Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].[CH:6]1([NH:9][C:10](=[O:40])[C:11]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[CH:12][C:13]2[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH:27]=[CH:28][C:29](OC)=[O:30])=[O:22])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1>CO.C(Cl)Cl.O>[CH:6]1([NH:9][C:10](=[O:40])/[C:11](/[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[CH:12]/[C:13]2[CH:14]=[CH:15][C:16]([CH:19]=[CH:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH:2][OH:3])=[O:30])=[O:22])=[CH:17][CH:18]=2)[CH2:8][CH2:7]1
Reactant: NO
Reactant: COC(=O)C=CCCCNC(=O)/C=C/c1ccc(C=C(C(=O)NC2CC2)c2ccc(F)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: O=C(C=Cc1ccc(/C=C(/C(=O)NC2CC2)c2ccc(F)cc2)cc1)NCCCCCC(=O)NO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.3 %

Procedure:
Hydroxylamine hydrochloride (0.63 g, 9 mmol) in methanol (3 mL) was mixed with KOH (0.51 g, 12.3 mmol) in methanol (3 mL) at 0° C., and sonicated for. 2 minutes and the white precipitate formed was filtered. The filtrate was added to the methyl 6-(3-(E)-(4-(3-(cyclopropylamino)-2-(4-fluorophenyl)-3-oxoprop-1-en-1-yl) phenyl)acrylamido)hexenoate (0.24 g, 0.5 mmol) in DCM (1.5 mL) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (1×200 mL). The ethyl acetate layer was washed with water (100 mL), dried over anhydrous Na2SO4 and concentrated to obtain a sticky compound, subsequently triturated with DCM (15 mL), to obtain a solid. The solid obtained was filtered and washed with DCM (5 mL) to afford the title compound (0.075 g, 32% yield). 1H NMR (DMSO-d6) δ (ppm): 0.51 (2H, m, —CH2), 0.62-0.64 (2H, t, —CH2), 1.24 (2H, m, —CH2), 1.40-1.49 (4H, m, —CH2), 1.91-1.93 (2H, d, —CH2), 2.74-2.76 (1H, m, —CH), 3.12-3.13 (2H, d, —CH2) 6.53-6.57 (1H, d, ═CH), 6.99-7.01 (2H, d, Ar—H), 7.18-7.22 (4H, m, Ar—H), 7.27 (1H, s, ═CH), 7.28-7.32 (1H, d, ═CH), 7.37-7.39 (2H, d, Ar—H), 7.82-7.83 (1H, d, —NH), 8.06 (1H, s, —NH), 8.67 (1H, s, —OH), 10.34 (1H, s, —NH). MS m/z: 480.3 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.Cl.C(N=C=NCCCN(C)C)C.O.O[N:29]1[C:33]2[CH:34]=[CH:35][CH:36]=CC=2N=N1.C(N(C(C)C)C(C)C)C.C1(N)CCC1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([NH:29][CH:33]1[CH2:34][CH2:35][CH2:36]1)=[O:14])[CH:6]=[CH:5]2
Reactant: O=C(O)c1ccc2cc(Br)ccc2c1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC1CCC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CCC1)c1ccc2cc(Br)ccc2c1
Yield: 72.7 %

Procedure:
By reactions similar to those in Reference Example 2, using 6-bromo-2-naphthoic acid (1.01 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.92 g), 1-hydroxy-1H-benzotriazole monohydrate (0.735 g; HOBt), dimethylformamide (16 ml), N-ethyldiisopropylamine (0.62 g) and cyclobutylamine (0.45 g), the title compound (0.89 g) was obtained as colorless needle crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=3)[N:13]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)[CH:14]=2)=[CH:6][CH:5]=1.Br[CH2:34][C:35]([O:37][CH3:38])=[O:36]>>[CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=3)[N:13]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:17][CH:16]=3)[CH:14]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(-c2cn(-c3ccc([N+](=O)[O-])cc3)c(Cc3ccc(Br)cc3)n2)cc1
Reactant: COC(=O)CBr
Product: COC(=O)CNc1ccc(-n2cc(-c3ccc(C(=O)OC)cc3)nc2Cc2ccc(Br)cc2)cc1

Procedure:
4-[2-(4-Bromo-benzyl)-1-(4-Nitro-phenyl)-1H-imidazol-4-yl]-benzoicacid methyl ester (9.8 g, 20 mmol) was reduced to amine and was reacted with methyl bromoacetate following general procedures D & E to give 4-{2-(4-Bromo-benzyl)-1-[4-(methoxycarbonylmethyl-amino)-phenyl]-1H-imidazol-4-yl}-benzoic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]23[O:15][C@:12]([CH:16]([OH:23])[C:17]#[C:18][Si](C)(C)C)([CH2:13][O:14]2)[C@@H:11]([OH:24])[C@H:10]([OH:25])[C@H:9]3[OH:26])=[CH:4][C:3]=1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH3:36])=[CH:30][CH:29]=1.[OH-].[Na+].[Cl-].[NH4+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]23[O:15][C@:12]([CH:16]([OH:23])[C:17]#[CH:18])([CH2:13][O:14]2)[C@@H:11]([OH:24])[C@H:10]([OH:25])[C@H:9]3[OH:26])=[CH:4][C:3]=1[CH2:27][C:28]1[CH:29]=[CH:30][C:31]([O:34][CH2:35][CH3:36])=[CH:32][CH:33]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@@](C(O)C#C[Si](C)(C)C)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: C#CC(O)[C@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCC)cc4)c3)(O1)[C@H](O)[C@@H](O)[C@@H]2O
Temperature: 25 °C
Reaction time: 10 h
Yield: 14.8 %

Procedure:
To a solution of (1S,2S,3S,4R,5S)-5-[4-chloro-3 [(4-ethoxyphenyl)methyl]phenyl]-1-(1-hydroxy-3-trimethysilyl-prop-2-ynyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol 4b (0.44 g, 0.82 mmol) in anhydrous methanol (20 mL) was added sodium hydroxide (32.9 mg, 8.2 mmol). The mixture was stirred at room temperature for 10 hours. The reaction mixture was adjusted to pH 6-7 with saturated aqueous ammonium chloride, and extracted with ethyl acetate (40 mL×3). The combined organic layers were washed with water (30 mL×2) and then saturated aqueous sodium chloride (20 mL×2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by prep-HPLC to give the title compound 4 (56 mg, 14.7%, HPLC: 84.2%) as colorless oil. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 461.1[M+H]+; and 1H NMR (400 MHz, DMSO-d6) δ(ppm): 7.41 (m, 2H), 7.31 (m, 1H), 7.09 (d, 2H), 6.83 (d, 2H), 5.69 (d, 1H), 5.37 (d, 1H), 5.06 (d, 1H), 4.97 (d, 1H), 4.45 (m, 2H), 3.97 (m, 5H), 3.81 (s, 1H), 3.77 (d, 1H), 3.76 (t, 1H), 3.51 (m, 1H), 1.29 (t, 3H).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([CH2:12][CH:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:22][CH2:23][CH:24]([C:26]1[CH:27]=[CH:28][C:29]([OH:37])=[C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=1)[OH:25]>>[O:18]=[C:16]1[NH:15][C:14](=[O:19])[CH:13]([CH2:12][C:11]2[CH:20]=[CH:21][C:8]([N:5]3[CH2:6][CH2:7][CH:2]([NH:22][CH2:23][CH:24]([C:26]4[CH:27]=[CH:28][C:29]([OH:37])=[C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=4)[OH:25])[CH2:3][CH2:4]3)=[CH:9][CH:10]=2)[S:17]1
Reactant: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Product: CS(=O)(=O)Nc1cc(C(O)CNC2CCN(c3ccc(CC4SC(=O)NC4=O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 5-[4-(4-oxo-piperidin-1-yl)-benzyl]-thiazolidine-2,4-dione (which was obtained in Example 38) and N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 9) according to the procedure of Example 73 as a pale yellowish solid; mp>150° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.40–1.60 (m, 2 H), 1.90–2.10 (m, 2 H), 2.55–3.60 (m, 7 H), 2.93 (s, 3 H), 3.67 (brd, J=12.8 Hz, 2 H), 4.56 (dd, J=9.6, 4.0 Hz, 1 H), 4.64 (brd, J=6.5 Hz, 1 H), 6.70–6.95 (m, 3 H), 6.95–7.15 (m, 3 H), 7.22 (d, J=2.1 Hz, 1 H); MS (ES) m/z: 535.0 (MH+); HRMS Calcd. for C24H31N4O6S2 (MH+): 535.1685. Found: 535.1720.
Reaction SMILES: C(O)(=O)C.[N:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.Cl.CN.[BH3-][C:22]#[N:23].[Na+]>CO>[CH3:22][NH:23][CH:14]1[CH2:15][CH2:16][N:11]([C:8]2[CH:9]=[CH:10][N:5]=[CH:6][CH:7]=2)[CH2:12][CH2:13]1
Reactant: O=C1CCN(c2ccncc2)CC1
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNC1CCN(c2ccncc2)CC1
Reaction time: 0.33 h
Yield: 82 %

Procedure:
Acetic acid (150 μl) was added to a solution of 1-(pyridin-4-yl)piperidin-4-one (450 mg, 2.55 mmol, 1 eq) and methylamine hydrochloride (190 mg, 2.81 mmol, 1.1 eq) in methanol (10 ml), and stirring was carried out for 20 min at RT. Then NaBH3CN (166 mg, 2.81 mmol, 1.1 eq) was added in portions and stirring was carried out for 16 h at RT. The solvent was concentrated, and the residue was taken up in chloroform (100 ml), washed with sat. K2CO3 solution (30 ml) and sat. NaCl solution (30 ml), dried over sodium sulfate and concentrated under reduced pressure. The product (yellow solid) was used in the next stage without being purified further. Yield: 82% (400 mg, 2.09 mmol).
Reaction SMILES: Cl.O1CCOCC1.[S:8]1[C:12]2[CH:13]=[C:14]([N:17]3[CH2:21][CH2:20][N:19]([C:22]4[CH:23]=[C:24]5[CH:30]=[CH:29][N:28](COCC[Si](C)(C)C)[C:25]5=[N:26][CH:27]=4)[C:18]3=[O:39])[CH:15]=[CH:16][C:11]=2[N:10]=[CH:9]1.CO.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[S:8]1[C:12]2[CH:13]=[C:14]([N:17]3[CH2:21][CH2:20][N:19]([C:22]4[CH:23]=[C:24]5[CH:30]=[CH:29][NH:28][C:25]5=[N:26][CH:27]=4)[C:18]3=[O:39])[CH:15]=[CH:16][C:11]=2[N:10]=[CH:9]1
Reactant: C[Si](C)(C)CCOCn1ccc2cc(N3CCN(c4ccc5ncsc5c4)C3=O)cnc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: O=C1N(c2cnc3[nH]ccc3c2)CCN1c1ccc2ncsc2c1
Temperature: 110 °C
Yield: 2.7 %

Procedure:
1,4-Dioxane HCl (10 ml) was added to 1-(benzothiazol-6-yl)-3-(1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)imidazolidin-2-one (I-187b: 0.07 g, 0.19 mmol) and the resulting mixture was heated to 110° C. for 2 days. The reaction was monitored by TLC (20% MeOH in CHCl3). The reaction mixture was basified with Na2CO3 solution (pH˜8), cooled to room temperature, concentrated and the concentrate was washed with diethyl ether. Purification by preparative HPLC afforded 1.7 mg of the product (25.6% yield).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][C:7]=1[S:15](=[O:18])(=[O:17])[NH2:16].[C:19]1([O:25][CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)C>C(Cl)Cl.C(OCC)(=O)C>[CH3:26][O:25][C:19]1[CH:24]=[CH:23][C:22]([C:10]([C:9]2[CH:13]=[CH:14][C:6]([CH3:5])=[C:7]([S:15]([NH2:16])(=[O:18])=[O:17])[CH:8]=2)=[O:11])=[CH:21][CH:20]=1
Reactant: Cc1ccc(C(=O)Cl)cc1S(N)(=O)=O
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COc1ccc(C(=O)c2ccc(C)c(S(N)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.5 %

Procedure:
To a suspension of aluminium chloride (906 mg, 6.8 mmol) in methylene chloride (20 mL) is added 4-methyl-3-sulfamoyl-benzoyl chloride (1.1 g, 4.7 mmol) and anisole (1.1 g, 10.2 mmol). After the mixture is stirred at room temperature for 16 h, the reaction is quenched with 6 N HCl, and extracted with methylene chloride three times. The combined organic layers are washed with a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo. On standing, crystals form and trituration with diethyl ether and ethyl acetate provides 0.84 g (58% yield) of the title compound as a white solid. MS (m/z): 306 (M+1).
Reaction SMILES: COC(=O)CC.NC1C=CC(C(N)=O)=CC=1C.C([O:20][C:21](=[O:39])[CH2:22][CH2:23][C:24](=[O:38])[CH2:25][CH2:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:37])[NH2:36])=[CH:31][CH:30]=1)=[O:28])C.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCO.ClCCl>[C:35]([C:32]1[CH:31]=[CH:30][C:29]([C:27](=[O:28])[CH2:26][CH2:25][C:24](=[O:38])[CH2:23][CH2:22][C:21]([OH:39])=[O:20])=[CH:34][CH:33]=1)(=[O:37])[NH2:36]
Reactant: CCOC(=O)CCC(=O)CCC(=O)c1ccc(C(N)=O)cc1
Agent: Cc1cc(C(N)=O)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: ClCCl
Solvent: CCC(=O)OC
Product: NC(=O)c1ccc(C(=O)CCC(=O)CCC(=O)O)cc1

Procedure:
Synthesis of 3-[1-carbamoyl-2-methyl-phenyl)-5-(4-carbamoyl-phenyl)-1H-pyrrole-2-yl]-propanoic acid methyl ester. 4-amino-3-methyl benzamide (20 mg, 0.13 mmol) was added to 7-(4-carbamoyl-phenyl)-4,7-dioxo-heptanoic acid ethyl ester mixture (˜0.11 mmol) in EtOH, followed by the addition of p-toluenesulfonic acid (2 mg, 0.01 mmol). The resultant mixture was heated at 80° C. for 12 hours. The residue of the crude reaction mixture was dissolved in dichloromethane and then purified by silica-gel chromatography using 5% methanol in chloroform as the solvent system (5 mg; product: 3-[1-carbamoyl-2-methyl-phenyl)-5-(4-carbamoyl-phenyl)-1H-pyrrole-2-yl]-propanoic acid methyl ester).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH:4]=O.Cl.[CH3:9][C@@H:10]([NH2:14])[CH2:11][CH2:12][CH3:13].C(N(CC)CC)C>CO.[Pd]>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:14][C@@H:10]([CH2:11][CH2:12][CH3:13])[CH3:9]
Reactant: COC(C=O)OC
Reactant: CCC[C@@H](C)N
Agent: [Pd]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCC[C@@H](C)NCC(OC)OC
Reaction time: 2 h

Procedure:
2,2-Dimethoxyacetaldehyde (0.59 mL) was added to a solution of (R)-pentan-2-amine hydrochloride (0.48 g) and triethylamine (0.54 mL) in methanol (4 mL) and the mixture stirred for 2 h. A slurry of palladium on carbon (10%, 20 mg) in methanol (1 mL) was added and the mixture hydrogenated at 5 bar for 20 h. The mixture was then filtered and in vacuo. The resulting residue was triturated with diethyl ether (5 mL) and the resulting white solid extracted with further diethyl ether (2×5 mL). The combined ether fractions were concentrated in vacuo to afford (R)—N-(2,2-dimethoxyethyl)pentan-2-amine (0.745 g) as an oil. 1H NMR (400 MHz, CDCl3) δ 4.92 (t, J=5.4 Hz, 1H), 3.47 (s, 3H), 3.47 (s, 3H), 3.25-3.15 (m, 1H), 2.99 (ddd, J=27.9, 12.7, 5.5 Hz, 2H), 1.86-1.77 (m, 1H), 1.64-1.54 (m, 1H), 1.49-1.32 (m, 5H), 0.95 (t, J=7.3 Hz, 3H)
Reaction SMILES: [CH2:1]([O:8][C:9]1([CH3:25])[CH2:18][CH2:17][C:16]2[N:15]=[CH:14][C:13]([C:19]([O:21]CC)=O)=[C:12](Cl)[C:11]=2[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][NH2:34])=[CH:29][CH:28]=1>C(O)CCC>[CH2:1]([O:8][C:9]1([CH3:25])[CH2:10][CH2:11][C:16]2[NH:15][CH:14]=[C:13]3[C:19](=[O:21])[N:33]([C:30]4[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=4)[N:34]=[C:12]3[C:17]=2[CH2:18]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnc2c(c1Cl)CC(C)(OCc1ccccc1)CC2
Reactant: NNc1ccc(Cl)cc1
Solvent: CCCCO
Product: CC1(OCc2ccccc2)CCc2[nH]cc3c(=O)n(-c4ccc(Cl)cc4)nc-3c2C1

Procedure:
A solution of ethyl 6-benzyloxy-4-chloro-6-methyl-5,6,7,8-tetrahydroquinoline-3-carboxylate (5.0 g) and p-chlorophenylhydrazine (2.0 g) in 75 mL of n-butanol is stirred at room temperature for 4 hours, then refluxed overnight. The reaction mixture is evaporated and the residue is treated with Et2O and 2N NaOH. The alkaline layer is separated, the pH is adjusted at 8 with dilute HCl, and the resulting precipitate is collected. This material is washed with EtOH/Et2O and air-dried to obtain 8-benzyloxy-2-p-chlorophenyl-8-methyl-2,3,6,7,8,9-hexahydropyrazolo[4,3-c]quinolin-3(5H)-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[Cl:19])[C:8]([CH2:20][NH2:21])=[CH: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:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[Cl:19])[C:8]([CH2:20][NH:21][C:23]1[N:31]=[CH:30][N:29]=[C:28]3[C:24]=1[N:25]=[CH:26][NH:27]3)=[CH:7]2
Reactant: Clc1ncnc2nc[nH]c12
Reactant: NCc1cc2cccc(Cl)c2nc1-c1cc(F)ccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Fc1ccc(Cl)c(-c2nc3c(Cl)cccc3cc2CNc2ncnc3[nH]cnc23)c1

Procedure:
Prepared according to Procedure H using (8-chloro-2-(2-chloro-5-fluorophenyl)-quinolin-3-yl)methanamine (0.050 g, 0.156 mmol), 6-chloropurine (0.027 g, 0.17 mmol, 1.2 eq) and DIEA (0.70 mmol, 2.0 eq) in n-butanol (3 mL). N-((8-chloro-2-(2-chloro-5-fluorophenyl)quinolin-3-yl)methyl)-9H-purin-6-amine [PI3Kδ IC50=71 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.30 (s, 1 H), 8.20 (s, 1 H), 7.80 (dd, J=7.58, 0.49 Hz, 2 H), 7.69-7.75 (m, 1 H), 7.42-7.47 (m, 1 H), 7.31-7.37 (m, 1 H), 7.11-7.16 (m, 1 H), 6.99-7.06 (m, 1 H), 4.90-497. (m, 2 H), Mass Spectrum (ESI) m/e=440 (M+1)
Reaction SMILES: C([NH:9][C:10](=[S:20])[NH:11][N:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]([NH2:19])=[O:18])(=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].CO.C(O)(=O)C>O.CC(C)=O>[NH:11]([N:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]([NH2:19])=[O:18])[C:10]([NH2:9])=[S:20]
Reactant: NC(=O)c1cccn1NC(=S)NC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: NC(=O)c1cccn1NC(N)=S
Temperature: 25 °C
Yield: 78.6 %

Procedure:
Compound 1A (2.2 g, 7.6 mmol) was treated with a solution of K2CO3 (2.0 g, 14.8 mmol) in water (9 mL) at ambient temperature. Methyl alcohol (70 mL) and acetone (70 mL) were added and the mixture was heated to reflux for 18 hours. The reaction was cooled to ambient temperature and treated with acetic acid (2.0 mL, 35 mmol), and then concentrated to approximately 30 mL. The resulting suspension was cooled to 0° C. and the product was recovered by vacuum filtration to afford 1B (1.1 g, 79%). HPLC tR=0.405 min (YMC S5 Combiscreen ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 254 nm). 1H NMR (400 MHz, DMSO-d6) δ 10.4 (s, 1H), 8.13 (br s, 2H), 7.31 (br s, 1H), 7.10 (br s, 1H), 6.88 (t, 1H, J=2.0 Hz), 6.75 (dd, 1H, J=1.6, 4.0 Hz), 6.05 (t, 1H, J=3.6 Hz).
Reaction SMILES: [CH:1]([N:4]([CH3:17])[C:5]1[O:6][C:7]2[C:8](=[C:10]([C:14]([O-:16])=O)[CH:11]=[CH:12][CH:13]=2)[N:9]=1)([CH3:3])[CH3:2].[Li+].Cl.Cl.[NH2:21][C@H:22]1[CH:27]2[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]2)[CH2:23]1>>[N:24]12[CH2:23][C@@H:22]([NH:21][C:14]([C:10]3[CH:11]=[CH:12][CH:13]=[C:7]4[O:6][C:5]([N:4]([CH:1]([CH3:2])[CH3:3])[CH3:17])=[N:9][C:8]=34)=[O:16])[CH:27]([CH2:28][CH2:29]1)[CH2:26][CH2:25]2
Reactant: CC(C)N(C)c1nc2c(C(=O)[O-])cccc2o1
Reactant: N[C@@H]1CN2CCC1CC2
Agent: Cl
Agent: [Li+]
Product: CC(C)N(C)c1nc2c(C(=O)N[C@@H]3CN4CCC3CC4)cccc2o1

Procedure:
Following general procedure GP-C1, a mixture of lithium 2-(isopropyl(methyl)amino)benzoxazole-4-carboxylate and (S)-(−)-3-aminoquinuclidine dihydrochloride were coupled to afford (S)—N-(quinuclidine-8-yl)-2-(isopropyl(methyl)amino)benzoxazole-4-carboxamide which was converted to the hydrochloride salt following general procedure GP-D1. 1H NMR and MS consistent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][N:22]=4)[CH2:17][CH2:16]3)[N:12]=[C:11]([C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].Br[CH:38]([CH3:40])[CH3:39].[BH4-].[Na+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[C:26]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:24]=[CH:23][N:22]=4)[CH2:17][CH2:16]3)[N:12]=[C:11]([C:31]3[CH2:36][CH2:35][N:34]([CH:38]([CH3:40])[CH3:39])[CH2:33][CH:32]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)Br
Reactant: Fc1ccc(-c2cc(N3CCN(c4ncccc4C(F)(F)F)CC3)nc(-c3ccncc3)n2)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N1CC=C(c2nc(-c3ccc(F)c(Cl)c3)cc(N3CCN(c4ncccc4C(F)(F)F)CC3)n2)CC1
Temperature: 120 °C
Reaction time: 20 h

Procedure:
Dissolve 4-(3-chloro-4-fluorophenyl)-6-(4-(3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)-2-(pyridin-4-yl)pyrimidine (40 mg) and 2-bromopropane (0.1 mL) in DMF (1.5 mL) under nitrogen atmosphere. Heat the mixture in a sealed tube at 120° C. for 48 hours. Cool the mixture to room temperature and then add NaBH4 (50 mg). Stir the mixture at room temperature for 20 hours, dilute with water (5 mL), extract with EtOAc (3×3 mL) and dry over MgSO4. Filter, and concentrate under vacuum to afford crude product and purify by flash column chromatography using 20% EtOAc/hexane to afford the title product as white solid. Mass spec m/z=561.27.
Reaction SMILES: Br[C:2]1[C:26]([Cl:27])=[CH:25][C:5]([O:6][C:7]2[C:12]([C:13]([N:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17][CH2:16]3)=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=2)=[C:4]([Cl:28])[CH:3]=1.[CH3:29][O:30][C:31](=[O:36])[CH2:32][CH2:33][C:34]#[CH:35].C(N(CC)CC)C>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].[Cu]I>[CH3:29][O:30][C:31](=[O:36])[CH2:32][CH2:33][C:34]#[C:35][C:2]1[CH:3]=[C:4]([Cl:28])[C:5]([O:6][C:7]2[C:12]([C:13]([N:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17][CH2:16]3)=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:25][C:26]=1[Cl:27]
Reactant: C#CCCC(=O)OC
Reactant: O=C(c1cccnc1Oc1cc(Cl)c(Br)cc1Cl)N1CCCc2ccccc21
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COC(=O)CCC#Cc1cc(Cl)c(Oc2ncccc2C(=O)N2CCCc3ccccc32)cc1Cl
Temperature: 60 °C
Yield: 5.9 %

Procedure:
To a degassed suspension of [2-(4-bromo-2,5-dichloro-phenoxy)-pyridin-3-yl]-(3,4-dihydro-2H-quinolin-1-yl)-methanone (50 mg, 0.10 mmol, 1.0 equiv; Example 165) in THF (2 mL) under Ar was added pent-4-ynoic acid methyl ester (34 mg, 0.30 mmol, 3 equiv; [CAS RN 21565-82-2]), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (1 mg, 0.001 mmol, 0.01 equiv; [CAS RN 52522-40-4]), copper(I) iodide (0.2 mg, 0.001 mmol, 0.01 equiv; [CAS RN 7681-65-4]) and triethylamine (20 mg, 28 μL, 0.20 mmol, 2.0 equiv; [CAS RN 121-44-8]). The reaction mixture was stirred at 60° C. over the weekend. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 3 mg (6%) of the title compound as a light brown oil. MS (ISP): 509.1 [M+H]+.
Reaction SMILES: C1COCC1.[C:6]1([CH3:14])[CH:11]=[CH:10][C:9]([Mg]Br)=[CH:8][CH:7]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.CO[C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[CH2:42][CH2:41][CH2:40][CH2:39]2>C(OCOCC)C>[CH3:14][C:6]1[CH:11]=[CH:10][C:9]([C:36]2[CH:37]=[C:38]3[C:43](=[CH:44][CH:45]=2)[CH2:42][CH2:41][CH2:40][CH2:39]3)=[CH:8][CH:7]=1
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: COc1ccc2c(c1)CCCC2
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: CCOCOCC
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)CCCC3)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 63.6 %

Procedure:
A THF solution of p-tolylmagnesium bromide (20.0 mL, 20.0 mmol) was placed under vacuum to remove the volatiles. The solvent was replaced with diethoxymethane (20.0 mL). In a separate flask, NiCl2(PCy3)2 (where Cy=cyclohexyl) (355 mg, 0.514 mmol), PCy3 (285 mg, 1.018 mmol), and 6-methoxy-1,2,3,4-tetrahydronaphthalene (1.639 g, 10.11 mmol) was combined in diethoxymethane (2.5 mL). The Grignard reagent was added to this mixture under a nitrogen atmosphere. The resulting solution was stirred 2 minutes at room temperature and then warmed to 90° C. for 15 hours. The reaction was quenched with half saturated aqueous ammonium chloride solution (30 mL) and was extracted with MTBE (3×30 mL). The combined organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography (eluted with heptane) to provide 6-(4-methylphenyl)-1,2,3,4-tetrahydronaphthalene (1.43 g, 64% yield)