Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([C@@H:18]([NH:26][C:27](=[O:48])[C@@H:28]([N:33]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]2[N:40]=[C:41]([CH2:44][O:45][CH3:46])[S:42][CH:43]=2)[C:34]1=[O:47])[C@@H:29]([CH3:32])[CH2:30][CH3:31])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][NH:4][NH:5][C:6]([C@@H:8]([NH:13][C:14](=[O:17])[O:15][CH3:16])[C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[CH:49](=O)[CH2:50][CH:51]([CH3:53])[CH3:52].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[OH:1][C@H:2]([C@@H:18]([NH:26][C:27](=[O:48])[C@@H:28]([N:33]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]2[N:40]=[C:41]([CH2:44][O:45][CH3:46])[S:42][CH:43]=2)[C:34]1=[O:47])[C@@H:29]([CH3:32])[CH2:30][CH3:31])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][N:4]([CH2:49][CH2:50][CH:51]([CH3:53])[CH3:52])[NH:5][C:6]([C@@H:8]([NH:13][C:14](=[O:17])[O:15][CH3:16])[C:9]([CH3:11])([CH3:10])[CH3:12])=[O:7]
Reactant: CC[C@H](C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CNNC(=O)[C@@H](NC(=O)OC)C(C)(C)C)N1CCN(Cc2csc(COC)n2)C1=O
Reactant: CC(C)CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC[C@H](C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(CCC(C)C)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)N1CCN(Cc2csc(COC)n2)C1=O
Yield: 36 %

Procedure:
A solution of Example 280A (20 mg, 0.029 mmol) in 1,2-dichloroethane (0.3 mL) was treated with isovaleraldehyde (6.2 μL, 2 equivalents), acetic acid (3.3 μL, 2 equivalents), and sodium triacetoxyborohydride (18.5 mg, 3 equivalents) at 25° C. for 16 hrs. The mixture was partitioned between dichloromethane and saturated sodium bicarbonate. The organic layer was separated, washed with brine, dried over magnesium sulfate, filtered, and the solvents were evaporated. The residue was purified by HPLC reverse phase chromatography using water (0.1% TFA):acetonitrile (95:5) to acetonitrile (100%) to give 8 mg (36%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.78 (dd, J=13.79, 6.43 Hz, 12H), 0.91 (m, 9H), 1.25 (m, 3H), 1.62 (m, 1H), 1.77 (d, J=8.82 Hz, 1H), 2.58 (m, 3H), 2.69 (m, 4H), 2.79 (m, 2H), 3.09 (m, 3H), 3.37 (s, 3H), 3.81 (m, 2H), 3.95 (m, 2H), 4.10 (s, 1H), 4.36 (m, 2H), 4.66 (s, 1H), 7.06 (m, 5H), 7.20 (m, 1H), 7.44 (m, 1H), 8.96 (s, 2H), 9.17 (s, 1H), 9.48 (s, 1H).
Reaction SMILES: [OH:1][CH:2]([P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:17]C1C=C(C=CC=1)C=O>>[F:17][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH:2]([P:9](=[O:16])([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15])[OH:1]
Reactant: CCOP(=O)(OCC)C(O)c1ccccc1
Reactant: O=Cc1cccc(F)c1
Product: CCOP(=O)(OCC)C(O)c1cccc(F)c1
Yield: 79 %

Procedure:
The procedure described for the preparation of Compound 19 is used except that 3-fluorobenzaldehyde (1.49 g, 0.012M) is used in place of benzaldehyde. The solid obtained is recrystallized from hexane to obtain 2.474 g (0.009 M, 79%) of colorless short needles: mp 81°-82° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)=[C:5]([CH3:13])[CH:4]=1>[Pd].C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:13])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=1
Reactant: COc1cc(C)c2c(c1)CCCC2
Agent: [Pd]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1cc(C)c2ccccc2c1

Procedure:
A mixture of 7-methoxy-5-methyl-1,2,3,4-tetrahydronaphthalene (1.0 g) and 10% palladium on charcoal (1.0 g) was stirred and heated in diphenyl ether (2 ml) at 200° C. for 1 hr. The mixture was purified by column chromatography over silica with light petroleum/dichloromethane (1:1 v/v) elution to give 2-methoxy-4-methylnaphthalene as a low melting point solid. Pmr spectrum (CDCl3 ; δ in ppm): 2.64 (3H,s); 3.89 (3H,s); 7.0-7.9 (6H,m).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:30]([CH3:31])=[CH:29][C:15]2[N:16]=[C:17]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[C:24](=[O:28])[NH:23][CH2:22]4)[S:18][C:14]=2[C:13]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:42].[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C@@H:6]([C:12]1[C:30]([CH3:31])=[CH:29][C:15]2[N:16]=[C:17]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[C:24](=[O:28])[N:23]([CH3:42])[CH2:22]4)[S:18][C:14]=2[C:13]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)CNC4=O)sc2c1-c1ccc(Cl)cc1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)CN(C)C4=O)sc2c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-oxoisoindolin-5-yl)benzo[d]thiazol-6-yl)acetate (94 mg, 0.171 mmol) in DMF (2.0 mL) was added NaH (˜10 mg, 60% oil dispersion) at 0° C. After 15 min, iodomethane (0.016 mL, 0.256 mmol) was added and after 30 min the reaction was allowed to warm to room temperature. Satd. aqueous NH4Cl was added and the reaction was diluted with EtOAc, washed sequentially with 5% aqueous LiCl and brine. The organic layer was dried over Na2SO4, concentrated and purified by flash column chromatography on silica gel using EtOAc to provide the title compound. LCMS-ESI+: calc'd for C31H31ClN2O4S: 563.2 (M+H+); found: 563.2 (M+H+).
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][C:7]1[N:8]([C:12]2[CH:13]=[C:14]([C:18]3[NH:19][C:20]4[C:26]([C:27]([NH2:29])=[O:28])=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)[CH:15]=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1)=O.[OH-].[Li+]>O>[NH2:5][CH2:6][C:7]1[N:8]([C:12]2[CH:13]=[C:14]([C:18]3[NH:19][C:20]4[C:26]([C:27]([NH2:29])=[O:28])=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)[CH:15]=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: NC(=O)c1cccc2nc(-c3cccc(-n4cccc4CNC(=O)C(F)(F)F)c3)[nH]c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: NCc1cccn1-c1cccc(-c2nc3cccc(C(N)=O)c3[nH]2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1.0 g (2.3 mmol) of the compound from Example 32 was dissolved in 100 ml of water and admixed with 0.56 g (23.4 mmol) of lithium hydroxide, dissolved in 20 ml of water. The entire mixture was stirred at room temperature for 90 minutes. The organic solvent was subsequently removed under reduced pressure and the resulting aqueous phase was neutralized carefully using dilute hydrochloric acid. The resulting precipitate was filtered off with suction. This gave 0.55 g of the product.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1[C:12]([N:13]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[CH:14]2)=[CH:11][CH:10]=[CH:9][C:8]=1[C:24]1[CH:32]=[CH:31][C:30]([C:33]([NH2:35])=[O:34])=[C:29]2[C:25]=1[C:26]1[CH2:39][NH:38][CH2:37][CH2:36][C:27]=1[NH:28]2>>[CH3:6][C:7]1[C:12]([N:13]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[CH:14]2)=[CH:11][CH:10]=[CH:9][C:8]=1[C:24]1[CH:32]=[CH:31][C:30]([C:33]([NH2:35])=[O:34])=[C:29]2[C:25]=1[C:26]1[CH2:39][N:38]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:37][CH2:36][C:27]=1[NH:28]2
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(-c2ccc(C(N)=O)c3[nH]c4c(c23)CNCC4)cccc1-n1cnc2ccccc2c1=O
Product: Cc1c(-c2ccc(C(N)=O)c3[nH]c4c(c23)CN(S(C)(=O)=O)CC4)cccc1-n1cnc2ccccc2c1=O
Yield: 34 %

Procedure:
Using the procedure of Example 43 but substituting methanesulfonyl chloride in place of acetic anhydride, 9-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-6-carboxamide (20 mg, 0.044 mmol) was converted into the desired product as a white solid (8.0 mg, 34% yield). LCMS (M+H)+ m/z 528.2, (M+Na)+550.2. 1H NMR (400 MHz, DMSO-d6) δ 8.40, 8.15 (1 H, 2s), 8.22 (1 H, ddd, J=13.9, 8.1, 1.3 Hz), 7.92 (1 H, t, J=7.8 Hz), 7.79 (1 H, dd, J=7.6, 4.5 Hz), 7.73 (1 H, t, J=8.3 Hz), 7.54-7.67 (2 H, m), 7.51 (1 H, t, J=7.7 Hz), 7.43 (1 H, dd, J=7.2, 5.6 Hz), 6.83-7.00 (1 H, m), 3.43-3.86 (3 H, m), 3.28-3.34 (3 H, m), 2.89-3.19 (3 H, m), 1.74 (3 H, 2s).
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])[N:5]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([OH:16])=[O:15])[N:5]=1)(=[O:3])[NH2:2]
Reactant: CC(C)(C)OC(=O)Cn1nc(C(N)=O)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1nn(CC(=O)O)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 2-(3-carbamoyl-1H-indazol-1-yl)acetate (3.42 g, 12.4 mmol) in CH2Cl2 (20 mL) was added TFA (10 mL, 130 mmol) and the resulting mixture was stirred at RT for 16 h. The reaction mixture was concentrated in vacuo, the residual solid was suspended in methanol and concentrated again in vacuo to give the title compound. MS (LC/MS): 220 [M+H]+; tR (HPLC conditions k): 1.79 min.
Reaction SMILES: [C:1]([C@@H:4]([C@H:6]([C:8]([O-:10])=[O:9])[OH:7])[OH:5])([O-:3])=[O:2].[Ca+2].Cl>O>[C:8]([OH:10])(=[O:9])[C@@H:6]([C@H:4]([C:1]([OH:3])=[O:2])[OH:5])[OH:7]
Reactant: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: Cl
Agent: [Ca+2]
Solvent: O
Product: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Yield: 89 %

Procedure:
The culture broth obtained similarly to Example 1 was centrifuged to separate the cells therefrom. The cells were suspended in 200 ml of a 0.05 mol/l phosphate buffer solution adjusted in advance to pH 7.0 and the suspension was again centrifuged to clean the cells. This cleaning was repeated to give a total of three cycles. A 0.5 g portion of the cleaned cells was added to a 100 ml of solution containing 1.0 g of dihydrated calcium hydrogen cis-epoxysuccinate and 0.3 g of calcium carbonate as the substrate. The resultant mixture was adjusted to pH 8.0 and shaken at 35° C for 4 hours. The substrate was wholly used up and the reaction mixture was found to have produced calcium L(+)-tartrate. The amount of calcium L(+)-tartrate thus produced was 1.09 g. The yield was 98%. The resultant reaction mixture was incorporated with both 1.0 g of dihydrated calcium hydrogen cis-epoxysuccinate and 0.3 g of calcium carbonate thereto and was shaken at 35° C for 4 hours. The substrate present in the reaction mixture was wholly used up and converted into calcium L(+)-tartrate. The amount of the product was 2.18 g and the yield thereof based on the charged substrate was 98%. In this manner, 1.0 g portions of dihydrated calcium hydrogen cis-epoxysuccinate and 0.3 portions of calcium carbonate were added one each at a time to respective totals of 20.0 g and 6.0 g. Finally, the substrate thus successively added was wholly used up to produce the precipitate of calcium L(+)-tartrate. The amount of the product thus produced was 22.0 g and the yield thereof was 99 percent. The calcium L(+)-tartrate was suspended in about 200 ml of water. While the suspension was kept under agitation, 1N hydrochloric acid was added until the precipitate of calcium L(+)-tartrate was dissolved. The resultant liquid was centrifuged to remove the microbic cells therefrom. The remaining solution was passed through a column measuring 3 × 80 cm and packed with Amberlite IR 120 (H+ type cation-exchange resin) and the adsorbate was eluted with water. By concentrating to dryness the eluate under reduced pressure, there was obtained 15.7 g of L(+)-tartaric acid in the form of crystals. The yield was 89 percent and the optical purity was 100 percent.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]([O:11][C:12]([N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=O)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[C:7]([O:11][C:12]([N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[CH2:1])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)c2ccccc21
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=C1CCN(C(=O)OC(C)(C)C)c2ccccc21
Reaction time: 1 h
Yield: 72.5 %

Procedure:
A solution of methyltriphenylphosphonium bromide (1.92 g, 5.38 mmol, 1.1 equiv; [CAS RN 1779-49-3]) and potassium tert-butoxide (0.60 g, 5.38 mmol, 1.1 equiv; [CAS RN 865-47-4]) in toluene (20 mL) were heated to reflux. After 1 h, 4-oxo-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (1.21 g, 4.89 mmol, 1.0 equiv; [CAS RN 179898-00-1]), dissolved in toluene (10 mL), was added and heating continued for one additional hour. The reaction mixture was extraction from a sat. solution of NH4Cl (100 mL) with ethyl acetate (3×50 mL) and the combined organic phases dried over MgSO4. Purification by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate afforded 0.87 g (73%) of the title compound as a colorless oil. MS (ISP): 246.4 [M+H]+.
Reaction SMILES: CNN.[CH3:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]([CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:12](=[O:25])[CH2:13][N:14]1[C:18](=[O:19])C2=CC=CC=C2C1=O.O.[CH3:35][C:36]1[CH:37]=[C:38]([N:42]=C=O)[CH:39]=[CH:40][CH:41]=1>ClCCl.O1CCCC1>[CH3:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]([CH2:26][C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[C:12](=[O:25])[CH2:13][NH:14][C:18]([NH:42][C:38]1[CH:39]=[CH:40][CH:41]=[C:36]([CH3:35])[CH:37]=1)=[O:19]
Reactant: Cc1ccccc1N(CC(=O)OC(C)(C)C)C(=O)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1cccc(N=C=O)c1
Agent: CNN
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2ccccc2C)c1
Temperature: 20 °C
Reaction time: 30 h
Yield: 19.2 %

Procedure:
Methyl hydrazine (2.13 g) is added at a temperature in the region of 0° C. to a solution of tert-butyl 2-[N-(2-methylphenyl)-2-phthalimidoacetamido]acetate (5.5 g) in dichloromethane (90 cc). The reaction mixture is stirred for 30 hours at a temperature in the region of 20° C. and then for 1 hour under reflux. After cooling, water (100 cc) is added, the mixture is stirred and the aqueous phase is separated after settling has taken place and re-extracted with dichloromethane (2×60 cc). The organic phases are combined, washed with water (2×15 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. tert-Butyl 2-[2-amino-N-(2-methylphenyl)acetamido]acetate is thereby obtained in the form of an oil, which is dissolved in anhydrous tetrahydrofuran (40 cc). 3-Methylphenyl isocyanate (1.77 g) is added to this solution and the reaction mixture is then stirred for 1 hour at a temperature in the region of 20° C. and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallisation in petroleum ether, tert-butyl 2-{N-(2-methylphenyl)-2-[3-(3-methylphenyl)ureido]acetamido}acetate (1.05 g), m.p. 133° C., is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][O:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:25](I)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CN(C=O)C>[CH2:25]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][O:9]2)=[CH:6][CH:7]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCC1CCC(c2ccc(O)cc2)OC1
Reactant: CCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCOc1ccc(C2CCC(CCCCC)CO2)cc1
Reaction time: 16 h

Procedure:
A mixture of 24.8 g of 2-p-hydroxyphenyl-5-pentyltetrahydropyran (obtainable by diazotization of 2-p-aminophenyl-5-pentyltetrahydropyran and hydrolysis), 6.9 g of K2CO3, 25 g of hexyl iodide and 250 ml of DMF is heated, with stirring, at 80° for 16 hours, then cooled and worked up as usual. 2-p-Hexoxyphenyl-5-pentyltetrahydropyran is obtained.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:21][CH2:20][N:19]([C:22](=[O:33])[CH2:23][NH:24][C:25]([CH2:27][C@H:28]4[CH2:30][C:29]4([CH3:32])[CH3:31])=[O:26])[CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1>C(O)C.[H][H].[C].[Pd]>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:17][CH2:18][N:19]([C:22](=[O:33])[CH2:23][NH:24][C:25]([CH2:27][C@H:28]4[CH2:30][C:29]4([CH3:31])[CH3:32])=[O:26])[CH2:20][CH2:21]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC1(C)C[C@@H]1CC(=O)NCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC1(C)C[C@@H]1CC(=O)NCC(=O)N1CCC(=C2c3ccccc3CCc3ccccc32)CC1

Procedure:
72.8 mg of palladium carbon (10% w/v) was added to 72.8 mg (0.171 mmol) of (1R)—N-{2-[4-(5H-dibenzo[a,d][7]annulen-5-ylidene)-1-piperidinyl]-2-oxoethyl}-2,2-dimethylcyclopropanecarboxyamide in 10 ml of ethanol, and they were stirred at 4.0 MPa in hydrogen gas atmosphere overnight. After the filtration, the solvent was evaporated under reduced pressure to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[S:3]([C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([N+:13]([O-])=O)[C:7]=1[OH:16])(=[O:5])=[O:4]>C(OCC)(=O)C.[Pd]>[CH3:1][N:2]([CH3:17])[S:3]([C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([NH2:13])[C:7]=1[OH:16])(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(N)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.7 %

Procedure:
To a solution of N,N-Dimethyl-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (550 mg, 1.96 mmol) in ethyl acetate, was added 10% Pd/C (550 mg). The mixture was flushed with argon, and then stirred under a hydrogen atmosphere at balloon pressure for 3 hours at room temperature. TLC showed the reaction was not complete. The mixture was filtered through celite and the celite was washed with methanol. The mixture was retreated under the same conditions as mentioned above. After 3 hours, the solvent was evaporated to give the desired product (480 mg, 98%). EI-MS (m/z) 250.82, 252.87 (M+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[N:5]=[C:4]([NH:15][CH2:16][CH2:17][OH:18])[N:3]=1.Cl.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH2:28][CH2:29][NH:30][CH2:31][CH:32]=2)=[CH:23][CH:22]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH:12]1([CH2:11][NH:10][C:6]2[C:7]([C:8]#[N:9])=[C:2]([N:30]3[CH2:29][CH:28]=[C:27]([C:24]4[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=4)[CH2:32][CH2:31]3)[N:3]=[C:4]([NH:15][CH2:16][CH2:17][OH:18])[N:5]=2)[CH2:14][CH2:13]1
Reactant: Fc1ccc(C2=CCNCC2)cc1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCC1CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(NCC2CC2)nc(NCCO)nc1N1CC=C(c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-6-(cyclopropylmethyl-amino)-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile (example 41b) was treated with 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride in dioxane in the presence of N-ethyl-diisopropylamine at 90° C. to yield 4-(cyclopropylmethyl-amino)-6-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=409.
Reaction SMILES: C([Li])CCC.[C:6]([C:8]1[CH:19]=[CH:18][C:11]([CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:10][CH:9]=1)#[CH:7].[C:20](=[O:22])=[O:21].Cl>CCCCCC.C1COCC1>[N:13]1([CH2:12][C:11]2[CH:18]=[CH:19][C:8]([C:6]#[C:7][C:20]([OH:22])=[O:21])=[CH:9][CH:10]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C=O
Reactant: C#Cc1ccc(CN2CCCC2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)C#Cc1ccc(CN2CCCC2)cc1
Reaction time: 1 h

Procedure:
5.98 mL (14.85 mmol) of a 1.6M butyllithium solution in n-hexane is added dropwise to a solution of 2.3 g (12.41 mmol) of 1-(4-ethynylbenzyl)pyrrolidine in 50 mL of THF at −78° C. and stirred for 1 hour at this temperature. Then dry ice is added to the reaction mixture. Then the reaction mixture is allowed to come up to ambient temperature and stirred for 14 hours. The reaction mixture is combined with dilute hydrochloric acid and extracted with dichloromethane. The organic phase is separated off and dried over sodium sulfate. The sodium sulfate is separated off and the solvent is removed. Yield: 0.3 g (10.5% of theory); C14H15NO2 (M=229.28); calc.: molecular ion peak (M+H)+: 230; found: molecular ion peak (M+H)+: 230; Rf value: 0.15 (silica gel, dichloromethane/methanol/ammonia (9:1:0.1)).
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH:7][CH2:8][CH3:9])=[CH:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1.N1C=CC=CC=1.[F:22][C:23]([F:33])([F:32])[CH2:24][CH2:25][S:26][CH2:27][CH2:28][C:29](Cl)=[O:30].O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[C:6]([N:7]([CH2:8][CH3:9])[C:29](=[O:30])[CH2:28][CH2:27][S:26][CH2:25][CH2:24][C:23]([F:33])([F:32])[F:22])=[CH:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1
Reactant: O=C(Cl)CCSCCC(F)(F)F
Reactant: CCNc1cn(-c2cccnc2)nc1Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN(C(=O)CCSCCC(F)(F)F)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a solution of 3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine (prepared as described in the U.S. Publication No. 2012/0110702 to Yap et al.) (10.0 g, 44.9 mmol) in CH2Cl2 (100 mL), at a temperature of about 0° C. and under N2, was added pyridine (5.45 mL, 67.4 mmol), 4-dimethylaminopyridine (DMAP) (2.74 g, 22.45 mmol), and 3-((3,3,3-trifluoropropyl)thio)propanoyl chloride (9.91 g, 44.9 mmol), sequentially. The reaction was warmed to room temperature and stirred for one hour. The reaction mixture was poured into water (100 mL), and the resulting mixture was stirred for five minutes. The mixture was transferred to a separatory funnel, and the layers were separated. The aqueous phase was extracted with CH2Cl2 (3×50 mL), and the combined organic extracts were dried over sodium sulfate (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified via normal phase flash chromatography (0% to 100% EtOAc/CH2Cl2) to provide the desired product as a pale yellow solid (17.21 g, 89%): IR (thin film) 1659 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.95 (d, J=2.6 Hz, 1H), 8.63 (dd, J=4.7, 1.3 Hz, 1H), 8.05 (ddd, J=8.3, 2.7, 1.4 Hz, 1H), 7.96 (s, 1H), 7.47 (dd, J=8.3, 4.8 Hz, 1H), 3.72 (q, J=7.1 Hz, 2H), 2.84 (t, J=7.2 Hz, 2H), 2.66 (m, 2H), 237 (t, J=7.2 Hz, 2H), 2.44 (m, 2H), 1.17 (t, J=7.2 Hz, 3H); ESIMS m/z 409 ([M+2H]+).
Reaction SMILES: [NH2:1][C:2]([CH3:14])([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][OH:4].[N+:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=O)=[CH:20][CH:19]=1)([O-:17])=[O:16]>C1(C)C(C)=CC=CC=1>[CH2:7]([O:6][CH2:5][C:2]1([CH3:14])[CH2:3][O:4][C:22]([C:21]2[CH:25]=[CH:26][C:18]([N+:15]([O-:17])=[O:16])=[CH:19][CH:20]=2)=[N:1]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(N)(CO)COCc1ccccc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1C
Product: CC1(COCc2ccccc2)COC(c2ccc([N+](=O)[O-])cc2)=N1
Reaction time: 15 h

Procedure:
2-Amino-3-benzyloxy-2-methylpropanol (13.5 grams) and 4-nitrobenzoic acid (11.7 grams) in dry xylene (100 milliliters) were heated together under reflux for 24 hours using a Dean-Stark trap for collection of the water formed during the reaction. The cooled solution was evaporated to dryness under reduced pressure and the residue was treated with ether and allowed to stand for 15 hours at 0°C. The yellow solid formed was recrystallized from ethanol to yield the desired product, melting point 65°-66°C.