Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(C)(C)C.[C:7]([NH:26][C@H:27]([C@H:33]([OH:49])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:28](OCC)=[O:29])(=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[BH4-].[Na+]>O>[C:7]([NH:26][C@H:27]([C@H:33]([OH:49])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH2:28][OH:29])(=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCCCCCCC(=O)N[C@@H](C(=O)OCC)[C@H](O)CCCCCCCCCCCCCCC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Product: CCCCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)CCCCCCCCCCCCCCC
Temperature: 23 °C
Reaction time: 48 h
Yield: 95.3 %

Procedure:
A t-butyl methyl ether suspension (2 mL) containing ethyl (2R,3R)-2-octadecanoylamino-3-hydroxyoctadecanoate (100 mg. 0.16 mmol) synthesized in the same method as Example 17 and sodium borohydride (20.3 mg, 0.54 mmol) was stirred at 23° C. for 48 hours. After water (5 mL) was added thereto, the reaction mixture was separated at 40° C. to separate the organic layer. It was confirmed by comparative analysis of the obtained organic layer with sample product using HPLC that the organic layer contained 86.6 mg of the title compound (yield: 93%). HPLC analysis was carried out to find that anti-form:syn-form was 93:7 and the optical purity of the anti-form was 100% ee.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.C(N(CC)CC)C.Cl.[F:15][C:16]([F:50])([F:49])[C:17]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[N:20]=[C:19]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([C:39]3[CH:40]=[C:41]([S:45](Cl)(=[O:47])=[O:46])[CH:42]=[CH:43][CH:44]=3)[CH:34]=2)[N:18]=1>C1COCC1>[F:50][C:16]([F:15])([F:49])[C:17]1[CH:22]=[C:21]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=2)[N:20]=[C:19]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([C:39]3[CH:40]=[C:41]([S:45]([N:1]4[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]4)(=[O:47])=[O:46])[CH:42]=[CH:43][CH:44]=3)[CH:34]=2)[N:18]=1
Reactant: OC1CCNC1
Reactant: O=S(=O)(Cl)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1)N1CCC(O)C1
Temperature: 0 °C
Yield: 82.4 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of (RS)-3-pyrrolidinol (0.27 g, 3.0 mmol), triethylamine (0.29 ml, 2.1 mmol) and THF (4 ml) was added drop wise a solution of 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonyl chloride hydrochloride (example I.1) (0.58 g, 1.0 mmol) in THF (6 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (dichloromethane/MeOH/hexane) yielded the title compound as a white solid (0.49 g, 88%). MS (ISP) 594.6 [(M+H)+]; mp 234° C.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:10]=[C:11]([C:15]3[N:20]=[CH:19][C:18]([C:21]([O:23]CC)=[O:22])=[CH:17][N:16]=3)[CH:12]=[CH:13][CH:14]=2)[N:6]=[C:5]([C:26]2[CH:31]=[C:30]([F:32])[C:29]([F:33])=[C:28]([F:34])[CH:27]=2)[CH:4]=[CH:3]1.[OH-].[Li+]>C1COCC1.O>[O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:10]=[C:11]([C:15]3[N:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][N:16]=3)[CH:12]=[CH:13][CH:14]=2)[N:6]=[C:5]([C:26]2[CH:27]=[C:28]([F:34])[C:29]([F:33])=[C:30]([F:32])[CH:31]=2)[CH:4]=[CH:3]1
Reactant: CCOC(=O)c1cnc(-c2cccc(Cn3nc(-c4cc(F)c(F)c(F)c4)ccc3=O)c2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc(-c2cccc(Cn3nc(-c4cc(F)c(F)c(F)c4)ccc3=O)c2)nc1
Temperature: 25 °C

Procedure:
3.4 g (7.29 mmol) of ethyl 2-{3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]phenyl}pyrimidine-5-carboxylate are dissolved in 300 ml of THF and 30 ml of water, and 713 mg (29.2 mmol) of lithium hydroxide are added. The reaction mixture is refluxed for 4 h and cooled to room temperature, and the organic solvent is removed by distillation in a rotary evaporator. 300 ml of water and 30 ml of THF are added to the residue, and conc. HCl is slowly added dropwise to this solution with stirring until the reaction is strongly acidic. The precipitate formed is filtered off with suction, washed with copious water and dried in a vacuum drying cabinet.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:17])[NH:10][CH2:11][C@H:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[C:23]([C@H:30]3[CH2:32][O:31]3)[CH:24]=[CH:25][N:26]=2)[N:21]=1>CN(C=O)C>[C:1]1([CH2:7][O:8][C:9](=[O:17])[NH:10][CH2:11][C@@H:12]2[CH2:16][CH2:15][N:14]([CH2:32][C@@H:30]([OH:31])[C:23]3[C:22]4[C:27](=[CH:28][CH:29]=[C:20]([O:19][CH3:18])[N:21]=4)[N:26]=[CH:25][CH:24]=3)[CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc2nccc([C@H]3CO3)c2n1
Reactant: O=C(NC[C@H]1CCNC1)OCc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc2nccc([C@H](O)CN3CC[C@@H](CNC(=O)OCc4ccccc4)C3)c2n1
Reaction time: 24 h
Yield: 24.4 %

Procedure:
To a solution of phenylmethyl[(3S)-3-pyrrolidinylmethyl]carbamate (0.53 g, 2.27 mmole) and LiClO4 (0.24 g, 2.27 mmole) in DMF (1 mL) was added 2-(methyloxy)-8-[(2S)-2-oxiranyl]-1,5-naphthyridine (0.45 g, 2.25 mmole). After 24 h at 80° C., the reaction contents were purified on silica gel (CHCl3/MeOH, 9:1, containing 5% NH4OH) to afford the title compound (0.24 g, 25%) as a light yellow oil: LC-MS (ES) m/e 437 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][CH3:13])=[CH:7][CH:6]=1)[CH3:2].C(N(CC)CC)C.[C:24](Cl)(=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[CH2:15]([O:14][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH3:13])[C:24](=[O:33])[O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:7][CH:6]=1)[CH3:16]
Reactant: CCOC(OCC)c1ccc(CNC)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(OCC)c1ccc(CN(C)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
To a stirred solution of 1-(4-(diethoxymethyl)phenyl)-N-methylmethanamine (1.1 g, 4.9 mmol) and triethylamine (0.75 g, 7.35 mmol) in anhydrous dichloromethane (10 mL) was added benzyl carbonochloridate (1.0 g, 5.88 mmol) at 0° C. After the addition, the mixture was allowed to stir at room temperature overnight. The mixture was diluted with dichloromethane (50 mL), washed with water (50 mL×3), brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give crude product which was purified by chromatography (silica gel, petroleum ether/ethyl acetate=100:1 to 20:1) to give benzyl 4-(diethoxymethyl)benzyl(methyl)carbamate (1.0 g, yield 57% for two steps) as a light yellow oil. 1H-NMR (400 MHz, CDCl3) δ: 3.82 (s, br 1H), 5.19 (s, 3H), 6.91-6.95 (m, 1H), 7.32-7.36 (m, 2H); LC-MS (ESI) m/z: 358 (M+1)+.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH:4]=[C:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7][CH2:6]1.C(=O)(O)[O-].[Na+].[ClH:26]>[Pd].CCOCC>[ClH:26].[ClH:26].[CH3:20][N:2]([CH3:1])[CH2:3][CH2:4][CH:5]1[CH2:6][CH2:7][N:8]([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:9][CH2:10]1
Reactant: CN(C)CC=C1CCN(CCOc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOCC
Product: CN(C)CCC1CCN(CCOc2ccccc2)CC1

Procedure:
A mixture of 4-(2-dimethylaminoethylidene)-1-(2-phenoxyethyl)piperidine (2.0 g) (The product of Example 37 was treated with aqueous sodium bicarbonate solution and ether. The ether was separated, washed, dried and evaporated to give the free base.) in IMS (200 ml) and a catalytic amount of 10% palladium on charcoal was hydrogenated at atmospheric pressure for 5 hours. The catalyst was removed by filtration. The filtrate was evaporated to give an oil which was dissolved in ether and then acidified with ethereal hydrogen chloride. The precipitate was collected by filtration and recrystallised from IMS to give 4-(2-dimethylamino-ethyl)-1-(2-phenoxyethyl)piperidine dihydrochloride, m.p. 286°-288° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[O:28]([CH2:35][C:36](Cl)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:15][C:14]=2[CH2:23][N:24]([CH2:25][CH3:26])[C:36](=[O:37])[CH2:35][O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: O=C(Cl)COc1ccccc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(=O)COc1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and phenoxyacetyl chloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=1B(O)O>>[F:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Product: COc1ccc(F)c(-c2ccncc2N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1

Procedure:
The title compound was prepared in analogy to example 58, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 2-fluoro-5-methoxy-phenylboronic acid (CAS RN 406482-19-7) and using preparative HPLC for the chromatographic purification. Off-white solid (45%). MS (ESI): m/z=473.2 [M+H]+.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:8]=[C:7]([O:17][CH3:18])[C:6]=12.[C-:19]#[N:20].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Cu]I.C(#N)C>[CH3:18][O:17][C:7]1[C:6]2[N:5]([N:4]=[CH:3][C:2]=2[C:19]#[N:20])[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=1
Reactant: [C-]#N
Reactant: COc1cc(-c2ccccc2)cn2ncc(I)c12
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC#N
Product: COc1cc(-c2ccccc2)cn2ncc(C#N)c12
Temperature: 65 °C
Reaction time: 16 h

Procedure:
3-iodo-4-methoxy-6-phenylpyrazolo[1,5-a]pyridine (25.0 mg, 0.071 mmol), sodium cyanide (7.0 mg, 0.14 mmol), tetrakis(triphenylphosphine)palladium (0) (4.1 mg, 0.004 mmol), and copper (I) iodide (1.4 mg, 0.007 mmol) were added to a dry flask. Acetonitrile (2 ml) was added and the mixture was sparged with argon for 3 minutes, then heated to 65° C. After 16 h, the reaction mixture cooled and purified by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water+0.05% TFA to give 4-methoxy-6-phenylpyrazolo[1,5-a]pyridine-3-carbonitrile. 1H NMR (600 MHz, DMSO-d6) δ 8.66 (d, 1H); 8.58 (s, 1H); 7.82 (d, 2H); 7.49 (d, 2H); 7.41 (m, 1H); 7.31 (s, 1H); 4.08 (s, 3H). LRMS (ESI) calculated for C15H12N3O [M+H]+, 250.1; found 250.0.
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]2[O:7][C:8]([CH3:19])([CH3:18])[C@@H:9]([OH:17])[C@H:10]([N:11]3[CH2:15][CH2:14][CH2:13][CH:12]3[OH:16])[C:5]=2[CH:4]=1)#[N:2].I([O-])(=O)(=O)=O.[Na+].C(Cl)(Cl)Cl.CO.CCCCCCC.C(OCC)(=O)C.C(N(CC)CC)C>O.CO>[C:1]([C:3]1[CH:21]=[CH:20][C:6]2[O:7][C:8]([CH3:19])([CH3:18])[C@@H:9]([OH:17])[C@H:10]([N:11]3[CH2:15][CH2:14][CH2:13][C:12]3=[O:16])[C:5]=2[CH:4]=1)#[N:2]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CCCC2O)[C@@H]1O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCCCCCC
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CCCC2=O)[C@@H]1O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
6-Cyano-3,4-dihyro-2,2-dimethyl-trans-4-(2-hydroxy-1-pyrrolidinyl)-2H-benzo[b]pyran-3-ol (5 mg), dissolved in methanol water (1 ml) was treated with an excess of sodium periodate with stirring during 15 hours at room temperature. Evaporation of solvents and extraction by ethyl acetate gave material having identical thin layer characteristics when applied to silica gel plates developed in either chloroform-methanol (15:1) or heptane-ethyl acetate-triethylamine and infra red spectrum to the title compound reported in Example 1 of U.S. Pat. No. 4,446,113.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH2:24]([C:28]1[CH2:32][C:31](=[O:33])[NH:30][N:29]=1)[CH:25]([CH3:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.C(OCC)(=O)C.O>[CH2:24]([C:28]1[NH:29][N:30]=[C:31]([O:33][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:32]=1)[CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)CC1=NNC(=O)C1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(CC(C)C)[nH]n3)ncnc2cc1OCCCN1CCOCC1
Temperature: 100 °C
Yield: 0 %

Procedure:
A suspension of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (150 mg, 0.44 mol), (prepared as described for the starting material in Example 2), and 3-isobutyl-4,5-dihydro-1H-pyrazol-5-one (75 mg, 0.53 mol), (Org. Synth. 1976, 55, 73), in DMF (2 ml) containing potassium carbonate (92 mg, 0.67 mol) was heated at 100° C. for 2.5 hours. After cooling, water was added and the aqueous layer was adjusted to pH6.5 with 2M hydrochloric acid. Ethyl acetate was added. The organic layer was separated, washed with water, brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was purified by column chromatography eluting the ethyl acetate/methylene chloride (1/1) followed by methanol/ethyl acetate/methylene chloride (1/4/5) and by methanol/methylene chloride (1/9) to give 4-(5-isobutylpyrazol-3-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline (85 mg, 43%).
Reaction SMILES: Cl.[OH:2][C@H:3]1[CH2:7][NH:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4]1.I[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[CH2:24]([N:6]1[CH2:7][C@H:3]([OH:2])[CH2:4][C@H:5]1[C:8]([O:10][CH3:11])=[O:9])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13]
Reactant: CCCCCCCCCCCCI
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCCCCCCCCN1C[C@H](O)C[C@H]1C(=O)OC
Temperature: 25 °C
Yield: 53.9 %

Procedure:
A solution of trans-4-hydroxy-L-proline, methyl ester, hydrochloride (4.0 g, 22.02 mmol) and 1-iodododecane (3.04 g, 44.04 mmol) in methanol (30 ml) was treated with potassium carbonate. The mixture was stirred and refluxed for 7 h, cooled to r.t., diluted with ethyl acetate (700 ml), washed with water (400 ml), brine (200 ml), dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (petroleum ether/ethyl acetate 60:40 to 40:60) to afford the title compound (3.72 g, 54%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:25]=[C:26]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([F:36])[CH:29]=1)[CH3:27]>CN(C=O)C.[Cu]I>[F:36][C:30]1[CH:29]=[C:28](/[C:26](/[CH3:27])=[CH:25]/[N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)[CH:33]=[CH:32][C:31]=1[O:34][CH3:35]
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: COc1ccc(C(C)=CBr)cc1F
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(/C(C)=C/n2c3c(c4cc(C)ccc42)CN(C)CC3)cc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (68 mg, 0.34 mmol) was dissolved in DMF (3 mL). Copper (I) iodide (6.5 mg, 0.034 mmol) L-proline (7.8 mg, 0.068 mmol) and potassium phosphate (144 mg, 0.68 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 4-(1-Bromoprop-1-en-2-yl)-2-fluoro-1-methoxybenzene (100 mg, 0.408 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 80° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). 1H NMR (CD3OD, HCl salt) δ (ppm): 7.42 (m, 2H), 7.30 (s, 1H), 7.18 (d, 1H), 7.10 (m, 2H), 7.0 (s, 1H), 4.75 (m, 1H), 4.40 (m, 1H), 3.95 (s, 3H), 3.85 (m, 1H), 3.60 (m, 1H), 3.20 (m, 2H), 3.10 (s, 3H), 2.42 (s, 3H), 1.90 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:12])[CH2:9][C:10]#[N:11].S(=O)(=O)(O)[OH:14]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:12])[CH2:9][C:10]([NH2:11])=[O:14]
Reactant: N#CCC(=O)c1ccccc1Cl
Reactant: O=S(=O)(O)O
Product: NC(=O)CC(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 17.0 g (94.65 mmole) of 3-(2-chloro-phenyl)-3-oxo-propionitrile and 50 mL of sulfuric acid was stirred at room temperature for 18 hours. The mixture was poured into ice-water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium carbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexanes (gradient 20:80-70:30) to give 14.12 g of 3-(2-chloro-phenyl)-3-oxo-propionamide.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].NC(C(O)=O)CCC.[CH3:18][CH2:19][CH:20]1[O:37][C:35](=[O:36])[CH2:34][CH:33]([O:38]C(C)=O)[CH:32]([CH3:42])[CH:31]([O:43][CH:44]2[O:49][CH:48]([CH3:50])[CH:47]([O:51][CH:52]3[O:57][CH:56]([CH3:58])[CH:55]([OH:59])[C:54]([OH:61])([CH3:60])[CH2:53]3)[CH:46]([N:62]([CH3:64])[CH3:63])[CH:45]2[OH:65])[CH:30]([CH2:66][CH:67]=[O:68])[CH2:29][CH:28]([CH3:69])[C:26](=[O:27])[CH:25]=[CH:24][C:23]([CH3:70])=[CH:22][CH:21]1[CH2:71][O:72][CH:73]1[O:78][CH:77]([CH3:79])[CH:76]([OH:80])[CH:75]([O:81][CH3:82])[CH:74]1[O:83][CH3:84]>>[CH3:18][CH2:19][C@H:20]1[O:37][C:35](=[O:36])[CH2:34][C@@H:33]([OH:38])[C@H:32]([CH3:42])[C@@H:31]([O:43][C@@H:44]2[O:49][C@H:48]([CH3:50])[C@@H:47]([O:51][C@@H:52]3[O:57][C@@H:56]([CH3:58])[C@H:55]([OH:59])[C@@:54]([OH:61])([CH3:60])[CH2:53]3)[C@H:46]([N:62]([CH3:64])[CH3:63])[C@H:45]2[OH:65])[C@@H:30]([CH2:66][CH:67]=[O:68])[CH2:29][C@@H:28]([CH3:69])[C:26](=[O:27])[CH:25]=[CH:24][C:23]([CH3:70])=[CH:22][C@@H:21]1[CH2:71][O:72][C@@H:73]1[O:78][C@H:77]([CH3:79])[C@@H:76]([OH:80])[C@@H:75]([O:81][CH3:82])[C@H:74]1[O:83][CH3:84].[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CCC1OC(=O)CC(OC(C)=O)C(C)C(OC2OC(C)C(OC3CC(C)(O)C(O)C(C)O3)C(N(C)C)C2O)C(CC=O)CC(C)C(=O)C=CC(C)=CC1COC1OC(C)C(O)C(OC)C1OC
Agent: CC(C)C[C@H](N)C(=O)O
Agent: CCC1OC(=O)CC(OC(C)=O)C(C)C(OC2OC(C)C(OC3CC(C)(O)C(O)C(C)O3)C(N(C)C)C2O)C(CC=O)CC(C)C(=O)/C=C/C(C)=C/C1COC1OC(C)C(O)C(OC)C1OC
Agent: CCCC(N)C(=O)O
Product: CC[C@H]1OC(=O)C[C@@H](O)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)[C@@H](O[C@H]3C[C@@](C)(O)[C@@H](O)[C@H](C)O3)[C@H](N(C)C)[C@H]2O)[C@@H](CC=O)C[C@@H](C)C(=O)C=CC(C)=C[C@@H]1CO[C@@H]1O[C@H](C)[C@@H](O)[C@@H](OC)[C@H]1OC

Procedure:
A similar cultivation and reaction as in Example 1 was carried out by substituting L-leucine as the isovaleryl donor for DL-norvaline. From 60 g of tylosin and 15 g of L-leucine, about 900 mg of white crystals of 4"-isovaleryltylosin and 17 g of white crystals of 3-acetyltylosin were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][S:9]2(=[O:14])=[O:13])[CH:5]=[CH:4][C:3]=1[C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][N:24]=2)[CH2:19][CH2:18]1)=[O:16].[C:31](Cl)(=[O:33])[CH3:32]>>[CH3:29][C:28]1[C:23]([N:20]2[CH2:19][CH2:18][N:17]([C:15]([C:3]3[CH:4]=[CH:5][C:6]([N:8]4[CH2:12][CH2:11][CH2:10][S:9]4(=[O:13])=[O:14])=[CH:7][C:2]=3[NH:1][C:31](=[O:33])[CH3:32])=[O:16])[CH2:22][CH2:21]2)=[N:24][CH:25]=[C:26]([CH3:30])[CH:27]=1
Reactant: CC(=O)Cl
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3N)CC2)c(C)c1
Product: CC(=O)Nc1cc(N2CCCS2(=O)=O)ccc1C(=O)N1CCN(c2ncc(C)cc2C)CC1

Procedure:
Using [2-amino-4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl][4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (300 mg) described in Example 136 and acetyl chloride (0.07 mL) and by the reaction and treatment in the same manner as in Example 107, the title compound (279 mg) was obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:10]=[CH:11][N:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:38]=[C:24]4[CH:25]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)[CH2:26][C:27](=[CH2:30])[CH2:28][CH2:29][N:23]4[N:22]=3)=[CH:16][C:15]=2[O:39][CH3:40])[CH:13]=1>C(O)C.[Pt]>[Cl:8][C:9]1[N:10]=[CH:11][N:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:38]=[C:24]4[CH:25]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)[CH2:26][CH:27]([CH3:30])[CH2:28][CH2:29][N:23]4[N:22]=3)=[CH:16][C:15]=2[O:39][CH3:40])[CH:13]=1
Reactant: C=C1CCn2nc(Nc3ccc(-n4cnc(Cl)c4)c(OC)c3)nc2C(c2ccc(F)cc2)C1
Agent: [Pt]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Nc2nc3n(n2)CCC(C)CC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-9-(4-fluorophenyl)-7-methylene-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine (65 mg, 0.140 mmol, from example 133) was dissolved in ethanol (5 mL), flushed with nitrogen, and chilled to 0° C. Platinum on sulfided carbon (136 mg, 0.140 mmol) was added and the flask was repeated evacuated and flushed with hydrogen gas (balloon). The reaction mixture was stirred under an atmosphere of hydrogen gas at rt for 16 h. The reaction mixture was purged with nitrogen, filtered over celite. The celite was washed with methanol and the combined filtrates were concentrated in vacuo. The crude product was purified using reverse phase preparatory HPLC (AcCN/water/ammonium acetate) to afford the titled compound as a mixture of diasteromers (51.6 mg, 74% yield). LC-MS (M+H)+ 467.2. 1H NMR (500 MHz, CHLOROFORM-d, mixture of diastereomers) δ ppm 7.53 (1 H, dd, J=16.2, 1.5 Hz), 7.41 (1 H, t, J=2.1 Hz), 7.29-7.34 (1 H, m), 6.95-7.16 (5 H, m), 6.71-6.79 (1 H, m), 4.62 (1 H, br. s.), 3.96-4.16 (1 H, m), 3.73-3.88 (3 H, m), 2.00-2.10 (2 H, m), 1.91 (1 H, dd, J=14.2, 6.6 Hz), 1.71-1.85 (1 H, m), 1.50-1.68 (2 H, m), 1.09 (3 H, dd, J=16.9, 6.6 Hz).