Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1.[Cl:12][C:13]1[CH:14]=[C:15]([OH:20])[CH:16]=[CH:17][C:18]=1[Cl:19]>>[Cl:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][C:18]=1[Cl:19])[O:20][CH2:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=[N+]([O-])c1cccnc1CBr
Reactant: Oc1ccc(Cl)c(Cl)c1
Product: O=[N+]([O-])c1cccnc1COc1ccc(Cl)c(Cl)c1
Yield: 72 %

Procedure:
In accordance with the same procedures as in Step 3 of Preparation 1, except for using 2-bromomethyl-3-nitropyridine prepared in Step 2 of Preparation 1 and 3,4-dichlorophenol, the titled compound was obtained as yellow solid. (Yield: 72%)
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH:9]([CH2:12][NH2:13])[C:8]3[CH:14]=[CH:15][CH:16]=[CH:17][C:7]=3[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:18]1(=[O:24])[O:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>O>[CH:1]1[C:11]2[CH2:10][CH:9]([CH2:12][NH:13][C:22](=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][OH:24])[C:8]3[CH:14]=[CH:15][CH:16]=[CH:17][C:7]=3[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCCCO1
Reactant: NCC1Cc2ccccc2Cc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(CCCCO)NCC1Cc2ccccc2Cc2ccccc21
Temperature: 60 °C
Reaction time: 8 h

Procedure:
10,11-Dihydro-5H-dibenzo[a,d]cycloheptene-10-methylamine, γmaxCHCl3 3390, 3300 cm-1, (52.3 g, 0.234 mole), is combined with δ-valerolactone (35 g, 0.35 mole). The mixture is heated for 2 hr. at 150° C (oil bath temperature). After partial cooling, ethanol (250 ml) is added followed by a solution of potassium carbonate (50 g, 0.36 mole) in water (150 ml). The two-phase mixture is stirred at 60° C overnight. The ethanol is removed under reduced pressure and the residual mixture extracted with chloroform. The chloroform solution is washed with water, dried and taken to dryness. The residue is crystallized from benzene (750 ml) -ether (ca 800 ml) affording N-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl)methyl]-5-hydroxyvaleramide, m.p. 96° - 98° C, γ maxCHCl3 3630, 3445, 3350, 1663 cm-1.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:4][C@@H:3]1[C:5](O)=[O:6].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:33][O:34][C:35](=[O:86])[NH:36][C@H:37]([C:41]([N:43]1[CH2:47][CH2:46][CH2:45][C@H:44]1[C:48]1[NH:49][CH:50]=[C:51]([C:53]2[CH:58]=[CH:57][C:56]([C:59]3[CH:64]=[C:63]([Cl:65])[C:62]([NH:66][C:67]([C:69]4[CH:70]=[N:71][C:72]([N:75]5[CH2:80][CH2:79][NH:78][CH2:77][C@H:76]5[CH3:81])=[CH:73][CH:74]=4)=[O:68])=[CH:61][C:60]=3[C:82]([F:85])([F:84])[F:83])=[CH:55][CH:54]=2)[N:52]=1)=[O:42])[CH:38]([CH3:40])[CH3:39].C(N(CC)C(C)C)(C)C>CC(N(C)C)=O>[CH3:33][O:34][C:35](=[O:86])[NH:36][C@H:37]([C:41]([N:43]1[CH2:47][CH2:46][CH2:45][C@H:44]1[C:48]1[NH:49][CH:50]=[C:51]([C:53]2[CH:58]=[CH:57][C:56]([C:59]3[CH:64]=[C:63]([Cl:65])[C:62]([NH:66][C:67]([C:69]4[CH:70]=[N:71][C:72]([N:75]5[CH2:80][CH2:79][N:78]([C:5]([C@H:3]6[CH2:4][C:2]6([CH3:8])[CH3:1])=[O:6])[CH2:77][C@H:76]5[CH3:81])=[CH:73][CH:74]=4)=[O:68])=[CH:61][C:60]=3[C:82]([F:84])([F:85])[F:83])=[CH:55][CH:54]=2)[N:52]=1)=[O:42])[CH:38]([CH3:40])[CH3:39]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(NC(=O)c4ccc(N5CCNC[C@H]5C)nc4)cc3C(F)(F)F)cc2)c[nH]1)C(C)C
Reactant: CC1(C)C[C@@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(NC(=O)c4ccc(N5CCN(C(=O)[C@H]6CC6(C)C)C[C@H]5C)nc4)cc3C(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.5 M (S)-(+)-2,2-dimethylcyclopropane carboxylic acid in DMA (28.9 μL, 0.015 mmol;). and HATU (8.25 mg, 0.022 mmol) dissolved in DMA (0.5 mL), was added ((S)-1-{(S)-2-[4-(5′-Chloro-4′-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethyl-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester 3 TFA (16 mg, 0.014 mmol; Preparation 53) and N,N-diisopropylethylamine (25.2 uL, 0.15 mmol) and the reaction mixture was stirred at RT overnight, concentrated, dissolved in 1:1 acetic acid:water (1.5 mL) and purified by reverse phase HPLC to provide the title compound (8.6 mg) as the di-TFA salt. (m/z): [M+H]+ calcd for C11H50ClF3N8O5 863.35 found 863.4.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[O:5][CH2:6][C:7]1[CH:11]=[CH:10][N:9]([CH3:12])[N:8]=1.C([O-])([O-])=O.[K+].[K+].[CH3:25][C:26]1[CH:31]=[C:30]([O:32][C:33]([F:36])([F:35])[F:34])[CH:29]=[CH:28][C:27]=1[CH2:37][NH2:38]>C(#N)C>[CH3:12][N:9]1[CH:10]=[CH:11][C:7]([CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([N+:16]([O-:18])=[O:17])=[C:2]([CH:3]=2)[NH:38][CH2:37][C:27]2[CH:28]=[CH:29][C:30]([O:32][C:33]([F:34])([F:35])[F:36])=[CH:31][C:26]=2[CH3:25])=[N:8]1
Reactant: Cn1ccc(COc2ccc([N+](=O)[O-])c(F)c2)n1
Reactant: Cc1cc(OC(F)(F)F)ccc1CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(OC(F)(F)F)ccc1CNc1cc(OCc2ccn(C)n2)ccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of 3-((3-fluoro-4-nitrophenoxy)methyl)-1-methyl-1H-pyrazole (143 mg, 0.573 mmol) in acetonitrile (10 mL) was added K2CO3 (317 mg, 2.3 mmol) followed by (2-methyl-4-(trifluoromethoxy)phenyl)methanamine (117 mg, 0.573 mmol). The mixture was stirred at 90° Celsius overnight. The reaction was cooled to RT and concentrated to dryness. The resulting residue was dissolved in DCM (50 mL) and washed with water (50 mL). The organic phase was concentrated to give the title compound. MS (ESI): mass calcd. for C20H19F3N4O4, 436.14; m/z found, 437 [M+H]+.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[N:10]=[C:9]([NH:11]C(=O)C)[CH:8]=[CH:7][C:6]=1[CH3:15]>CO.O>[CH3:3][O:4][C:5]1[N:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:6]=1[CH3:15]
Reactant: COc1nc(NC(C)=O)ccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1nc(N)ccc1C
Temperature: 90 °C
Yield: 194.3 %

Procedure:
A 10% solution of aqueous NaOH (40 mL) was added to a solution of N-(6-methoxy-5-methylpyridin-2-yl)acetamide (2.21 g, 12.3 mmol) in MeOH (160 mL) and the reaction mixture was heated at 90° C. for 3 d. After cooling to rt and concentration in vacuo to remove the MeOH the aqueous residue was combined with that from a previous batch derived from N-(6-methoxy-5-methylpyridin-2-yl)acetamide (2.21 g, 12.3 mmol). The aqueous phase was diluted with H2O (40 mL) and extracted with DCM (3×150 mL). The combined organic phases were washed with brine, dried (Na2SO4) and combined with a previous batch of crude 6-methoxy-5-methylpyridin-2-amine (266 mg). Concentration in vacuo yielded the title compound (3.30 g, 23.9 mmol).
Reaction SMILES: [CH3:1][N:2]([CH3:46])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]4[NH:23][C:24]([C:26]5[CH:27]=[N:28][C:29]([N:32]6[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]6)=[N:30][CH:31]=5)=[CH:25][C:18]=34)=[CH:15][N:14]([CH3:45])[N:13]=2)=[CH:8][CH:7]=1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][N:2]([CH3:46])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]4[NH:23][C:24]([C:26]5[CH:31]=[N:30][C:29]([N:32]6[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]6)=[N:28][CH:27]=5)=[CH:25][C:18]=34)=[CH:15][N:14]([CH3:45])[N:13]=2)=[CH:8][CH:7]=1)=[O:4]
Reactant: CN(C)C(=O)Nc1ccc(-c2nn(C)cc2-c2ccnc3[nH]c(-c4cnc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cc23)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)Nc1ccc(-c2nn(C)cc2-c2ccnc3[nH]c(-c4cnc(N5CCNCC5)nc4)cc23)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 43 %

Procedure:
To a solution of 1,1-dimethylethyl 4-(5-{4-[3-(4-{[(dimethylamino)carbonyl]amino}phenyl)-1-methyl-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}-2-pyrimidinyl)-1-piperazinecarboxylate (0.0883 mmol) in dichloromethane (20 ml) was added trifluoroacetic acid (1 ml) and the resulting solution stirred at room temperature for 4 hours. Concentration and purification by reverse-phase HPLC provided the title compound as a yellow solid (43%). ESMS [M+H]+: 523.2
Reaction SMILES: [CH2:1]1CCC(N=C=NC2CCCCC2)CC1.[O:16]=[C:17]1[CH2:20][CH:19]([C:21]([OH:23])=[O:22])[CH2:18]1.CO>C(Cl)Cl.CN(C1C=CN=CC=1)C>[O:16]=[C:17]1[CH2:20][CH:19]([C:21]([O:23][CH3:1])=[O:22])[CH2:18]1
Reactant: O=C1CC(C(=O)O)C1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1CC(=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.7 %

Procedure:
To a solution of DCC (5.96 g, 28.95 mmol) in DCM (20 ml) was added dropwise a mixture of 3-oxocyclobutanecarboxylic acid (3.0 g, 26.31 mmol), MeOH (1.68 g, 52.62 mmol) and DMAP (2.57 g, 21.05 mmol) in DCM (30 ml). The reaction mixture was stirred at RT overnight. The mixture was filtrated. The filtrate was washed with 0.5 M HCl solution (50 ml). The organic layer was dried over Na2SO4 and concentrated. The residue was purified by SGC (PE: EA=5:1) to obtain the title compound (4.0 g). 1H N.R (500 MHz, CDCl3): δ 3.77 (s, 3H), 3.42-3.26 (m, 5H) ppm.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]([CH3:34])([O:9][C:10]([N:12]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH2:33])[CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14]1)=[O:11])[CH3:8].C(N(CC)CC)C>O1CCCC1>[CH3:8][C:7]([CH3:34])([O:9][C:10]([N:12]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][S:2]([CH3:1])(=[O:4])=[O:3])[CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:15][CH2:14]1)=[O:11])[CH3:6]
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1N)C1CCN(Cc2ccccc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(Cc1ccccc1NS(C)(=O)=O)C1CCN(Cc2ccccc2)CC1
Reaction time: 12 h

Procedure:
1.64 ml. (21 mmol) of methanesulphonyl chloride was added dropwise to a solution of 7.91 g (20 mmol) of N-(1,1-dimethylethoxycarbonyl)-N-[(2-aminophenyl)methyl]-1-(phenylmethyl)-4-piperidineamine and 3.0 ml (21 mmol) of triethylamine in 100 ml of tetrahydrofuran and the mixture was then kept for 12 hours at ambient temperature. It was then diluted with 100 ml of EE and extracted twice with 70 ml of saturated sodium hydrogen carbonate solution. The ethyl acetate phase was dried over sodium sulphate and concentrated by evaporation in vacuo. 8.7 g (92% of theoretical) of a colourless substance were obtained, Rf 0.85 (El D), which were used in the next step without any further purification.
Reaction SMILES: [NH:1]([C:3]1[C:4](=[O:18])[N:5]([CH3:17])[C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=2)[NH2:2].C(N(CC)CC)C.[CH3:26][CH:27]([CH3:32])[CH2:28][C:29](Cl)=[O:30]>O1CCOCC1>[CH3:17][N:5]1[C:6]2[C:11](=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=2)[N:12]=[C:3]([NH:1][NH:2][C:29](=[O:30])[CH2:28][CH:27]([CH3:32])[CH3:26])[C:4]1=[O:18]
Reactant: CC(C)CC(=O)Cl
Reactant: Cn1c(=O)c(NN)nc2cc(C(F)(F)F)ccc21
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)CC(=O)NNc1nc2cc(C(F)(F)F)ccc2n(C)c1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 3-hydrazino-1-methyl-6-trifluoromethyl-1H-quinoxalin-2-one (10.0 g., 52.6 mmol) and triethylamine (6.38 g., 63.2 mmol) in 500 ml. of dioxane is added dropwise 3-methylbutanoyl chloride (7.62 g., 65.2 mmol) and the mixture stirred at room temperature for 20 hours. The dioxane is then removed under vacuum and the residue washed with water and ether, filtered and dried under vacuum to give the product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH2:22][NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:7]=1)[CH3:2].Cl[C:33]([O:35][CH3:36])=[O:34]>>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH2:22][N:23]([CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:33]([O:35][CH3:36])=[O:34])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CNCc2ccccc2)c1
Reactant: COC(=O)Cl
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CN(Cc2ccccc2)C(=O)OC)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 3, using the following starting materials: {3-[2-(benzylamino-methyl)-4-bromo-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and methyl chloroformate.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:28][C:29]1[CH:30]=[C:31]([CH2:39][NH2:40])[C:32]2[O:37][CH2:36][O:35][CH2:34][C:33]=2[CH:38]=1>>[F:28][C:29]1[CH:30]=[C:31]([CH2:39][NH:40][C:23]2[N:22]=[C:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([NH:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:16]=3)[CH:26]=[CH:25][N:24]=2)[C:32]2[O:37][CH2:36][O:35][CH2:34][C:33]=2[CH:38]=1
Reactant: NCc1cc(F)cc2c1OCOC2
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc(-c3ccnc(Cl)n3)c2)CC1
Product: Fc1cc(CNc2nccc(-c3cccc(NC4CCNCC4)c3)n2)c2c(c1)COCO2

Procedure:
Intermediate 7 was coupled with C-(6-fluoro-4H-benzo[1,3]dioxin-8-yl)-methylamine following procedure F and the resulting intermediate 4eprotected following procedure G. LC-MS showed the product had the expected M+H+ of 436. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) δ 8.6 (s, 1H) 8.4 (d, 1H) 8.3 (d, 1H) 7.8 (t, 1H) 7.4 (d, 1H), 7.2 (d, 1H), 7.1 (d, 2H), 6.6 (d, 2H), 3.4 (d, 2H), 2.8 (d, 2H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][NH:7][C:8](=[O:22])[C@@H:9]([NH2:21])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)(=[O:3])[CH3:2].FC(F)(F)[C:25]1([CH:40]=[CH:39][CH:38]=[CH:37][CH2:36]1)[O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=O)=[CH:29][CH:28]=1>>[C:1]([O:4][CH2:5][CH2:6][NH:7][C:8](=[O:22])[C@@H:9]([NH:21][C:31](=[O:33])[C:30]1[CH:29]=[CH:28][C:27]([O:26][C:25]2[CH:36]=[CH:37][C:38]([C:17]([F:20])([F:19])[F:18])=[CH:39][CH:40]=2)=[CH:35][CH:34]=1)[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:15][CH:16]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCNC(=O)[C@@H](N)Cc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)c1ccc(OC2(C(F)(F)F)C=CC=CC2)cc1
Product: CC(=O)OCCNC(=O)[C@H](Cc1ccc(C(F)(F)F)cc1)NC(=O)c1ccc(Oc2ccc(C(F)(F)F)cc2)cc1

Procedure:
A reaction similar to that described in Example 50 was conducted using 2-({(2S)-2-amino-3-[4-(trifluoromethyl)phenyl]propanoyl}amino)ethyl acetate and 4-[1-(trifluoromethyl)phenoxy]benzoic acid used in Example 41 (41a) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH:6]=[CH:7][C:8]([NH:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1.[OH-].[K+].C(O)C.Cl>O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH:6]=[CH:7][C:8]([NH:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C=Cc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(C=Cc1ccc(Cl)cc1)Nc1ccc(C(=O)O)cc1
Reaction time: 1.5 h

Procedure:
A solution of 7.1 g. of p-(p-chlorocinnamamido)benzoic acid, ethyl ester and 1.6 g. of potassium hydroxide in 50 ml. of 95% ethanol is stirred at 75° C. overnight. A 25 ml. portion of water and 200 mg. of potassium hydroxide are added, and stirring is continued at 75° C. for 1.5 hours. The mixture is then diluted with 150 ml. of water, adjusted to pH 3 with 37% hydrochloric acid, and the precipitate is collected and dried. The solid is boiled in 100 ml. of methyl cellosolve, cooled, and the solid is collected, washed with ethanol, and dried, giving 5.51 g. of the desired product as a white powder, m.p. 333°-336° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([S:19][CH3:20])[N:14]=2)=[CH:4][CH:3]=1.[OH-:30].[NH4+]>O.C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH2:21][CH2:22][CH2:23][N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([S:19]([CH3:20])=[O:30])[N:14]=2)=[CH:6][CH:7]=1
Reactant: CSc1nccc(-c2c(-c3ccc(F)cc3)ncn2CCCN2CCOCC2)n1
Reactant: [OH-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)c1nccc(-c2c(-c3ccc(F)cc3)ncn2CCCN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 73 %

Procedure:
A solution of K2S2O8 (0.20 g, 0.73 mmol) in water (5 mL) was added to 4-(4-fluorophenyl)-5-[2-(methylthio)-4pyrimidinyl]-1-[3-(4-morpholinyl)propyl]imidazole (0.20 g, 0.48 mmol) in glacial acetic acid (10 mL). After stirring at ambient temperature for 72 h, the reaction mixture was poured into water, neutralized with concentrated aqueous ammonium hydroxide and extracted four times with dichloromethane. The organic phases were combined and evaporated. The residue was purified by flash chromatography eluting successively with 1%, 2%, 4% and 10% methanol in dichloromethane to afford the title compound as a clear oil (0.15 g, 73%). 1H NMR (CDCl3) δ8.57(d, J=7 Hz, 1H), 7.77(s,1H), 7.47 (dd, 2H), 7.18(d, J=5 Hz, 1H)7.09(t, J=9 Hz, 2H), 4.56(m, 2H), 3.72(t, J=5 Hz, 4H), 3.00(s, 3H), 2.40(brd. s, 4H), 2.33(t, J=8 Hz, 2H), 1.94(m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH2:18][NH2:19])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([F:21])=[C:13]([F:20])[CH:14]=2)[N:9]=1.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:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH2:18][NH:19][C:23]2[N:31]=[CH:30][N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][NH:27]3)=[CH:16][C:15]2[C:10](=[CH:11][C:12]([F:21])=[C:13]([F:20])[CH:14]=2)[N:9]=1
Reactant: NCc1cc2cc(F)c(F)cc2nc1-c1ccccc1Cl
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cc2cc(CNc3ncnc4[nH]cnc34)c(-c3ccccc3Cl)nc2cc1F

Procedure:
Prepared according to Procedure H using (2-(2-chlorophenyl)-6,7-difluoroquinolin-3-yl)methanamine (0.080 g, 0.279 mmol), 6-chloropurine (0.065 g, 0.42 mmol, 1.5 eq) and DIEA (0.56 mmol, 2.0 eq) in n-butanol (3 mL). N-((2-(2-chlorophenyl)-6,7-difluoroquinolin-3-yl)methyl)-9H-purin-6-amine [PI3Kδ IC50=551 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.46 (s, 1H), 8.13 (s, 1H), 8.09 (s, 1H), 7.83-7.94 (m, 3H), 7.49-7.55 (m, 2H), 7.41-7.48 (m, 1H), 7.35-7.41 (m, 1H), 4.89-4.85 (m, 2H), Mass Spectrum (ESI) m/e=423 (M+1).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH:20]=1)[C:17]([OH:19])=O)(=[O:11])=[O:10].ClC(OCC)=O.[CH2:29]([N:31]1[CH2:35][CH:34]([NH2:36])[CH2:33][N:32]1[CH2:37][CH3:38])[CH3:30]>C(Cl)Cl>[CH2:29]([N:31]1[CH2:35][CH:34]([NH:36][C:17](=[O:19])[C:16]2[CH:20]=[C:12]([S:9]([CH3:8])(=[O:10])=[O:11])[CH:13]=[CH:14][C:15]=2[O:21][CH3:22])[CH2:33][N:32]1[CH2:37][CH3:38])[CH3:30]
Reactant: CCN1CC(N)CN1CC
Reactant: COc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN1CC(NC(=O)c2cc(S(C)(=O)=O)ccc2OC)CN1CC
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 109.7 %

Procedure:
Triethylamine (1.01 g, 0.010 mole) was added to a stirred mixture of 5-methylsulfonyl-2-methoxybenzoic acid (2.30 g, 0.010 mole) in 50 ml of methylene chloride. The mixture was cooled to 0° C. for 20 minutes and maintained at this temperature while ethyl chloroformate (1.09 g, 0.010 mole) was added dropwise. After another 20 minutes of stirring at 0° C., a solution of 1,2-diethyl-4-aminopyrazolidine (2.43 g, 0.010 mole) in 10 l of methylene chloride was added dropwise. The reaction mixture was allowed to come to ambient temperature and was stirred for 18 hrs. The reaction mixture was then extracted with 10% sodium bicarbonate solution, the methylene chloride layer separated and dried over magnesium sulfate. The methylene chloride solution was concentrated to give 3.90 g of a tanbrown solid which was recrystallized from water. A sulfate salt was prepared which was converted back to the free base. The solid free base that formed was recrystallized from ethanol-isopropyl ether to give 1.03 g (29%) of title compound; m.p. 123°-124° C. The compound was vacuum dried at 110° C.; the melting point was unchanged.
Reaction SMILES: [CH2:1]([C:3]1([CH2:18][CH3:19])[C:15]2[CH:14]=[C:13]([Br:16])[CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][C:6](Br)=[CH:7][CH:8]=2)[CH3:2].C([Li])CCC.CN([CH:28]=[O:29])C>C1COCC1.Cl.C1(C)C=CC=CC=1>[Br:16][C:13]1[CH:14]=[C:15]2[C:10]([C:9]3[CH:8]=[CH:7][C:6]([CH:28]=[O:29])=[CH:5][C:4]=3[C:3]2([CH2:1][CH3:2])[CH2:18][CH3:19])=[CH:11][CH:12]=1
Reactant: CCC1(CC)c2cc(Br)ccc2-c2ccc(Br)cc21
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCC1(CC)c2cc(Br)ccc2-c2ccc(C=O)cc21
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 78.4 %

Procedure:
To a mechanically stirred solution of 9,9-diethyl-2,7-dibromofluorene (59.38 g, 0.1563 mol) in THF (325 ml) cooled in a dry ice-ethanol bath, n-butyl lithium (104 ml of 1.6 M solution in hexanes, 0.1664 mol, 1.06 eq.) was added drop-wise over 25 minutes. After 20 minutes, DMF (17 ml, 0.22 mol) in THF (30 ml) was added, and the mixture was stirred in the cooling bath for 1.5 hours and outside the bath for 1 hour. The reaction was then cooled to 5° C. and treated with hydrochloric acid (12.5 ml of concentrated hydrochloric acid diluted with 50 ml water). The mixture was diluted with 200 ml of toluene, and the aqueous phase was separated and extracted with 200 ml of toluene. The combined organic phase was washed with dilute sodium bicarbonate solution, dried over magnesium sulfate, and concentrated. The residual solids were recrystallized from heptane-ethyl acetate (9:1) to obtain colorless solids, 40.29 g (78.4% yield) m.p. 126-128° C. The mother liquor, after chromatography over 150 g silica gel, elution with 1:1 heptane-toluene, and trituration of residual solids in hexanes, gave additional product, 6.56 g (12.8% yield, total 91% yield), m.p. 126-128° C. Mass Spec: m/z 328, 330, (M+). A sample for analysis was prepared by recrystallization from hexanes, m.p. 127-129° C. Analysis: Calculated for C18H17BrO, C, 65.55, H, 5.20, and Br 24.27%. Found, C, 65.60, H, 5.51, and Br 24.71%.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:27])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:4][CH2:5][CH2:6][S:7][CH2:8][CH2:9][CH2:10][C:11]([CH3:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:12][OH:13].OO.ClCCl.C(OCC)(=[O:35])C>C(O)(=O)C>[OH:1][CH2:2][C:3]([CH3:27])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:4][CH2:5][CH2:6][S:7]([CH2:8][CH2:9][CH2:10][C:11]([CH3:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:12][OH:13])=[O:35]
Reactant: CCOC(C)=O
Reactant: CC(CO)(CCCSCCCC(C)(CO)c1ccccc1)c1ccccc1
Agent: OO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(CO)(CCCS(=O)CCCC(C)(CO)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
To a solution of 5-(5-hydroxy-4-methyl-4-phenylpentylsulfanyl)-2-methyl-2-phenylpentan-1-ol (3.37 g, 8.14 mmol) in glacial acetic acid (100 mL) was added 50% aqueous hydrogen peroxide solution (0.55 g, 8.14 mmol) drop-wise at rt over 5 min. The reaction mixture was stirred at rt for 3 h, while the reaction progress was monitored by TLC (dichloromethane/ethyl acetate=2/1). The reaction mixture was concentrated to yield a crude product (3.5 g) that was purified by column chromatography on silica gel (dichloromethane, then dichloromethane/ethyl acetate=1/1, followed by dichloromethane/ethanol=1/1). The product-containing fractions were concentrated and dried at 120° C. under high vacuo for 2.5 h to give 5-(5-hydroxy-4-methyl-4-phenylpentylsulfinyl)-2-methyl-2-phenylpentan-1-ol (2.55 g, 71%) as colorless, viscous oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 7.30 (m, 8 H), 7.20 (m, 2 H), 3.66-3.56 (m, 4 H), 2.54-2.38 (m, 4 H), 2.13 (br., 2 H), 1.90-1.43 (m, 8 H), 1.33 (s, 6 H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 144.56, 128.68, 126.66, 126.62, 126.62, 71.82, 71.57, 52.92, 43.38, 43.35, 37.56, 37.43, 22.14, 21.77, 17.87, 17.71. HRMS (LSIMS, gly): Calcd. for C24H35O3S1 (MH+): 403.2307, found: 403.2295.