Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:15][C@@H:14]([CH3:16])[C@H:13](/[CH:17]=[CH:18]/[C@@H:19]([O:27]C2CCCCO2)[C:20]([CH3:26])([CH3:25])[CH2:21][C:22]#[C:23][CH3:24])[C@H:3]1[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]>C(O)(=O)C.O.C1COCC1>[OH:27][C@@H:19]([C:20]([CH3:25])([CH3:26])[CH2:21][C:22]#[C:23][CH3:24])/[CH:18]=[CH:17]/[C@@H:13]1[C@@H:3]([CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:2](=[O:1])[CH2:15][C@H:14]1[CH3:16]
Reactant: CC#CCC(C)(C)[C@@H](/C=C/[C@H]1[C@H](C)CC(=O)[C@@H]1C/C=C\CCCC(=O)O)OC1CCCCO1
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC#CCC(C)(C)[C@H](O)/C=C/[C@H]1[C@H](C)CC(=O)[C@@H]1C/C=C\CCCC(=O)O

Procedure:
300 mg. of (5Z,13E)-(11R,15R)-9-oxo-15-(tetrahydropyran-2-yloxy)-11,16,16-trimethyl-5,13-prostadien-18-ynoic acid is agitated for 16 hours at room temperature with 10 ml. of a mixture of glacial acetic acid/water/THF (65/35/10); the reaction mixture is evaporated under vacuum and the residue purified by chromatography on silica gel. With methylene chloride/2% methanol, 180 mg. of the title compound is obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:19])=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=O)[CH2:8]1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].Cl.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[S:3][C:4]([Cl:19])=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=[N:24][NH:23][C:20]([NH2:22])=[NH:21])[CH2:8]1
Reactant: Cc1ccnc2c1C(=O)CC(c1cc(Cl)sc1Cl)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1cc(Cl)sc1Cl)C2
Temperature: 100 °C
Reaction time: 14 h
Yield: 176.9 %

Procedure:
A mixture of 7-(2,5-dichlorothiophene-3-yl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (218 mg), aminoguanidine hydrochloride (83 mg) and concentrated hydrochloric acid (0.1 ml) in ethanol (4 ml) was stirred at 100° C. (bath temperature) for 14 hours. The reaction solution was cooled, and precipitated crystals were filtered, washed with ethanol and dried to give 7-(2,5-dichlorothiophene-3-yl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 102) (250 mg) as pale yellow crystals.
Reaction SMILES: [C:1](=[S:3])=[S:2].[OH-].[K+].[NH2:6][C:7]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:8]=1[CH2:9]O>C(O)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:7]2[NH:6][C:1](=[S:3])[S:2][CH2:9][C:8]=2[CH:11]=1
Reactant: S=C=S
Reactant: Nc1ccc(Cl)cc1CO
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: S=C1Nc2ccc(Cl)cc2CS1
Yield: 102.4 %

Procedure:
Carbon disulfide (180 ml, 3.0 moles) was added dropwise to a stirred solution of 84 g (1.5 moles) of potassium hydroxide in 400 ml of absolute ethanol with external cooling. To this mixture was added 157 g (1.0 mole) of 2-amino-5-chlorobenzyl alcohol. The reaction mixture was heated under reflux for 20 hours and the solvent was removed by distillation. The solid residue was stirred with 2000 ml of 10% aqueous potassium hydroxide, and the mixture was filtered to remove neutral impurities. The clear filtrate was made acidic with dil. hydrochloric acid, and the solid which was deposited was collected by filtration to give 221 g (100%) of product. Recrystallization from methanol gave an analytical sample, m.p. 217°-222°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].[CH:12]1([N:18]=[C:19]=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C1COCC1>[CH:12]1([NH:18][C:19]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C=NC1CCCCC1
Reactant: NCc1cccc([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: O=C(NCc1cccc([N+](=O)[O-])c1)NC1CCCCC1
Reaction time: 2 h

Procedure:
3-Nitro-benzyl-amine (5 g) was suspended in THF (130 ml) and cyclohexyl isocyanate (7 ml) was added dropwise at 25° C. After stirring for 2 h the resulting precipitate was filtered off, washed with diethyl ether and treated with 5% aqueous NH4OH. After filtering and drying the title compound was isolated (4.5 g, FP 168-169° C.)
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C@@H:7]([NH:16][CH2:17][C@@H:18]([OH:46])[C@@H:19]([NH:29][C:30](=[O:45])[C@@H:31]([N:35]2[CH2:39][CH2:38][C@H:37]([CH2:40][CH2:41][CH2:42][CH3:43])[C:36]2=[O:44])[CH2:32][CH:33]=C)[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)[CH2:6]1)[CH:2]=C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:40]([C@H:37]1[CH2:38][CH2:39][N:35]([C@H:31]2[CH2:32][CH:33]=[CH:2][CH2:1][O:4][C@@H:5]3[CH2:6][C@@H:7]([C:8]4[CH:9]=[C:10]([O:14][CH3:15])[CH:11]=[CH:12][C:13]=43)[NH:16][CH2:17][C@@H:18]([OH:46])[C@H:19]([CH2:20][C:21]3[CH:22]=[C:23]([F:28])[CH:24]=[C:25]([F:27])[CH:26]=3)[NH:29][C:30]2=[O:45])[C:36]1=[O:44])[CH2:41][CH2:42][CH3:43]
Reactant: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)[C@H](CC=C)N2CC[C@H](CCCC)C2=O)c2cc(OC)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC[C@H]1CCN([C@H]2CC=CCO[C@@H]3C[C@H](NC[C@@H](O)[C@H](Cc4cc(F)cc(F)c4)NC2=O)c2cc(OC)ccc23)C1=O
Reaction time: 72 h
Yield: 54.7 %

Procedure:
Step J (2): Hoveyda-Grubb's catalyst [(1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(O-isoproproxylphenylmethylene)ruthenium] (6.6 mg, 7.8 μmol, Aldrich) was added to flask charge with a solution of (S)—N-((2S,3R)-4-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-2-((S)-3-butyl-2-oxopyrrolidin-1-yl)pent-4-enamide (59 mg, 0.0783 mmol, TFA salt) from stepH(1) in CH2Cl2 at room temperature. The mixture was stirred for 3 days. The resulting solution was evaporated to dryness, dissolved in MeOH, and filtered through Celite. Purified using reverse phase preparatory HPLC to give 26.2 mg (46% yield) of the title compound as a TFA salt: LC-MS (M+H)+=612.51; 1H NMR (500 MHz, CDCl3) δ 7.35 (d, J=8.55 Hz, 1H), 7.14 (s, 1H), 6.92-7.10 (m, 2H), 6.41-6.80 (m, 3H), 5.59-5.74 (m, 1H), 5.43-5.57 (m, 1H), 4.78-5.16 (m, 4H), 4.72 (d, J=5.49 Hz, 1H), 4.40 (d, J=9.77 Hz, 1H), 3.98-4.16 (m, 2H), 3.66-3.98 (m, 4H), 3.07-3.39 (m, 3H), 2.47-2.85 (m, 3H), 2.24-2.50 (m, 2H), 1.93-2.20 (m, 2H), 1.68-1.88 (m, 1H), 1.05-1.53 (m, 6H), 0.74-0.94 (m, 3H).
Reaction SMILES: C1C=CC(C2C=CC([C:13]3[NH:34][C:32](=O)[C:15]4=[C:16](C5C=CC(C6C=CC=CC=6)=CC=5)[NH:17][C:18](=[O:19])[C:14]=34)=CC=2)=CC=1.N(CCO)(CCO)CC[OH:38]>O>[O:38]=[C:14]1[C:13]2[C:16]([CH:15]=[CH:32][N:34]=2)=[N:17][C:18]1=[O:19]
Reactant: OCCN(CCO)CCO
Reactant: O=C1NC(c2ccc(-c3ccccc3)cc2)=C2C(=O)NC(c3ccc(-c4ccccc4)cc3)=C12
Solvent: O
Product: O=c1nc2ccnc-2c1=O
Reaction time: 7 h

Procedure:
20 g of C.I. pigment red 264 (in which the content of metal ions having a valence of at least 2 was 520 ppm), 60 g of the same aqueous dispersion of the pigment derivative (n) as that obtained in Example 45 and 60 g of deionized water were mixed, 11 g of 2% by weight triethanolamine was added so as to adjust the neutralization ratio of the pigment derivative to 100%, and the mixture was dispersed with a paint shaker in the presence of zirconia beads as media for approximately 7 hours, to obtain a pigment dispersion.
Reaction SMILES: [CH2:1]([C@H:8]([NH:48]C(=O)OC(C)(C)C)[C@@H:9]([OH:47])[CH2:10][C@@H:11]([NH:25][C:26](=[O:46])[C@@H:27]([N:32]1[CH2:36][CH2:35][N:34]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[N:39]=2)[C:33]1=[O:45])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[CH3:63][O:64][C:65]([NH:67][C@@H:68]([C:72]([CH3:75])([CH3:74])[CH3:73])[C:69]([OH:71])=O)=[O:66].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>ClCCl.C1COCC1>[CH2:1]([C@H:8]([NH:48][C:69]([C@@H:68]([NH:67][C:65](=[O:66])[O:64][CH3:63])[C:72]([CH3:75])([CH3:74])[CH3:73])=[O:71])[C@@H:9]([OH:47])[CH2:10][C@@H:11]([NH:25][C:26](=[O:46])[C@@H:27]([N:32]1[CH2:36][CH2:35][N:34]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[N:39]=2)[C:33]1=[O:45])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(CN2CCN([C@H](C(=O)N[C@@H](Cc3ccc(-c4ccccn4)cc3)C[C@H](O)[C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)C(C)(C)C)C2=O)n1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](N1CCN(Cc2cccc(C)n2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.9 %

Procedure:
A solution containing the product from Example 24A (0.129 g, 0.17 mmol) in dichloromethane (0.8 mL) was treated with trifluoroacetic acid (0.8 mL), stirred at 25° C. for 1 hour and concentrated. A solution of the residue (0.17 mmol) in THF (1.8 mL) was treated with the product from Example 1F (0.033g, 0.17 mmol), DEPBT (0.077 g, 0.26 mmol), and N,N-diisopropylethylamine (0.30 mL, 1.72 mmol), stirred at 25° C. for 18 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-5% methanol/ethyl acetate to give the title compound (0.057 g, 40% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.85 (d, J=1.10 Hz, 18 H), 1.55 (m, 2 H), 2.43 (m, 5 H), 2.72 (m, 4 H), 2.95 (m, 1 H), 3.19(m, 1 H), 3.58 (m, 4 H), 3.93 (d, J=9.56 Hz, 1 H), 3.99 (s, 1 H), 4.28 (m, 4 H), 4.84 (d, J=5.52 Hz, 1 H), 6.82 (d, J=9.93 Hz, 1 H), 6.97 (d, J=7.72 Hz, 1 H), 7.16 (m, 8 H), 7.29 (m, 1 H), 7.52 (d, J=8.82 Hz, 1 H), 7.61 (t, J=7.72 Hz, 1 H), 7.79 (m, 4 H), 7.95 (d, J=8.82 Hz, 1 H), 8.61 (d, J=4.78 Hz, 1 H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].[C:16]1(=[O:26])[O:21][C:19](=[O:20])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12>>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([NH:6][C:16]([C:17]2[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=2[C:19]([OH:21])=[O:20])=[O:26])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1OC(=O)c2ccccc21
Product: O=C(O)c1ccccc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
From 2.3 g of 3,5-bistrifluoromethyl aniline and 1.5 g of phthalic anhydride used as starting materials, the title compound was obtained in the same manner as in Example 1.
Reaction SMILES: [CH:1]1([C:9]([O:11]C)=[O:10])[CH2:5][CH2:4][N:3]2[CH:6]=[CH:7][CH:8]=[C:2]12.[CH:13]([C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1)=[CH2:14]>C1(C)C(C)=CC=CC=1>[CH:13]([C:15]1[CH:23]=[CH:22][C:18]([C:19]([C:6]2[N:3]3[CH2:4][CH2:5][CH:1]([C:9]([OH:11])=[O:10])[C:2]3=[CH:8][CH:7]=2)=[O:20])=[CH:17][CH:16]=1)=[CH2:14]
Reactant: C=Cc1ccc(C(=O)O)cc1
Reactant: COC(=O)C1CCn2cccc21
Solvent: Cc1ccccc1C
Product: C=Cc1ccc(C(=O)c2ccc3n2CCC3C(=O)O)cc1
Yield: 36 %

Procedure:
A solution of methyl 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate (Formula B where Y is hydrogen) the synthesis of which is described in Preparations 1 and 2 hereinabove, (3.0 g, 18 mmol) and the acid chloride of 4-vinylbenzoic acid [J. Chem. Education, 55, 813 (1978)] (10.0 g, 60 mmol) in anhydrous xylene (100 ml) was heated at reflux temperature for 6 hours. The solvent was removed in vacuo and the residue was purified by column chromatography on Act II neutral alumina (Fluka, 200 g). The product was eluted with hexane-ethyl acetate (95:5) to give 5-(4-vinylbenzoyl)-1,2-dihydro-3H-pyrrolo[1,2,a]pyrrole-1-carboxylic acid, (36%) which had mp 99°-100° after crystallization from methanol. The purified product exhibited the following characteristics:
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH3:27][CH:28]([CH3:34])[CH2:29][CH2:30][C:31](O)=[O:32]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:31](=[O:32])[CH2:30][CH2:29][CH:28]([CH3:34])[CH3:27])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: CC(C)CCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CC(C)CCC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (77 mg, 73%), MS (ISP) m/z=427.4 [(M+H)+], mp 188° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydro chloride (intermediate B) (100 mg, 0.25 mmol) and 4-methyl-pentanoic acid.
Reaction SMILES: C([O:4][CH:5]([C:7]1[CH:16]=[CH:15][C:14]2[C:13]([CH3:18])([CH3:17])[CH2:12][CH2:11][C:10]([CH3:20])([CH3:19])[C:9]=2[CH:8]=1)[CH3:6])(=O)C.[OH-].[Na+]>CO>[CH3:18][C:13]1([CH3:17])[CH2:12][CH2:11][C:10]([CH3:19])([CH3:20])[C:9]2[CH:8]=[C:7]([CH:5]([OH:4])[CH3:6])[CH:16]=[CH:15][C:14]1=2
Reactant: CC(=O)OC(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 93 %

Procedure:
2.2 g (8 mmol), obtained in Example 59 (a), of acetoxy-1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethane, dissolved in 20 ml of methanol, are treated with 1.6 g of sodium hydroxide and left stirring for 24 h at room temperature. After evaporation and acidification with 1N HCl, the precipitate is extracted with ethyl ether to yield 1.75 g (93%) of the expected alcohol, melting point 61°-2° C. (αD =-27.2°; c=1, ethanol).
Reaction SMILES: [C:1]([O:7][C@H:8]1[C@H:13]([CH:14]([CH3:16])[CH3:15])[CH2:12][CH2:11][C@@H:10]([CH3:17])[CH2:9]1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[C:18](OCC)(=[O:22])/[CH:19]=[CH:20]/[CH3:21]>C(O)(C)(C)C>[CH3:21][C@@H:20]1[CH2:19][C:18](=[O:22])[CH2:5][C:3](=[O:4])[C@H:2]1[C:1]([O:7][C@H:8]1[C@H:13]([CH:14]([CH3:16])[CH3:15])[CH2:12][CH2:11][C@@H:10]([CH3:17])[CH2:9]1)=[O:6]
Reactant: C/C=C/C(=O)OCC
Reactant: CC(=O)CC(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Solvent: CC(C)(C)O
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)[C@@H]1C(=O)CC(=O)C[C@H]1C
Temperature: 23 °C

Procedure:
A 2-L 3-necked round bottom flask fitted with a reflux condenser, a mechanical stirrer, and a glass stopper was charged with t-butyl alcohol (300 mL) and potassium 1-butoxide (68.7 g, 612 mmol, 1.04 equiv). The glass stopper was removed and, with efficient mechanical stirring, (1R,3R,4S)-p-menth-3-yl acetoacetate (1, 150 g, 624 mmol, 1.06 equiv) was added rapidly to the yellow slurry. The open neck of the reaction flask was fitted with a 100-mL addition funnel containing (E)-ethyl crotonate (73.2 mL, 588 mmol, 1 equiv). The largely solid reaction mixture was heated to reflux with a heating mantle. At this point, (E)-ethyl crotonate was added to the refluxing, dark yellow slurry over 15 min via the addition funnel. The addition funnel was replaced with a glass stopper and heating at reflux was continued. Solids were observed to dissolve within 1 h after addition of (E)-ethyl crotonate; the product began to crystallize from solution after about 1.5 h. After a total reflux period of 2.5 h (from addition of (E)-ethyl crotonate), heating was discontinued and the reaction mixture was allowed to cool to 23° C. The cooled reaction mixture was partitioned between aqueous sulfuric acid solution (5% v/v, 500 mL) and dichloromethane (600 mL). The aqueous layer was separated and extracted further with two 600-mL portions of dichloromethane. The combined organic layers were dried over sodium sulfate and then were concentrated. The solid residue was dissolved in boiling benzene (ca. 600 mL) and the resulting solution was allowed to cool slowly to 23° C. whereupon (1R,3R,4S)-p-menth-3-yl(1R,2S)-2-methyl-4,6-dioxocyclo-hexanecarboxylate (2) crystallized as a white powder (mp 180°-181° C., 64.5 g, 36%). To isolate the diastereomeric diketone product, (1R,3R,4S)-p-menth-3-yl(1S,2R)-2-methyl-4,6-dioxocyclohexanecarboxylate (3), the mother liquors were concentrated and the solid residue was dissolved in boiling ethyl acetate (ca. 200 mL). Hexanes (50 mL) were added to the hot solution and the mixture was allowed to cool to 23° C. Further cooling to -20° C. induced crystallization of diketone diastereomer 3 over a period of 12 h (mp 140°-141° C., 45 g, 25%). ##STR15##
Reaction SMILES: [SH:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH-].[Na+].Cl.[CH3:15][N:16]([CH3:25])[C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Cl>C(O)C.O>[CH3:15][N:16]([CH3:25])[C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][S:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CN(C)c1ccccc1CCl
Reactant: Sc1cnc2ccccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN(C)c1ccccc1CSc1cnc2ccccc2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.4 %

Procedure:
To a solution of 1 g of 2-mercaptoquinoxaline in 40 ml of ethanol was added a solution of 530 mg of sodium hydroxide in 2 ml of water, and subsequently added 1.27 g of 2-dimethylaminobenzyl chloride hydrochloride. The resulting mixture was stirred at room temperature for 18 hrs., and the solvent was removed under reduced pressure. The residue was extracted with ethyl acetate. The organic layer was washed successively with 5% aqueous sodium hydroxide solution, water, and saturated aqueous sodium chloride solution, and dried over soidum sulfate. The sodium sulfate was removed by filtration, and the filtrate was placed under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (hexane/acetone) to give 1.5 g of 2-(2-dimethylaminobenzylthio)quinoxaline as a yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([NH:12][C:13]3[N:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]4)[C:16]([C:33]([F:36])([F:35])[F:34])=[CH:15][N:14]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.C=O.[C:39](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:39][N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[CH:11]=[C:10]([NH:12][C:13]3[N:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4([C:30]([NH2:32])=[O:31])[CH2:28][CH2:29]4)[C:16]([C:33]([F:35])([F:34])[F:36])=[CH:15][N:14]=3)[CH:9]=[N:8]2)[CH2:5][CH2:6]1
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Nc3cnn(C4CCNCC4)c3)ncc2C(F)(F)F)CC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCC(n2cc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4C4(C(N)=O)CC4)n3)cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.4 %

Procedure:
A mixture of 1-(2-(2-(2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide 66 (0.081 g, 0.16 mmol) and formaldehyde (37 wt % in H2O; 36 μL, 0.49 mmol) in MeOH (5 mL) was stirred at room temperature for 10 minutes. Sodium triacetoxyborohydride (0.137 g, 0.649 mmol) was then added and stirring was continued for 3 hours at room temperature. The volatiles were removed in vacuo and sat. aq. NaHCO3 (20 mL) was added to the residue. The aqueous phase was extracted with EtOAc (3×20 mL) and the combined organics were washed with brine, dried (MgSO4) and the solvent was removed in vacuo. The yellow residue was taken up in MeOH and loaded onto an SCX cartridge (10 g). The column was eluted with 5 column volumes of MeOH and then 5 column volumes of 2% v/v aqueous ammonia in MeOH to release the amine product. The solvent was evaporated under reduced pressure, the residue was taken up in DCM and a solid was precipitated by the addition of petroleum benzine 40-60° C. The solid was isolated by filtration and air dried to give the title compound 67 as a yellow solid (0.048 g, 58%). LCMS-A: rt 4.82 min; m/z 514 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[CH2:23]([O:25][C:26]1[CH:27]=[CH:28][C:29]([OH:39])=[C:30]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:31]=1)[CH3:24].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:23]([O:25][C:26]1[CH:27]=[CH:28][C:29]([O:39][CH2:2][C:3]2[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:12][C:13]=3[CH3:14])=[CH:5][CH:4]=2)=[C:30]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:31]=1)[CH3:24]
Reactant: CCOC(=O)CCc1cc(OCC)ccc1O
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cc(OCC)ccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 72.6 %

Procedure:
A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.44 g), ethyl 3-(5-ethoxy-2-hydroxyphenyl)propionate (1.0 g), anhydrous potassium carbonate (0.58 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 2 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give ethyl 3-[5-ethoxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionate as an oil (1.57 g, 72%) from a fraction eluted with ethyl acetate-hexane (1:6, v/v).
Reaction SMILES: [CH3:1][C:2]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[N:17]([CH3:41])[C:18]3[C:23]([N:24]=2)=[C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:21]=[C:20]([N:31]2[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[N:33]=[C:32]2[CH3:40])[N:19]=3)[CH2:11][CH2:10]1)([CH3:8])[C:3]([O:5]CC)=[O:4]>[Li+].[OH-].C1COCC1>[CH3:8][C:2]([N:9]1[CH2:10][CH2:11][N:12]([CH2:15][C:16]2[N:17]([CH3:41])[C:18]3[C:23]([N:24]=2)=[C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:21]=[C:20]([N:31]2[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[N:33]=[C:32]2[CH3:40])[N:19]=3)[CH2:13][CH2:14]1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C)N1CCN(Cc2nc3c(N4CCOCC4)nc(-n4c(C)nc5ccccc54)nc3n2C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)(C)C(=O)O)CC3)n(C)c2n1
Temperature: 25 °C

Procedure:
A mixture of ethyl 2-methyl-2-(4-((9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-morpholino-9H-purin-8-yl)methyl)piperazin-1-yl)propanoate 507 (0.14 g, 0.25 mmol) in 2M LiOH (5.0 mL) and THF (8 mL) was stirred at reflux for 18 hours. The reaction was then cooled to room temperature and concentrated down to ⅓ of original volume. The residue was then loaded onto a SCX-2 column. The column was first washed with MeOH. The product was then eluted with 2M NH3 in MeOH and then concentrated. The residue was purified by RP-HPLC to give 506. LCMS m/z: 534.3 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]([N:15]=[N+]=[N-])[CH2:11][N:12]=[N+]=[N-])=[CH:4][CH:3]=1>CO.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH:10]([NH2:15])[CH2:11][NH2:12])=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=NCC(COc1ccc(Cl)cc1)N=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: NCC(N)COc1ccc(Cl)cc1
Reaction time: 1 h
Yield: 27.1 %

Procedure:
To a solution of rac-1-chloro-4-(2,3-diazido-propoxy)-benzene (0.89 g, 3.5 mmol) in methanol (5 ml) was added palladium on charcoal (50 mg) and the mixture was hydrogenated at atmospheric pressure for 1 hour. The catalyst was removed by filtration over celite and the filtrate was evaporated. The residue was purified by chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: ethyl acetate) to yield a light yellow liquid (0.19 g, 27%); MS (ISP): 201.3 ((M+H)+).