({5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-propionic acid in 4 ml DMF were added 0.32 ml DIPEA, 177 mg HATU and 0.07 ml 1-ethoxycarbonyl-piperazine. After stirring for 1 h it was diluted with dichlormethane and extracted with aqueous LiCl (4% w/w), aqueous NaHCO3 and 0.1 M HCl. The crude product obtained after evaporation of the solvent was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[CH:2].[NH2:11]/[C:12](/[CH3:18])=[CH:13]\[C:14]([O:16][CH3:17])=[O:15].[C:19]([O:25][CH2:26][CH3:27])(=[O:24])[CH2:20][C:21]([CH3:23])=O.C(OCC)C>C(O)C>[CH2:26]([O:25][C:19]([C:20]1[CH:6]([C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([C:1]#[CH:2])[CH:4]=2)[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:21]=1[CH3:23])=[O:24])[CH3:27]
Reactant: CCOC(=O)CC(C)=O
Reactant: COC(=O)/C=C(/C)N
Reactant: C#Cc1cccc(C=O)c1
Solvent: CCO
Solvent: CCOCC
Product: C#Cc1cccc(C2C(C(=O)OC)=C(C)NC(C)=C2C(=O)OCC)c1
Temperature: 80 °C
Yield: 68.8 %

Procedure:
In 20 ml of ethyl alcohol was dissolved 1.95 g (15 mmol) of 3-ethynylbenzaldehyde. Thereto were added 1.73 g (15 mmol) of methyl 3-aminocrotonate and 1.95 g (15 mmol) of ethyl acetoacetate. The mixture was stirred with heating for 16 hours at 80° C. After completing the reaction, the reaction solution was concentrated. The obtained precipitate was washed with ether and then recrystallized from the mixture solution of n-pentane and diethylether (n-pentane: diethylether =3 : 1 (by volume, hereinafter the same)) to give 3.5 g of the desired compound as yellow needle crystals (yield: 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([CH2:19][NH2:20])=[CH:7]2.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[NH:24][CH:25]=[N:26]2.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([CH2:19][NH:20][C:22]1[N:30]=[CH:29][N:28]=[C:27]3[C:23]=1[N:24]=[CH:25][NH:26]3)=[CH:7]2
Reactant: Clc1ncnc2nc[nH]c12
Reactant: NCc1cc2cccc(Cl)c2nc1Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Clc1cccc2cc(CNc3ncnc4[nH]cnc34)c(Oc3ccccc3)nc12

Procedure:
Prepared according to Procedure H using (8-chloro-2-phenoxyquinolin-3-yl)-methanamine (0.110 g, 0.360 mmol), 6-chloropurine (0.072 g, 0.46 mmol, 1.2 eq) and DIEA (0.72 mmol, 2.0 eq) in n-butanol (3 mL). N-((8-chloro-2-phenoxyquinolin-3-yl)methyl)-9H-purin-6-amine [PI3Kδ IC50=125 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.18-8.24 (s, 1 H), 8.14-8.20 (s, 1 H), 7.85-7.91 (d, J=7.58, 1 H), 7.72-7.79 (d, J=7.34, 1 H), 7.47-7.55 (m, 3 H), 7.42-7.47 (m, 3 H), 7.35-7.42 (m, 1 H), 4.01-4.14 (m, 2 H), Mass Spectrum (ESI) m/e=403 (M+1)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1.[CH2:21]([NH2:25])[CH2:22][CH2:23][CH3:24]>>[CH2:21]([NH:25][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCN
Reactant: O=C(c1ccc(F)cc1)N1CCC[C@H]1CN1CCCC1
Product: CCCCNc1ccc(C(=O)N2CCC[C@H]2CN2CCCC2)cc1

Procedure:
(4-Butylamino-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone is prepared from (4-Fluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and n-butylamine in a manner substantially similar to Procedure A. MS (APCI+) 330 (MA-H)+.