Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[C:7]([C:10]2([CH3:15])[O:14][CH2:13][CH2:12][O:11]2)[O:8][CH:9]=1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C1COCC1>[CH3:15][C:10]1([C:7]2[O:8][CH:9]=[C:5]([CH2:4][NH2:1])[N:6]=2)[O:14][CH2:13][CH2:12][O:11]1
Reactant: CC1(c2nc(CN=[N+]=[N-])co2)OCCO1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC1(c2nc(CN)co2)OCCO1
Temperature: 60 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (2-(2-methyl-[1,3]dioxolan-2-yl)oxazol-4-yl)methanol (235 mg, 1.27 mmol) in dry CH2Cl2 (10 mL) was treated at 0° C. with Et3N (0.24 mL, 1.68 mmol) followed by DMAP (16 mg, 0.13 mmol) and Ms-Cl (0.13 mL, 1.65 mmol). After stirring at 0° C. for 1 h, the reaction was quenched with water (10 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude (2-(2-methyl-[1,3]dioxolan-2-yl)oxazol-4-yl)methyl methanesulfonate as a brown oil. The crude material was dissolved in dry DMF (6 mL) and treated with NaN3 (93 mg, 1.41 mmol) at 80° C. until completion of the reaction. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 4-(azidomethyl)-2-(2-methyl-1,3-dioxolan-2-yl)oxazole as a brown oil. To a solution of the crude azide in THF (6 mL) were added polymer-supported Ph3P (1.2 eq.) and water (2 mL). The reaction mixture was stirred at 60° C. until completion of the reaction, cooled down to rt and filtered. The filtrate was partitioned between EA and aq. sat. NaHCO3 and the layers separated. The aq. layer was concentrated under reduced pressure, the residue triturated in EtOH and the solid filtered off. The filtrate was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound as an orange oil. LC-MS-conditions 01: tR=0.31 min; [M+H]+=185.01.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C:19]2(SCC)[S:23][CH2:24][CH3:25])[C@H:15]2[C@@:6]1([F:31])[C@:7]1([CH3:30])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:29])[CH:9]=[CH:8]1)(=[O:3])[CH3:2]>C(C1C=CC=CC=1CC)C>[C:1]([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH:18]=[C:19]2[S:23][CH2:24][CH3:25])[C@H:15]2[C@@:6]1([F:31])[C@:7]1([CH3:30])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:29])[CH:9]=[CH:8]1)(=[O:3])[CH3:2]
Reactant: CCSC1(SCC)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](OC(C)=O)C[C@@]21C
Agent: CCc1ccccc1CC
Product: CCSC1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](OC(C)=O)C[C@]12C
Temperature: 180 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
A suspension of 5.2 g of 11β-acetyloxy-17,17-bis(ethylthio)-9-fluoroandrosta-1,4-dien-3-one in 85 ml of dry diethylbenzene is stirred at 180° C. (oil bath temperature) for 1.0 hour; the suspension gradually becomes a homogeneous solution during the heating. The resulting solution is cooled to 0° C. and the solid that precipitates is filtered and dried in vacuo to give 3.6 g of the title compound, melting point 211°-215° C., with consistent spectral data.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[Br:10]C1C(=O)C(Br)=CC(Br)(Br)C=1>C(Cl)Cl>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: O=C1C(Br)=CC(Br)(Br)C=C1Br
Reactant: Nc1ccccc1CO
Solvent: ClCCl
Product: Nc1ccc(Br)cc1CO
Temperature: 25 °C

Procedure:
To a solution of 2-aminobenzyl alcohol (7.12 g, 58 mmol) in methylene chloride (200 mL) at −10° C., 2,4,4,6-tetrabromo-2,5-cyclohexadien-1-one (25 g, 61 mmol) was added in portions. During the addition, the temperature of the reaction mixture was maintained between −10° C. and 0° C. The reaction mixture was warmed up to room temperature and then extracted with 2 N sodium hydroxide solution (2×50 mL). The organic layer was washed with water and dried over MgSO4, filtered and concentrated in vacuo to afford 2-amino-5-bromobenzylalcohol as a yellow solid which was used without further purification.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH:4]([O:29][CH2:30][CH2:31][O:32][CH3:33])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:17][CH:16]=2)=[CH:8][CH:7]=1.[OH-].[Li+]>O1CCCC1.O.O>[C:25]([O:24][C:22]([NH:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][O:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH:4]([O:29][CH2:30][CH2:31][O:32][CH3:33])[C:3]([OH:34])=[O:2])=[CH:11][CH:10]=2)=[CH:20][CH:19]=1)=[O:23])([CH3:26])([CH3:27])[CH3:28]
Reactant: COCCOC(Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COCCOC(Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
3-[4-(2-{4-tert-Butoxycarbonylaminophenyl}ethoxy)phenyl]-2-(2-methoxyethoxy)propanoic acid methyl ester (described in Example 58) (0.26 g; 0.55 mmole) was dissolved in tetrahydrofuran:water (1:3, 4 ml). Lithium hydroxide (16.0 mg; 0.66 mmole) dissolved in a small amount of water was added. The reaction mixture was stirred two hours at room temperature and then evaporated. The residue was redissolved in diethyl ether and hydrochloric acid (2M) and extracted. The organic phase was dried with magnesium sulfate and evaporated to give 0.235 g (92% yield) of 3-[4-(2-{4-tert-butoxycarbonylaminophenyl}ethoxy)phenyl]-2-(2-methoxyethoxy)propanoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[N:11]=1)[C:6]([OH:8])=O.CC1(C)[O:22][C@H:21]([CH2:23][O:24][C:25]2[C:34]([CH3:35])=[CH:33][C:28]([C:29]([NH:31]O)=[NH:30])=[CH:27][C:26]=2[CH2:36][CH3:37])[CH2:20][O:19]1>>[CH2:36]([C:26]1[CH:27]=[C:28]([C:29]2[N:31]=[C:6]([C:5]3[CH:9]=[C:10]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[N:11]=[C:3]([O:2][CH3:1])[CH:4]=3)[O:8][N:30]=2)[CH:33]=[C:34]([CH3:35])[C:25]=1[O:24][CH2:23][C@@H:21]([OH:22])[CH2:20][OH:19])[CH3:37]
Reactant: CCc1cc(C(=N)NO)cc(C)c1OC[C@@H]1COC(C)(C)O1
Reactant: COc1cc(C(=O)O)cc(CCC(C)C)n1
Product: CCc1cc(-c2noc(-c3cc(CCC(C)C)nc(OC)c3)n2)cc(C)c1OC[C@@H](O)CO

Procedure:
The title compound is prepared in analogy to Example 1 starting from 2-methoxy-6-(3-methyl-butyl)-isonicotinic acid and (R)-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3-ethyl-N-hydroxy-5-methyl-benzamidine; LC-MS: tR=1.14 min, [M+H]+=456.16; 1H NMR (CDCl3): δ 1.00 (d, J=6.3 Hz, 6H), 1.33 (t, J=7.5 Hz, 3H), 1.64-1.74 (m, 3H), 2.41 (s, 3H), 2.77 (q, J=7.5 Hz, 2H), 2.81-2.86 (m, 2H), 3.82-3.94 (m, 2H), 3.94-3.98 (m, 2H), 4.03 (s, 3H), 4.14-4.21 (m, 1H), 7.32 (d, J=0.8 Hz, 1H), 7.49 (d, J=0.8 Hz, 1H), 7.88 (s, 1H), 7.89 (s, 1H).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5]([C:7]1[S:8][C:9]([C:13]([CH2:31][CH3:32])([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH:24]([OH:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[C:18]([CH3:30])[CH:17]=2)[CH2:14][CH3:15])=[CH:10][C:11]=1[CH3:12])=[O:6]>>[CH2:14]([C:13]([C:9]1[S:8][C:7]([C:5]([OH:6])=[O:4])=[C:11]([CH3:12])[CH:10]=1)([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH:24]([OH:29])[C:25]([CH3:27])([CH3:28])[CH3:26])=[C:18]([CH3:30])[CH:17]=1)[CH2:31][CH3:32])[CH3:15]
Reactant: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1cc(C)c(C(=O)OC)s1
Agent: [Li+]
Agent: [OH-]
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1cc(C)c(C(=O)O)s1
Yield: 94 %

Procedure:
Using LiOH hydrolysis as described in Example 137, 5-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid methyl ester gives the title compound (94%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1)[CH3:11].[S-:20][C:21]#[N:22].[K+].BrBr>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]=[C:21]([NH2:22])[S:20][C:18]=2[CH:19]=1)[CH3:11]
Reactant: CC(Oc1ccc(N)cc1)c1c(Cl)ccc(Cl)c1Cl
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Product: CC(Oc1ccc2nc(N)sc2c1)c1c(Cl)ccc(Cl)c1Cl
Yield: 100 %

Procedure:
6-[1-(2,3,6-Trichlorophenyl)ethoxy]-1,3-benzothiazol-2-amine was prepared according to the method described in Example 20d but from 1.5 g of 4-[1-(2,3,6-trichlorophenyl)ethoxy]aniline, 1.84 g of potassium thiocyanate and 0.243 cm3 of dibromine. We obtain 1.77 g of 6-[1-(2,3,6-trichlorophenyl)ethoxy]-1,3-benzothiazol-2-amine in the form of an orange-coloured resin, which has the following characteristics:
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[OH:28][C:29]1([C:35](O)=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:35]([C:29]5([OH:28])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]5)=[O:36])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: O=C(O)C1(O)CCCCC1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1)C1(O)CCCCC1

Procedure:
The title compound, white solid (20 mg, 61%), MS (ISP) m/z=458.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (Intermediate A) (30 mg, 68.1 mmol) and 1-hydroxycyclohexanecarboxylic acid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[NH2:34])[CH2:24][CH:23]2[OH:35])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].C(N(CC)CC)C.Cl[C:44]([O:46][CH2:47][CH3:48])=[O:45]>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[NH:34][C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:24][CH:23]2[OH:35])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11]
Reactant: Nc1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(O)C1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Nc1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(O)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The solution of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexane carbonyl]amino]-1-(2-aminophenyl)piperidin-3-one (0.9 g) obtained in Step 2 of Example 43 in 20 ml of dichloromethane was cooled to 0° C. 0.54 ml of triethylamine and 0.37 ml of ethyl chloroformate were added to the reaction mixture, which was then stirred for about 3 hours at room temperature. 20 ml of ice water was added to the reaction mixture. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was purified with column chromatography to give 600 mg of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:28]=1)[C:7]([N:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([CH3:15])[C@H:10]1[CH2:16][N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27])=[O:8].C([Sn](CCCC)(CCCC)[C:35]1[N:40]=[CH:39][CH:38]=[CH:37][N:36]=1)CCC.[F-].[Cs+]>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>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:35]2[N:40]=[CH:39][CH:38]=[CH:37][N:36]=2)=[C:6]([CH:28]=1)[C:7]([N:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([CH3:15])[C@H:10]1[CH2:16][N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27])=[O:8]
Reactant: C[C@@H]1CCCN(C(=O)c2cc(Cl)ccc2I)[C@@H]1CN1C(=O)c2ccccc2C1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@@H]1CCCN(C(=O)c2cc(Cl)ccc2-c2ncccn2)[C@@H]1CN1C(=O)c2ccccc2C1=O
Temperature: 120 °C
Yield: 67.2 %

Procedure:
A mixture of 2-(((2S,3R)-1-(5-chloro-2-iodobenzoyl)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione (0.22 g, 0.42 mmol), 2-(tributylstannyl)pyrimidine (0.16 ml, 0.51 mmol), CsF (128 mg, 0.84 mmol), CuI (16 mg, 0.08 mmol) and Pd(PPh3)4 (49 mg, 0.04 mmol) in DMF (5 mL) was degassed and heated at 120° C. for 1 h in a microwave reactor. The solvent was removed in vacuo to obtain the crude which was purified by silica gel chromatography (0˜100% EtOAc/hexanes) to yield the title compound as a white solid (0.134 g, 67%). MS (ESI) 475 (M+H).
Reaction SMILES: CS[C:3]1[NH:12][C:11](=[O:13])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.[F:14][C:15]([F:23])([F:22])[CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(N(CC)CC)C>C(O)CC(C)C>[F:14][C:15]([F:23])([F:22])[CH:16]1[CH2:21][CH2:20][N:19]([C:3]2[NH:12][C:11](=[O:13])[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[N:4]=2)[CH2:18][CH2:17]1
Reactant: FC(F)(F)C1CCNCC1
Reactant: CSc1nc2c(c(=O)[nH]1)CCCC2
Solvent: CCN(CC)CC
Solvent: CC(C)CCO
Product: O=c1[nH]c(N2CCC(C(F)(F)F)CC2)nc2c1CCCC2

Procedure:
2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51 mmol), 4-trifluoromethylpiperidine * HCl (97 mg; 0.51 mmol) and triethylamine (141.3 μl; 1.02 mmol) are reacted in isoamyl alcohol (1 ml) in accordance with the procedure for Example 1 (reaction time 4 h) and worked up. The crude product obtained in this way is purified by column chromatography; yield: 43 mg (28%), crystals;
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6](Br)[N:7]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(O)C.C(OCC)(=O)C.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>[NH2:9][C:3]1[C:2]([Br:1])=[N:7][C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][N:4]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Nc1ncc(-c2ccccc2)nc1Br
Temperature: 75 °C
Reaction time: 12 h
Yield: 88 %

Procedure:
To a stirred solution of 3,5-dibromo-2-aminopyrazine (200 mg; 0.79 mmol) and phenyl boronic acid (106 mg; 0.87 mmol) in dioxane (4 mL) and ethanol (2 mL) was added cesium carbonate (571 mg; 1.75 mmol in 2 mL of water) followed by Pd(PPh3)4 (46 mg; 0.04 mmol). The reaction was heated to 75° C. and stirred for 12 hours. The reaction was cooled to room temperature, diluted with 50 mL of ethyl acetate and washed with aqueous 10% sodium carbonate (1×50 mL), brine (50 mL), then dried (MgSO4) and filtered. The material was purified using a biotage 12L cartridge eluting with hexanes and ethyl acetate (3:1) to yield an off white solid (88% yield).
Reaction SMILES: [OH-].[Na+].CO.FC(F)(F)C(CCCCCC)CCO[C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][CH:12]=1>O>[C:15]([OH:17])(=[O:16])[C:14]1[CH:20]=[CH:21][CH:11]=[CH:12][CH:13]=1
Reactant: CCCCCCC(CCOc1ccc(C(=O)OCC)cc1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccccc1
Temperature: 50 °C
Yield: 77.2 %

Procedure:
72 mg of sodium hydroxide was dissolved in 0.5 ml of water, followed by addition of 0.5 ml of methanol and 205 mg of ethyl p-(3-trifluoromethylnonyloxy)benzoate and 4 hours of stirring at 50° C. After the reaction, water was added, methanol was removed by distillation under a reduced pressure, and 2N-hydrochloric acid was added, followed by extration with diethyl ether. The ether solution was dried with sodium sulfate, and the solvent was distilled off to obtain 146 mg of optically active p-3-trifluoromethylnonyloxy)benzoic acid (yield: 77.2%).
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:26][C:27]4[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)=[N:18][C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:10]=2)=CC=1>C(O)(C(F)(F)F)=O.FC(F)(F)S(O)(=O)=O>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[C:17]([NH:26][C:27]3[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=3)=[N:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc4ccccc4nc3Nc3ccc(OC)nc3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2nc3ccccc3cc2-c2nc(C)nc(N)n2)cn1
Temperature: 90 °C
Reaction time: 18 h
Yield: 34.6 %

Procedure:
A solution of 3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-N-(6-methoxypyridin-3-yl)quinolin-2-amine (0.16 g, 0.26 mmol) in TFA (3 mL) was treated with a couple of drops of trifluoromethane sulfonic acid. The reaction mixture was stirred at 90° C. for 18 h, allowed to cool to room temperature, and the solvent was removed in vacuo. Purification by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 90% over 18 min gave 3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-N-(6-methoxypyridin-3-yl)quinolin-2-amine (31 mg, 0.09 mmol, 33% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 11.99 (br. s., 1H); 9.33 (s, 1H); 8.88 (br. s., 1H); 8.42 (d, J=7.43 Hz, 1H); 7.77-8.09 (m, 3H); 7.67 (br. s., 2H); 7.33 (br. s., 1H); 6.87 (d, J=8.80 Hz, 1H); 3.87 (s, 3H); 2.49 (s, 3H). m/z (ESI, +ve ion) 359.9 (M+H)+.
Reaction SMILES: C([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][OH:21])[C:13](=[O:22])[N:12]([CH2:23][CH3:24])[C:11]=2[N:10]=[C:9]1[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:36])([F:35])[F:34])[CH:27]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH2:23]([N:12]1[C:11]2[N:10]=[C:9]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:35])([F:36])[F:34])[CH:27]=3)[NH:8][C:16]=2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][OH:21])[C:13]1=[O:22])[CH3:24]
Reactant: CCn1c(=O)n(CCCO)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCn1c(=O)n(CCCO)c(=O)c2[nH]c(Oc3cccc(OC(F)(F)F)c3)nc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 117.7 %

Procedure:
7-benzyl-3-ethyl-1-(3-hydroxypropyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (0.62 g, 1.23 mmol, example 60) was dissolved in ethanol (20 mL); then the mixture was degassed and refilled with nitrogen three times. Ammonium formate (0.5 g, 7.94 mmol) and 10% Pd/C (30 mg) were added. The mixture was again degassed and refilled with nitrogen three times; then it was stirred at 80° C. overnight. The reaction was cooled and filtered. The filter cake was washed with methanol. The filtrate was concentrated to give 3-ethyl-1-(3-hydroxypropyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (0.6 g, 100% yield) as white solid. 1H-NMR (DMSO-d6) δ 7.61-7.57(t, 1H), 7.50(s, 1H), 7.40-7.38(dd, 1H), 7.31-7.29(d, 1H), 4.50(s, 1H), 3.95-3.85(m, 4H), 3.44-3.43(m, 2H), 1.73-1.66(t, 2H), 1.17-1.13(t, 3H). LCMS retention time 1.350 min; LCMS MH+ 415.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]4)[CH2:10]2)[CH2:16]3)=[O:8])[CH2:2]1.C1(C)C=CC(S(O[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][CH:32]=2)(=O)=O)=CC=1>>[Br:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][CH2:29][N:1]2[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]34[CH2:18][CH:13]5[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]5)[CH2:10]3)[CH2:16]4)=[O:8])[CH2:2]2)=[CH:32][CH:33]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(Br)cc2)cc1
Reactant: O=C(N[C@H]1CCNC1)C12CC3CC(CC(C3)C1)C2
Product: O=C(N[C@H]1CCN(CCc2ccc(Br)cc2)C1)C12CC3CC(CC(C3)C1)C2

Procedure:
(S)-N-(Pyrrolidin-3-yl)-1-adamantanecarboxamide and 2-(4-bromophenyl)ethyl p-toluenesulfonate were reacted under the same conditions as in Example 6 to give (S)-N-(1-(2-(4-bromophenyl)ethyl)pyrrolidin-3-yl)-1-adamantanecarboxamide.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:13]([N:15]1[CH2:20][CH2:19][CH:18]([N:21]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:29][CH:28]=2)[CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH2:17][CH2:16]1)=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@@H:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:13]([N:15]1[CH2:20][CH2:19][CH:18]([N:21]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:31][CH:32]=2)[CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH2:17][CH2:16]1)=[O:14]
Reactant: CC(C)=CCN(c1ccc(OCc2ccccc2)cc1)C1CCN(C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)=CCN(c1ccc(OCc2ccccc2)cc1)C1CCN(C(=O)[C@@H](N)CC(C)C)CC1
Reaction time: 0.42 h
Yield: 98.8 %

Procedure:
(S)-(1-{4-[(4-Benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidine-1-carbonyl}-3-methyl-butyl)-carbamic acid tert-butyl ester (1.07 g, 1.90 mmol) was dissolved in CH2Cl2 (4.5 mL) and treated with TFA (4.5 mL). The reaction was stirred for 25 minutes, then concentrated in vacuo. The residue was dissolved in EtOAc (175 mL) and solution was washed twice with saturated bicarbonate solution and brine, dried over Na2SO4, and concentrated in vacuo to give 0.87 g (99%) of the desired product as a pale oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:17]([NH2:19])=[O:18])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH3:16])[CH:10]=2)=[CH:6][N+:7]=1[O-].P(Cl)(Cl)([Cl:22])=O.O.[OH-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:17]([NH2:19])=[O:18])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH3:16])[CH:10]=2)=[C:6]([Cl:22])[N:7]=1
Reactant: Cn1cc(-c2c[n+]([O-])c(N)c(C(N)=O)n2)ccc1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2nc(C(N)=O)c(N)nc2Cl)ccc1=O
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a suspension of 3-amino-6-(1-methyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazinecarboxamide 4-oxide (1.0 g) in DMF was added phosphoric trichloride (1.07 ml) at −40° C. for 20 minutes. This reaction mixture was warmed to −10° C. and stirred for 1 hour. To this solution was added water (40 ml) and stirred at 40° C. for 14 hours. The pH of the resulting suspension was adjusted to 4.5 with 30% The pH of the aqueous mixture was adjusted to 6-7 with 12% aq. NaOH. The precipitate was collected by filtration and washed with water to give 3-amino-5-chloro-6-(1-methyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazinecarboxamide (263 mg) as a yellow powder.