Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][N:13]3[C:21]4[C:20](=[O:22])[N:19]([CH3:23])[C:18](=[O:24])[N:17]([CH3:25])[C:16]=4[N:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][N:3]=1.[N:30]1([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>N1C=CC=CC=1.O>[CH3:23][N:19]1[C:20](=[O:22])[C:21]2[N:13]([CH2:12][C:11]3[CH:26]=[CH:27][C:8]([C:6](=[O:7])[C:5]4[CH:28]=[CH:29][C:2]([N:39]5[CH2:40][CH2:41][CH:36]([N:30]6[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]6)[CH2:37][CH2:38]5)=[N:3][CH:4]=4)=[CH:9][CH:10]=3)[CH:14]=[N:15][C:16]=2[N:17]([CH3:25])[C:18]1=[O:24]
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: Cn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(Cl)nc3)cc2)n(C)c1=O
Solvent: c1ccncc1
Solvent: O
Product: Cn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(N4CCC(N5CCCCC5)CC4)nc3)cc2)n(C)c1=O
Yield: 41.7 %

Procedure:
A solution of 7-[4-(6-chloronicotinoyl)benzyl]-1,3-dimethylxanthine (196 mg) and 4-piperidinopiperidine (102 mg) in pyridine (10 ml) was stirred at 60° C. for 5 hours. This reaction mixture was poured in water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: acetone: triethylamine 1:1:0.1) to provide the title compound (108 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(O)(C)C.Cl>[Fe].O>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=2)=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: Nc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Yield: 80.6 %

Procedure:
A mixture of 3-chloro-5-trifluoromethyl-2-(4-nitrophenoxy)pyridine (1.0 g), iron powder (3.2 g), isopropyl alcohol (60 ml), water (6 ml) and dilute hydrochloric acid (0.2 ml of a 2N solution), were heated at the reflux temperature for 12 hours. After cooling and filtering to remove the solid matter, the filtrate was concentrated by evaporation of the volatile portion under reduced pressure. The residual solid was recrystallised from n-hexane to yield 2-(4-aminophenoxy)-3-chloro-5-trifluoromethylpyridine (0.73 g) m.p. 85°-87° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([Cl:12])[N:3]=1.NC1C=CC=CN=1.[CH3:20][O:21][Na]>CO>[Cl:12][C:4]1[N:3]=[C:2]([O:21][CH3:20])[C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: CO[Na]
Reactant: Clc1cc2ccccc2c(Cl)n1
Agent: Nc1ccccn1
Solvent: CO
Product: COc1nc(Cl)cc2ccccc12
Temperature: 125 °C

Procedure:
Into a sealed tube were added 1,3-dichloroisoquinoline (501 mg, 2.45 mmol), 2-aminopyridine (31 mg, 0.33 mmol), cuprous monochloride (37.2 mg, 0.162 mmol), MeONa (824 mg, 5.92 mmol), MeOH (3 ml) and diglyne (8 ml). The tube was sealed, evacuated and filled with N2 three times. The combined mixture was heated at 125° C. for 3 days under an atmosphere of nitrogen. After that time, the mixture was treated with water (20 ml) and extracted with EtOAc (3×50 ml). The organic extracts were washed with water (3×30 ml), brine (30 ml), dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as light-yellow solid. 1H NMR (400 MHz, CDCl3): δ=4.15 (s, 3H), 7.26 (d, J=0.6 Hz, 1H), 7.51 (ddd, J=3.6, 4.6, 8.2 Hz, 1H), 7.64-7.69 (m, 2H), 8.20 (dd, J=8.4, 1.2 Hz, 1H). MS(ES+): m/z=194.08/196.01 (80/28) [MH+]. HPLC: tR=4.00 min (polar—5 min, ZQ3).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](S(C)=O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][N:28]1[C:33]2[CH:34]=[C:35]([NH2:38])[CH:36]=[CH:37][C:32]=2[O:31][CH2:30][CH2:29]1>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:38][C:35]4[CH:36]=[CH:37][C:32]5[O:31][CH2:30][CH2:29][N:28]([CH3:27])[C:33]=5[CH:34]=4)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)c1ncc2ccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2n1
Reactant: CN1CCOc2ccc(N)cc21
Product: CN1CCOc2ccc(Nc3ncc4ccc(-c5cccc(S(=O)(=O)NC(C)(C)C)c5)n4n3)cc21
Yield: 33 %

Procedure:
The titled compound was prepared in analogous fashion as Example 113 using N-tert-butyl-3-(2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzene sulfonamide and 4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylamine to give N-tert-butyl-3-[2-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-benzenesulfonamide as a light tan foam (45.5 mg, 33% yield). LCMS (E/I+) 493 (M+H). 1H NMR (CDCl3; 400 MHz) δ 8.71 (s, 1H), 8.59 (s, 1H), 8.43 (d, 1H, J=8.0 Hz), 7.83 (d, 1H, J=8 Hz), 7.54 (t, 1H, J=8 Hz), 7.04 (d, 1H, J=4.8 Hz), 6.88 (m, 2H), 6.82 (m, 2H), 6.66 (s, 1H), 4.64 (s, 1H), 4.3 (t, 2H, J=4.4 Hz), 3.29 (t, 2H, J=4.4 Hz), 2.76 (s, 3H), 1.21 (s, 9H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:27])[CH2:11][CH2:12][N:13]2[CH2:18][CH:17]=[C:16]([S:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[CH:5][CH:4]=1.OO.[C:30]([OH:39])(=[O:38])[CH:31]([CH:33]([C:35]([OH:37])=[O:36])[OH:34])[OH:32]>C(O)(=O)C>[OH:34][CH:33]([CH:31]([OH:32])[C:30]([OH:39])=[O:38])[C:35]([OH:37])=[O:36].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:27])[CH2:11][CH2:12][N:13]2[CH2:14][CH:15]=[C:16]([S:19]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)=[O:32])[CH2:17][CH2:18]2)=[CH:5][CH:4]=1
Reactant: O=C(CCN1CC=C(Sc2ccc(F)cc2)CC1)Cc1ccc(F)cc1
Agent: Cl
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: OO
Solvent: CC(=O)O
Product: O=C(CCN1CC=C(S(=O)c2ccc(F)cc2)CC1)Cc1ccc(F)cc1
Reaction time: 48 h
Yield: 66.2 %

Procedure:
To a solution of 10.0 g of 1-(4-fluorophenyl)-4-{4-[(4-fluorophenyl)thio]-1,2,3,6-tetrahydro-1-pyridinyl}butanone hydrochloride in 75 ml of glacial acetic acid at room temperature is added dropwise a solution of 2.77 g of 30% hydrogen peroxide in 25 ml of acetic acid over 20 minutes. The solution is allowed to stand at room temperature for 48 hours after which the solvent is removed in vacuo. The residue is neutralized with aqueous sodium bicarbonate, and the product is extracted into methylene chloride. The organic extracts is dried over anhydrous sodium sulfate and evaporated to give an orange oil. The oil is treated with methanolic tartaric acid. Crystallization is induced, and the product is collected to yield 9.00 g (66.2%) of white powder, m.p. 151°-154° C. Recrystallization from methanol gives white crystals, m.p. 154°-155° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11](=[CH:12][CH:13]=1)[O:10][CH2:9][C:6]1([CH2:8][CH2:7]1)[C:5]2([NH:19][C:20]([NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[S:21])[C:14]([F:18])([F:17])[CH2:15]O.ClC(N(C)C)=C(C)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]3([C:14]([F:17])([F:18])[CH2:15][S:21][C:20]([NH:22][C:23](=[O:30])[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[N:19]3)[C:6]3([CH2:7][CH2:8]3)[CH2:9][O:10][C:11]2=[CH:12][CH:13]=1
Reactant: O=C(NC(=S)NC1(C(F)(F)CO)c2cc(Br)ccc2OCC12CC2)c1ccccc1
Agent: CC(C)=C(Cl)N(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(NC1=NC2(c3cc(Br)ccc3OCC23CC3)C(F)(F)CS1)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 60.4 %

Procedure:
Under ice cooling, to a solution of N-{[6-bromo-4-(1,1-difluoro-2-hydroxyethyl)-4H-spiro[chromene-3,1′-cyclopropan]-4-yl]carbamothioyl}benzamide (340 mg, 0.684 mmol) in CH2Cl2 (9 mL) was added 1-chloro-N,N,2-trimethylprop-1-en-1-amine (206 mg, 1.54 mmol), and the mixture was stirred for 17 hours at room temperature. Ice was added and the mixture was neutralized by 10% aqueous K2CO3 and extracted with CH2Cl2. The organic layer was washed with brine and dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (EtOAc/hexane=1:99-40:60) to afford N-(6′-bromo-5″,5″-difluoro-5″,6″-dihydrodispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]thiazin]-2″-yl)benzamide (198 mg).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]([NH:21][NH:22][C:23]([NH:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)=O)=[O:20])[CH:17]=4)[NH:12][CH:11]=3)[CH:7]=[N:6][CH:5]=2)[CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O>>[CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]5[O:20][C:23]([NH:25][C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=6)=[N:22][N:21]=5)[CH:17]=4)[NH:12][CH:11]=3)[CH:7]=[N:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=C(NNC(=O)c1ccc2[nH]cc(-c3cncc(C4CC4)n3)c2c1)Nc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc(Nc2nnc(-c3ccc4[nH]cc(-c5cncc(C6CC6)n5)c4c3)o2)cc1
Temperature: 25 °C
Yield: 31.7 %

Procedure:
A brown solution of 2-(3-(6-cyclopropylpyrazin-2-yl)-1H-indole-5-carbonyl)-N-phenylhydrazinecarboxamide (118.5 mg, 0.287 mmol) and phosphorus oxychloride (3.5 mL, 37.56 mmol) was stirred at 100° C. for 13 h. The reaction was cooled to RT, and excess POCl3 was removed in vacuo. The residue was partitioned between EtOAc (80 mL) and saturated aq NaHCO3 (50 mL). The organic layer was separated, washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 10-100% EtOAc/Hex) furnished 5-(3-(6-cyclopropylpyrazin-2-yl)-1H-indol-5-yl)-N-phenyl-1,3,4-oxadiazol-2-amine (36.0 mg, 0.091 mmol, 32%) as a tan solid: MS (ESI, pos. ion) m/z: 395.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.01 (1H, br. s.), 10.53 (1H, s), 9.02 (1H, s), 8.91 (1H, s), 8.37 (1H, d, J=2.7 Hz), 8.36 (1H, s), 7.69-7.74 (1H, m), 7.63 (3H, dd, J=8.5, 1.7 Hz), 7.37 (2H, t, J=7.9 Hz), 7.02 (1H, t, J=7.3 Hz), 2.20-2.30 (1H, m), 1.16-1.21 (2H, m), 1.09-1.15 (2H, m).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9][C:6]2=[N:7][CH:8]=1.[S:19]1[CH:23]=[CH:22][N:21]=[C:20]1[CH2:24]O.C(C=P(CCCC)(CCCC)CCCC)#N>>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:9]([CH2:24][C:20]3[S:19][CH:23]=[CH:22][N:21]=3)[C:6]2=[N:7][CH:8]=1
Reactant: CCOC(=O)c1cc2cc(C(F)(F)F)cnc2[nH]1
Reactant: OCc1nccs1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Product: CCOC(=O)c1cc2cc(C(F)(F)F)cnc2n1Cc1nccs1
Yield: 83.1 %

Procedure:
This compound was prepared according to a process similar to that described in step 5.1. by reacting 390 mg (1.51 mmol) of ethyl 5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (WO2008/107543) with 348 mg (3.02 mmol) of thiazol-2-ylmethanol in the presence of 0.92 g (3.826 mmol) of (cyanomethylene)-tributylphosphorane (CMBP). The reaction mixture is then purified by flash chromatography on a column of silica gel in a mixture of heptane and ethyl acetate to give 446 mg of the expected product in the form of an oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH:24]([O:27][C:28]1[C:29]([O:43][CH3:44])=[N:30][CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=1)([CH3:26])[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:31]=[N:30][C:29]([O:43][CH3:44])=[C:28]([O:27][CH:24]([CH3:25])[CH3:26])[CH:33]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1OC(C)C
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: COc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cc1OC(C)C

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-isopropoxy-2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 93.1.1) to give the title compound as a white solid. (HPLC: tR 2.73 min (Method A); M+H=459 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.96 (s, 1H), 8.11-8.07 (m, 2H), 7.97-7.93 (m, 1H), 7.92-7.90 (m, 1H), 7.53-7.51 (m, 1H), 7.23-7.21 (m, 1H), 4.70 (hp, 2H), 3.89 (s, 3H), 3.89 (s, 3H), 3.58 (s, 3H), 1.98 (s, 3H), 1.36-1.30 (m, 6H))
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH3:22])=[CH:18][N:17]([CH3:23])[C:16]2=[O:24])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[Br:25]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][Br:25])=[CH:18][N:17]([CH3:23])[C:16]2=[O:24])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: Cc1cn(C)c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c1=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)OC(=O)c1cc(-n2c(=O)c(CBr)cn(C)c2=O)c(F)cc1Cl

Procedure:
A solution of 3.5 g of isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-3,5-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate in 100 ml of carbon tetrachloride is heated to reflux temperature while stirring for 1 hour with 1.8 g of N-bromosuccinimide and some dibenzoyl peroxide. The reaction mixture is irradiated with a 150 W bulb. The succinimide is filtered off under suction and the filtrate is evaporated to dryness under reduced pressure. The residue is purified by chromatography on a silica gel column using methylene chloride/ethyl acetate (7:1) as the eluent. There is obtained isopropyl 2-chloro-4-fluoro-5-[5-bromomethyl-3,6-dihydro-3-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, 1H--NMR (CDCl3, 400 MHz) 7.84 ppm. (d, 1H), 7.58 ppm (s, 1H), 7.36 ppm (d, 1H), 5.24 ppm (m, 1H), 4.35 ppm (d, 1H), 4.29 ppm (d, 1H), 3.48 ppm (s, 3H), 1.37 ppm (2d, 6H).
Reaction SMILES: C[C@@H]1[C@@H](C)O[C@]2([O:10][C@@H]3CC=C(C)C[C@@H](C)C=CC=C4CO[C@@H]5[C@H](O)C(C)=C[C@@H](C(O[C@@H](C3)C2)=O)[C@]45O)CC1.[CH3:39][C@@H:40]1[C@@H:75]([CH:76]([CH3:78])[CH3:77])[O:74][C@:43]2([O:48][C@@H:47]3[CH2:49][CH:50]=[C:51]([CH3:73])[CH2:52][C@@H:53]([CH3:72])[CH:54]=[CH:55][CH:56]=[C:57]4[CH2:58][O:59][C@@H:60]5[C@H:65]([OH:66])[C:64]([CH3:67])=[CH:63][C@@H:62]([C:68]([O:70][C@@H:45]([CH2:46]3)[CH2:44]2)=[O:69])[C@:61]45[OH:71])[CH2:42][CH2:41]1.C[C@@H]1[C@@H](C)O[C@]2(O[C@@H]3CC=C(C)[C@H](O)[C@@H](C)C=CC=C4CO[C@@H]5[C@H](O)C(C)=C[C@@H](C(O[C@@H](C3)C2)=O)[C@]45O)CC1>>[CH3:39][C@@H:40]1[C@@H:75]([CH:76]([CH3:78])[CH3:77])[O:74][C@:43]2([O:48][C@@H:47]3[CH2:49][CH:50]=[C:51]([CH3:73])[C@H:52]([OH:10])[C@@H:53]([CH3:72])[CH:54]=[CH:55][CH:56]=[C:57]4[CH2:58][O:59][C@@H:60]5[C@H:65]([OH:66])[C:64]([CH3:67])=[CH:63][C@@H:62]([C:68]([O:70][C@@H:45]([CH2:46]3)[CH2:44]2)=[O:69])[C@:61]45[OH:71])[CH2:42][CH2:41]1
Reactant: CC1=CC[C@@H]2C[C@@H](C[C@]3(CC[C@H](C)[C@@H](C)O3)O2)OC(=O)[C@@H]2C=C(C)[C@@H](O)[C@H]3OCC(=CC=C[C@H](C)C1)[C@]32O
Reactant: CC1=CC[C@@H]2C[C@@H](C[C@]3(CC[C@H](C)[C@@H](C(C)C)O3)O2)OC(=O)[C@@H]2C=C(C)[C@@H](O)[C@H]3OCC(=CC=C[C@H](C)C1)[C@]32O
Agent: CC1=C[C@H]2C(=O)O[C@H]3C[C@@H](C/C=C(/C)[C@H](O)[C@@H](C)/C=C\C=C4\CO[C@H]([C@@H]1O)[C@@]42O)O[C@@]1(CC[C@H](C)[C@@H](C(C)C)O1)C3
Agent: CC1=C[C@H]2C(=O)O[C@H]3C[C@@H](C/C=C(/C)[C@H](O)[C@@H](C)/C=C\C=C4\CO[C@H]([C@@H]1O)[C@@]42O)O[C@@]1(CC[C@H](C)[C@@H](C)O1)C3
Agent: CC1=C[C@H]2C(=O)O[C@H]3C[C@@H](C/C=C(\C)C[C@@H](C)/C=C/C=C4\CO[C@H]([C@@H]1O)[C@@]42O)O[C@@]1(CC[C@H](C)[C@@H](C(C)C)O1)C3
Product: CC1=C[C@H]2C(=O)O[C@H]3C[C@@H](CC=C(C)[C@H](O)[C@@H](C)C=CC=C4CO[C@H]([C@@H]1O)[C@@]42O)O[C@@]1(CC[C@H](C)[C@@H](C(C)C)O1)C3

Procedure:
If milbemycin A3 or milbemycin D is reacted in an analogous manner, for example at a conversion rate of 10% a ratio of 40% 13β-hydroxymilbemycin A3 and 60% 14,15-epoxymilbemycin A3 is obtained or, at a conversion rate of 13%, a ratio of 29% 13β-hydroxymilbemycin D to 71% 14,15-epoxymilbemycin D is obtained (HPLC analysis).
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][CH2:15][C@:16]2([OH:24])[C:17](=[O:20])[CH2:18][SH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:26])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:25])[CH2:6][CH2:5]1.[CH:27]([NH:29][C@H:30]([C:35](O)=[O:36])[CH2:31][CH2:32][S:33][CH3:34])=[O:28]>>[CH:27]([NH:29][CH:30]([CH2:31][CH2:32][S:33][CH3:34])[C:35](=[O:36])[S:19][CH2:18][C:17](=[O:20])[C@:16]1([OH:24])[C@:21]2([CH3:23])[C@H:13]([C@H:12]3[C@H:3]([C@@H:2]([OH:1])[CH2:22]2)[C@:4]2([CH3:26])[C:9](=[CH:8][C:7](=[O:25])[CH2:6][CH2:5]2)[CH2:10][CH2:11]3)[CH2:14][CH2:15]1)=[O:28]
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CS
Reactant: CSCC[C@H](NC=O)C(=O)O
Product: CSCCC(NC=O)C(=O)SCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Yield: 26.7 %

Procedure:
The title compound (0.38 gm) was prepared from 11β,17-dihydroxy-pregna-4-ene-3,20-dione-21-thiol (1.00 gm) and N-formyl-L-methionine (1.41 gm) in the same manner as in Synthetic Example 1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[F:15])[N:5]=[C:4]2[O:16][N:17]=[C:18]([CH3:19])[C:3]=12.[CH3:20][O:21][C:22](=[O:30])[C:23]1[C:28]([NH2:29])=[CH:27][CH:26]=[N:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH3:20][O:21][C:22](=[O:30])[C:23]1[C:28]([NH:29][C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=3[F:15])[N:5]=[C:4]3[O:16][N:17]=[C:18]([CH3:19])[C:3]=23)=[CH:27][CH:26]=[N:25][CH:24]=1
Reactant: COC(=O)c1cnccc1N
Reactant: Cc1noc2nc(-c3cc(Cl)ccc3F)nc(Cl)c12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2onc(C)c12
Temperature: 90 °C

Procedure:
4-Chloro-6-(5-chloro-2-fluoro-phenyl)-3-methyl-isoxazolo[5,4-d]pyrimidine (prepared by method used for compound of formula (43) (298 mg, 1 mmole) was dissolved in dioxane (4 ml), and BINAP (4.67 mg, 0.0075 mmole), 4-Amino-nicotinic acid methyl ester (182 mg, 1.2 mmole), cesium carbonate (456 mg, 1.4 mmole), and Pd2(dba)3 (2.29 mg, 0.0025 mmole) were added to the mixture and heated to 90° C. overnight. Dioxane was removed under vacuum and the residue was triturated with ethyl acetate (5 ml) and the product was isolated by filtration. 525 mg of solid were obtained which also contained cesium carbonate as by-product.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1I)[CH3:2].FC1C=CC(B(O)O)=CC=1.[N+:31]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)([O-:33])=[O:32]>>[CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1[C:37]1[CH:38]=[CH:39][C:34]([N+:31]([O-:33])=[O:32])=[CH:35][CH:36]=1)[CH3:2]
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: CCc1c(I)[nH]c(C=O)c1C(=O)OCc1ccccc1
Agent: OB(O)c1ccc(F)cc1
Product: CCc1c(-c2ccc([N+](=O)[O-])cc2)[nH]c(C=O)c1C(=O)OCc1ccccc1

Procedure:
Following the procedures described in Example 5, replacing methyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate with benzyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate and 4-fluorophenylboronic acid with 4-nitrophenylboronic acid, the title compound was obtained. Proton NMR for the product was consistent with the title compound. HRMS (ES) exact mass calculated for C21H19N2O5 (M+H): 379.1216. Found 379.1270
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[I:6][C:7]1[C:14]([I:15])=[CH:13][C:12]([I:16])=[CH:11][C:8]=1[CH2:9][OH:10].C(N(C(C)C)CC)(C)C.O>ClCCl>[S:1]([O:10][CH2:9][C:8]1[CH:11]=[C:12]([I:16])[CH:13]=[C:14]([I:15])[C:7]=1[I:6])(=[O:3])(=[O:2])[CH3:4]
Reactant: OCc1cc(I)cc(I)c1I
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCc1cc(I)cc(I)c1I
Temperature: 0 °C
Yield: 84 %

Procedure:
Mesyl chloride (0.6 ml, 8 mmol) was added dropwise to a suspension of 2,3,5-triiodobenzyl alcohol 1 (1.94 g, 4 mmol) in dry dichloromethane (30 ml) containing diisopropylethylamine (1.4 ml, 8 mmol) at 0° C. under dry nitrogen gas flow. The reaction mixture was stirred 1 h15 at 0° C., then cold H2O (40 ml) was added. The resulting aqueous phase was extracted with dichloromethane (10 ml). The combined organic extracts were washed with H2O (8 ml) then dried (Na2SO4), filtered and concentrated. The pale yellow solid was also washed with cold methanol (35 ml). 1.894 g of 2,3,5-triiodobenzyl mesylate in the form of a white clean solid was obtained in 84% yield.
Reaction SMILES: C([O:5][C:6](=[O:27])[CH2:7][N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:10]=[C:9]1[C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(C)(C)C>FC(F)(F)C(O)=O>[C:19]([C:9]1[N:8]([CH2:7][C:6]([OH:27])=[O:5])[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:10]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)Cn1c(C(=O)c2ccccc2)ccc1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cn1c(C(=O)c2ccccc2)ccc1-c1ccccc1
Yield: 99.9 %

Procedure:
A solution of tert-butyl(2-benzoyl-5-phenyl-1H-pyrrol-1-yl)acetate (148 mg, 0.41 mmol) in trifluoroacetic acid was stirred for 2 h at room temperature. After removal of trifluoroacetic acid, the residue was treated with CH2Cl2 (10 ml), MeOH (1 ml) and H2O (10 ml). The two layers were separated and the aqueous was extracted with CH2Cl2 (3×10 ml). The combined organic extracts were washed with H2O (10 ml), brine (10 ml), dried (Na2SO4) filtered and concentrated. The crude material was purified by chromatography (silica gel, EtOAc/hexane/HCO2H: 10/40/0.1) to afford (2-benzoyl-5-phenyl-1H-pyrrol-1-yl)acetic acid (125 mg, 100%) as an oil. To a stirred solution of (2-benzoyl-5-phenyl-1H-pyrrol-1-yl)acetic acid (260 mg, 0.85 mmol) in DMF (2.0 ml) was added 1,1′-carbonyldiimidazole (166 mg, 1.02 mmol) at room temperature. After stirring for 1 h, the reaction mixture was treated with a solution of guanidine hydrochloride (244 mg, 2.55 mmol) in DMF (2.5 ml) and triethylamine (0.54 ml, 2.55 mmol). After stirring over night, the reaction mixture was quenched with H2O (30 ml). The aqueous was extracted with Et2O (3×30 ml), EtOAc (10 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude material was purified by chromatography (silica gel; EtOAc/hexane/2M NH3 in MeOH: 65/35/1) to give the titled compound (169 mg, 58%) as a white solid: mp 201-203° C.; MS (−) ES, 345 (M−H)−.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[C:7]([C:14]([F:17])([F:16])[F:15])[CH:6]=1)(=[O:4])=[O:3].FC(F)(F)C1C=C([N+]([O-])=O)C=CC=1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([C:14]([F:15])([F:16])[F:17])[CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Agent: O=[N+]([O-])c1cccc(C(F)(F)F)c1
Product: CS(=O)(=O)c1ccc(N)c(C(F)(F)F)c1

Procedure:
The subtitle compound was prepared according to the procedure of Example 135 using 4-(methylsulfonyl)-2-(trifluoromethyl)nitrobenzene instead of 4-methylsulfonyl)-3-(trifluoromethyl)nitrobenzene in step 2.
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].Br[C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([O:16][CH3:17])=[CH:11][CH:10]=2.[H-].[Na+].C(OCC)(=O)C>CN(C)C=O.CCCCCC>[CH3:17][O:16][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:1][CH2:2][CH2:3][OH:4])=[CH:15]2
Reactant: COc1ccc2ncc(Br)cc2c1
Reactant: OCCS
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COc1ccc2ncc(SCCO)cc2c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 78.3 %

Procedure:
2-Mercaptoethanol (0.11 mL, 1.51 mmol, 2.0 eq) is added at room temperature to a stirred solution of 3-bromo-6-methoxy-quinoline (200 mg, 0.76 mmol, 1.0 eq) in N,N-dimethylformamide (10 mL), followed by sodium hydride (50%, 174 mg, 3.78 mol, 5.0 eq). After 4 hours stirring at 80° C., solvent is evaporated and the residue is extracted with ethyl acetate (3×50 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: ethyl acetate:hexane, 1:4 to 1:2, v/v) to afford 2-(6-methoxy-quinolin-3-ylsulfanyl)-ethanol as a yellow viscous oil (140 mg, 79% yield).