Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11]C(=O)OCC)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].NC1C=CC=CC=1>C(O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH2:11])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)Nc1ccc(C(C)(C)C)cc1
Solvent: CCO
Solvent: Nc1ccccc1
Product: CC(C)(C)c1ccc(N)cc1
Temperature: 180 °C
Reaction time: 6 h
Yield: 80 %

Procedure:
A mixture of 110 parts of ethyl N-(4-tert.-butyl-phenyl)-carbamate, 370 parts of aniline and 700 parts of ethanol is heated to 180° C. in an autoclave and kept at this temperature for 6 hours. The mixture is then subjected to fractional distillation under reduced pressure. 60 parts (80% of theory) of 4-tert.-butylaniline, of boiling point 93°-94° C./4 mbar, are obtained.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1)=[O:15].C([O-])([O-])=O.[K+].[K+].C(#N)C>O>[C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:2]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=2[C:4]#[N:5])=[CH:18][CH:17]=1)(=[O:15])[CH3:13]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(=O)c1ccc(Oc2ccc([N+](=O)[O-])cc2C#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.1 %

Procedure:
In a 250 ml single-neck flask equipped with a magnetic stirrer and a reflux condenser fitted with a nitrogen bubbler were placed 9.13 g (0.05 moles) of 2-chloro-5-nitrobenzonitrile, 7.01 g (0.0515 moles) of 4-hydroxyacetophenone, 7.10 g (0.0515 moles) of anhydrous K2CO3, and 75 ml of acetonitrile. The mixture was heated to reflux and held there for 3 hrs. The reaction mixture was then cooled to room temperature and diluted with 150 ml of water. The product separated as a solid. The solid was filtered off, washed thoroughly with water, and air-dried. The air-dried solid was recrystallized twice from 300 ml of absolute ethanol to give 4.95 g (35% yield) of purified 2-(4-acetylphenoxy)-5-nitrobenzonitrile, mp 135°-136.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:11]1)([O-])=O.CC(O)=O.O>[Fe]>[NH2:1][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:11]1
Reactant: O=C(N[C@H]1CCCN(c2ccncc2[N+](=O)[O-])C1)OCc1ccccc1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Nc1cnccc1N1CCC[C@H](NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.7 %

Procedure:
To a solution of benzyl [(3S)-1-(3-nitropyridin-4-yl)piperidin-3-yl]carbamate (2.96 g, 8.30 mmol) in AcOH (36.00 mL, 633.2 mmol), iron powder (2.703 g, 48.40 mmol) was added followed by water (5.00 mL, 278 mmol). After stirring at room temperature for 2 h, the reaction mixture was concentrated under reduced pressure. EtOAc (100 mL) was added to the resulting residue. The mixture was filtered through a pad of diatomaceous earth (CELITE®). The diatomaceous earth pad was washed with a 10 wt % aq. K3PO4 (150 mL) and EtOAc (100 mL). The organic layer was washed with brine (150 mL), dried over Na2SO4 and concentrated. The resulting residue was purified by flash chromatography on silica gel (0-20% MeOH in DCM) to give the sub-title compound as an off-white solid (2.24 g, 83%). LCMS calc. for C18H23N4O2 (M+H)+: m/z=327.2. found 327.2.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[CH:18]=[CH:17][C:9]2[C:10]([CH2:13][C:14](O)=[O:15])=[CH:11][S:12][C:8]=2[CH:7]=1.Cl.[NH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C([O-])(O)=O.[Na+].O.C(N(CC)CC)C>[Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[CH:18]=[CH:17][C:9]2[C:10]([CH2:13][C:14]([NH:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:15])=[CH:11][S:12][C:8]=2[CH:7]=1
Reactant: O=C(O)Cc1csc2cc(OCc3ccc(Cl)cc3Cl)ccc12
Reactant: CCOC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)Cc1csc2cc(OCc3ccc(Cl)cc3Cl)ccc12
Temperature: 25 °C
Reaction time: 17 h
Yield: 85.5 %

Procedure:
To a mixture of (6-((2,4-dichlorobenzyl)oxy)-1-benzothiophen-3-yl)acetic acid (150 mg) in DMF (dry) (3.0 mL) were added ethyl 2-aminoacetate hydrochloride (57.0 mg), HOBt (71.7 mg), EDCI (102 mg) and triethylamine (0.171 mL). The mixture was stirred at room temperature for 17 h. The mixture was diluted with saturated aqueous NaHCO3 and water. The mixture was extracted with EtOAc. The combined organic layer was washed successively with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was washed with hexane to give the title compound (158 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:14])[O:12][CH3:13])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(#N)C>[CH3:22][S:23]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([O:12][CH3:13])=[O:14])=[CH:8][CH:9]=1)(=[O:25])=[O:24]
Reactant: COC(=O)Nc1ccc(CCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)Nc1ccc(CCOS(C)(=O)=O)cc1
Yield: 89.4 %

Procedure:
6.0 g (30.7 mmole) methyl N-[4-(2-hydroxyethyl)phenyl]carbamate was dissolved in acetonitrile. 6.17 g (61 mmole) triethylamine and 7.0 g (61 mmole) methanesulfonyl chloride were added. The mixture was stirred until completion, then the solvent was evaporated in vacuo, water was added to the residue and the product was extracted with dichloromethane to give 7.5 g (yield 89.4%) of 4-[(methoxycarbonyl)amino]phenethyl methanesulfonate.
Reaction SMILES: Cl.[CH2:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([NH:11][C:12](Br)([OH:25])[N:13]2[CH2:16][C:17]2[CH:18]=[N:19][C:20]([Cl:24])=[C:21]([Cl:23])[CH:22]=2)=[C:9]([NH2:27])[N:8]=1)[CH2:3][CH2:4][CH3:5]>C(O)CCC>[CH2:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([OH:25])[N:13]2[CH2:16][C:17]2[CH:18]=[N:19][C:20]([Cl:24])=[C:21]([Cl:23])[CH:22]=2)=[C:9]([NH2:27])[N:8]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCOc1nc(N)c2c(n1)N(Cc1cnc(Cl)c(Cl)c1)C(O)(Br)N2
Agent: Cl
Solvent: CCCCO
Product: CCCCOc1nc(N)c2nc(O)n(Cc3cnc(Cl)c(Cl)c3)c2n1
Yield: 34.5 %

Procedure:
Concentrated hydrochloric acid (4 ml) was added to a butanol suspension (4 ml) comprising 2-n-butoxy-8-bromo-9-(5,6-dichloro-3-pyridylmethyl)-8-hydroxyadenine (150 mg, 0.34 mmol) obtained in the same manner as in Reference Example 2, and the resultant was allowed to react at 70° C. for 9 hours. The reaction solution was concentrated under reduced pressure, water (30 ml) was added to the residue under ice cooling, and the solution was neutralized with an aqueous solution of 1N sodium hydroxide. The precipitated solid was collected by filtration, crude crystal was purified by silica gel column chromatography (methylene chloride:methanol=25:1), and 45 mg of the title compound was obtained as a white powdery crystal (yield: 35%).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Br[CH2:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=1>CN(C=O)C.C(OCC)C>[CH2:1]([N:8]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:38][CH:39]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Cc1c(NCc2ccccc2)cccc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1ccc(CN(Cc2ccccc2)c2cccc([N+](=O)[O-])c2C)cc1
Temperature: 90 °C
Yield: 84.9 %

Procedure:
The product from Example 6A (0.92 g, 3.8 mmoles) and diisopropylethylamine (1.7 mL, 9.5 mmoles) in DMF (9.5 mL) were treated with methyl 4-(bromomethyl)benzoate (0.74 g, 7.6 mmoles) and heated for 18 hours at 90° C. After cooling to room temperature, the mixture was diluted with diethyl ether (200 mL). The mixture was washed with saturated ammonium chloride (200 mL), water (2×200 mL), brine (150 mL), dried (Na2SO4), filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 10:1→4:1 hexanes:ethyl acetate) to provide the title compound as a yellow solid (1.26 g, 85%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:12]([CH2:19][CH:20]([F:22])[F:21])[CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:56][CH2:57][C:58]1[C:59](=[O:66])[NH:60][C:61]([CH3:65])=[CH:62][C:63]=1[CH3:64]>CN(C=O)C.O.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([N:12]([CH2:19][CH:20]([F:21])[F:22])[CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([NH:56][CH2:57][C:58]1[C:59](=[O:66])[NH:60][C:61]([CH3:65])=[CH:62][C:63]=1[CH3:64])=[O:9]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: Cc1c(C(=O)O)cc(Br)cc1N(CC(F)F)C1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(CC(F)F)C3CCOCC3)c2C)c(=O)[nH]1
Reaction time: 0.08 h
Yield: 76.6 %

Procedure:
A stirred solution of 5-bromo-3-[(2,2-difluoroethyl)(oxan-4-yl)amino]-2-methylbenzoic acid (250 mg, 0.66 mmol) in dry DMF (3.0 ml) at 0° C. under a balloon of nitrogen, was treated with HATU (327 mg, 0.86 mmol) and DIPEA (230 μl, 1.3 mmol) dropwise. The resulting solution was stirred for 5 minutes and then treated with 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89%, 136 mg, 0.79 mmol). The resulting suspension was stirred at 0° C. for 20 minutes and then stirred at room temperature overnight. After 18 hours, 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (25 mg) was added and stirring continued for a further 25 hours. The reaction mixture was diluted with water (30 ml) and CH2Cl2 (30 ml). The layers were separated and the aqueous phase was extracted with CH2Cl2 (3×15 ml). The combined organic phases were washed with a saturated solution of NaHCO3 (aq) (45 ml), water (2×50 ml), brine (2×50 ml), dried (MgSO4), filtered and concentrated in-vacuo. The residue was purified by column chromatography (10 g SNAP cartridge, Isolera, 0-3% MeOH:CH2Cl2) and then triturated with ether. The resulting solid was collected by filtration and dried in-vacuo at 40° C. to give the title compound (259 mg, 77%) as an off white solid. LC-MS 100%, 4.04 min (7 minute LC-MS method), m/z=512.0, 513.0, 514.0, 515.0; 1H NMR (500 MHz, Acetone) δ 10.71 (s, 1H), 7.57-7.49 (m, 2H), 7.25 (d, J=1.9 Hz, 1H), 5.91 (s, 1H), 5.76 (tt, J=56.2, 4.3 Hz, 1H), 4.40 (d, J=5.5 Hz, 2H), 3.88 (dd, J=11.3, 4.2 Hz, 2H), 3.52 (td, J=14.6, 4.2 Hz, 2H), 3.33-3.23 (m, 2H), 3.02 (tt, J=11.6, 3.9 Hz, 1H), 2.32 (s, 3H), 2.28 (s, 3H), 2.24 (s, 3H), 1.73 (dd, J=12.4, 1.9 Hz, 2H), 1.59 (qd, J=12.2, 4.5 Hz, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[CH:16]([CH2:17][CH:18]([O:28][CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])[CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[CH:16]([CH2:17][CH:18]([O:28][CH2:29][C:30]([OH:32])=[O:31])[CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4CC(OCC(=O)OC(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4CC(OCC(=O)O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
tert-Butyl 2-(cholestan-3-yloxy)acetate 129 (634 mg, 1.26 mmol) was taken up in DCM (4 mL) before TFA (1 mL) was added. The solution was stirred at room temperature for 90 mins. The solvent was evaporated and the residue purified using a short silica plug (SiO2: DCM to 100:5 DCM:MeOH) before being recrystallized from hexane to yield 439 mg of the white solid product (78%). 1H nmr (400 MHz, CDCl3) δ: 4.25 (s, 2H, CH2O), 3.37 (m, 1H, CHO), 1.99-0.58 (m, 31H), 0.89 (d, 3H, J=6.6, CH3), 0.85 (d, 3H, J=2.0, CH3), 0.84 (d, 3H, J=1.4, CH3), 0.80 (s, 3H, CH3), 0.64 (s, 3H, CH3).
Reaction SMILES: F[C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH:12][C:13]1C=CC(C(O)=O)=C[CH:14]=1.C(OC1C=CC(C(Cl)=O)=CC=1)(=O)CCCCCCCCC>>[C:13]([O:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[CH:2][CH:10]=1)(=[O:12])[CH3:14]
Reactant: O=C(O)c1ccc(O)cc1F
Reactant: O=C(O)c1ccc(O)cc1
Agent: CCCCCCCCCC(=O)Oc1ccc(C(=O)Cl)cc1
Product: CC(=O)Oc1ccc(C(=O)O)cc1

Procedure:
p-Acetoxybenzoic acid was prepared in the same manner as in Example 1(2) except that the 2-fluoro-4-hydroxybenzoic acid was replaced with p-hydroxybenzoic acid. The p-hydroxybenzoic acid was chlorinated in the same manner as in the above (2), to obtain an acid chloride. 1.8 Grams of the acid chloride and 2 g of the (R)-(+)-2-fluoro-4-hydroxy-1-(1-trifluoromethyl-6-ethoxyhexyloxycarbonyl)benzene obtained in Example 1 were dissolved in 50 ml of toluene, 6 ml of pyridine was added, and the mixture was stirred for 1 day. The reaction mixture was poured into water, consecutively washed with a hydrochloric acid aqueous solution, with a sodium hydroxide aqueous solution and with water, and dried over anhydrous sodium sulfate, and the solvent was distilled off to give a crude product. The crude product was purified by silica gel column chromatography(eluting solvent: ethyl acetate/hexane=15/85), to give 2.8 g of an end product.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:17]=[CH:16][C:8](/[CH:9]=[N:10]/[CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1.[Cl-].[NH4+].C(OCC)(=O)C>CO.C1COCC1>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=1
Reactant: COC(=O)C/N=C/c1ccc(OC)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)CNCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (438 mg, 1.2 mmol) was added to a solution of (E)-methyl 2-(4-methoxybenzylideneamino)acetate (2.0 g, 9.6 mmol) in a mixture of methanol (22 mL) and THF (11 mL) at 0° C. The reaction mixture was stirred 1 hour at room temperature then partioned between a solution of saturated ammonium chloride (20 mL) and ethyl acetate (30 mL). The aqueous phase was separated and extracted with ethyl acetate (3×50 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated to dryness. The title compound was obtained as a white oil (1.7 g, 85%).
Reaction SMILES: [CH3:1][C@H:2]1[C:24](=[O:25])[C:23]2[C@H:12]([C@H:13]3[C@@H:21]([CH:22]=2)[C@H:20]2[C@@H:16]([CH2:17][C@@H:18]([O:26][C@@H:27]4[O:32][C@@H:31]([CH3:33])[C@H:30]([O:34][CH3:35])[C@@H:29]([O:36][CH3:37])[C@H:28]4[O:38][CH3:39])[CH2:19]2)[CH:15]=[CH:14]3)[CH2:11][C:9](=[O:10])[O:8][C@@H:7]([CH:40]2[CH2:43][CH2:42][CH2:41]2)[CH2:6][CH2:5][CH2:4][C@@H:3]1[O:44][C@@H:45]1[O:50][C@H:49]([CH3:51])[C@@H:48]([N:52]([CH3:54])[CH3:53])[CH2:47][CH2:46]1>C1(C)C=CC=CC=1.C(O)C>[CH3:1][C@H:2]1[C:24](=[O:25])[C:23]2[C@H:12]([C@H:13]3[C@@H:21]([CH:22]=2)[C@H:20]2[C@@H:16]([CH2:17][C@@H:18]([O:26][C@@H:27]4[O:32][C@@H:31]([CH3:33])[C@H:30]([O:34][CH3:35])[C@@H:29]([O:36][CH3:37])[C@H:28]4[O:38][CH3:39])[CH2:19]2)[CH2:15][CH2:14]3)[CH2:11][C:9](=[O:10])[O:8][C@@H:7]([CH:40]2[CH2:43][CH2:42][CH2:41]2)[CH2:6][CH2:5][CH2:4][C@@H:3]1[O:44][C@@H:45]1[O:50][C@H:49]([CH3:51])[C@@H:48]([N:52]([CH3:53])[CH3:54])[CH2:47][CH2:46]1
Reactant: CO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](O[C@H]2C[C@H]3[C@@H]4C=C5C(=O)[C@H](C)[C@@H](O[C@H]6CC[C@H](N(C)C)[C@@H](C)O6)CCC[C@H](C6CCC6)OC(=O)C[C@H]5[C@@H]4C=C[C@@H]3C2)[C@@H]1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: CO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](O[C@@H]2C[C@H]3CC[C@@H]4[C@@H](C=C5C(=O)[C@H](C)[C@@H](O[C@H]6CC[C@H](N(C)C)[C@@H](C)O6)CCC[C@H](C6CCC6)OC(=O)C[C@H]54)[C@@H]3C2)[C@@H]1OC
Reaction time: 16 h
Yield: 69.1 %

Procedure:
A solution of 21-desethyl-21-cyclobutyl spinosyn A (3.1 mg, 0.004 mmol) in 2 mL of toluene and 0.5 mL of ethanol was purged with a slow stream of nitrogen for 20 minutes, then 2 mg of chlorotris(triphenylphosphine) rhodium was added and the solution hydrogenated at 60° C. and 1 atm. for 16 hours. After cooling and removal of solvent, the residue was chromatographed using a 10 cm×2 cm silica gel column, eluting with 5×25 mL fractions of dichloromethane containing 0%, 2%, 3%, 4%, and 5% MeOH respectively. The product-containing fractions were combined and concentrated to give 2.1 mg of 5,6-dihydro-21-desethyl-21-cyclobutyl spinosyn A. MS M+760.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:15][C:16]([OH:18])=O)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([F:14])[CH:9]=1.[N:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[C:25]1[CH:26]=[CH:27][C:28]([NH2:31])=[N:29][CH:30]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:15][C:16]([NH:31][C:28]2[CH:27]=[CH:26][C:25]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][N:19]=3)=[CH:30][N:29]=2)=[O:18])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([F:14])[CH:9]=1
Reactant: O=C(O)Cc1ccc(-c2ccnc(F)c2)c(F)c1
Reactant: Nc1ccc(-c2cnccn2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(-c2ccnc(F)c2)c(F)c1)Nc1ccc(-c2cnccn2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(3-fluoro-4-(2-fluoropyridin-4-yl)phenyl)acetic acid 207-6 (50 mg, 0.20 mmol), was dissolved in DMF (2 mL), 5-(pyrazin-2-yl)pyridin-2-amine (41 mg, 0.24 mmol) and DIEA (174 uL, 1.0 mmol) were added to the solution before O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (114 mg, 0.30 mmol). The mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give 2-(3-fluoro-4-(2-fluoropyridin-4-yl)phenyl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide 212. MS m/z 404.1 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 11.10 (s, 1H), 9.31 (d, 1H), 9.11 (dd, 1H), 8.73-8.71 (m, 1H), 8.63 (d, 1H), 8.52 (dd, 1H), 8.34 (d, 1H), 8.21 (d, 1H), 7.70-7.52 (m, 2H), 7.43-7.34 (m, 3H), 3.89 (s, 2H).
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21]C3C=CC=CC=3)=[O:20])[CH2:15][CH2:14]2)=[CH:8][CH:7]=1)[CH3:4].I([O-])(=O)(=O)=O.[Na+].[O-2:34].[Al+3].[O-2].[O-2].[Al+3]>>[ClH:1].[CH2:5]([O:21][C:19]([N:16]1[CH2:17][CH2:18][CH:13]([S:12]([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][N:3]([CH3:2])[CH3:4])=[CH:7][CH:8]=2)=[O:34])[CH2:14][CH2:15]1)=[O:20])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [O-2]
Reactant: CN(C)Cc1ccc(SC2CCN(C(=O)Oc3ccccc3)CC2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Na+]
Product: CN(C)Cc1ccc(S(=O)C2CCN(C(=O)OCc3ccccc3)CC2)cc1

Procedure:
from 4-[4-(dimethylaminomethyl)phenylthio]-N-phenoxycarbonylpiperidine-hydrochloride and sodium metaperiodate; colourless powder; Rf value of the free base: 0.4 (aluminium oxide, ethyl acetate/petroleum ether=1:1, v:v).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[F:11][C:12]1[N:17]=[CH:16][C:15]([CH:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH3:19])=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:11][C:12]1[N:17]=[CH:16][C:15]([CH:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH3:19])=[CH:14][C:13]=1[C:2]1[CH:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1
Reactant: CSc1cc(Cl)nc(C)n1
Reactant: CC(c1cnc(F)c(B2OC(C)(C)C(C)(C)O2)c1)N1CCOCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CSc1cc(-c2cc(C(C)N3CCOCC3)cnc2F)nc(C)n1
Temperature: 90 °C
Yield: 78.8 %

Procedure:
To a 20 mL microwave vials was added 4-chloro-2-methyl-6-(methylthio)pyrimidine (0.175 g, 1.002 mmol), 2-fluoro-5-(1-morpholinoethyl)pyridin-3-ylboronic acid (Example 339 Step 3) (0.305 g, 1.202 mmol), trans-dichlorobis(triphenyl-phosphine)palladium (II) (Strem) (0.056 g, 0.080 mmol), sodium carbonate (JT Baker) (0.531 mg, 5.01 mmol), DME (10 mL), and water (2.5 mL). The vial was degassed by bubbling N2 for 5 min then sealed off and microwave heated at 90° C. for 20 min. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (40 g, 10% to 20% acetone in hexanes) to afford the product as white solid (275 mg). MS (ESI pos. ion) m/z: 349.1. 1H NMR (300 MHz, CDCl3) δ ppm 1.43 (d, J=6.72 Hz, 3H) 2.33-2.46 (m, 2H) 2.48-2.58 (m, 2H) 2.61 (s, 3H) 2.74 (s, 3H) 3.52 (q, J=6.58 Hz, 1H) 3.71 (t, J=4.46 Hz, 4H) 7.55 (s, 1H) 8.25 (s, 1H) 8.56 (dd, J=9.43, 2.27 Hz, 1H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:15]3[C:11](=[N:12][N:13]=[C:14]3[C@H:16]3[CH2:21][CH2:20][C@H:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:18][CH2:17]3)[CH2:10][NH:9][CH2:8][C:7]=2[CH:29]=1.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:15]3[C:11](=[N:12][N:13]=[C:14]3[C@H:16]3[CH2:17][CH2:18][C@H:19]([O:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:20][CH2:21]3)[CH2:10][N:9]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:8][C:7]=2[CH:29]=1
Reactant: CS(=O)(=O)Cl
Reactant: Clc1ccc2c(c1)CNCc1nnc([C@H]3CC[C@H](Oc4ccccc4)CC3)n1-2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](Oc3ccccc3)CC2)C1
Reaction time: 20 h

Procedure:
To a solution of trans-8-chloro-1-(4-phenoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride (0.065 g, 0.15 mmol) and triethylamine (0.044 ml, 0.32 mmol) in dichloromethane (5 ml) was added methanesulfonyl chloride (0.013 ml, 0.17 mmol) at room temperature. After stirring for 20 h the reaction mixture was transferred directly onto a silica gel chromatography column Elution with n-heptane/ethyl acetate gave the title compound (0.051 g, 72%) as white solid. MS m/e: 473 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[C:9]([CH3:16])=[N:10][N:11]2[CH:15]=[CH:14][S:13][C:12]=12)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[Br:23]C(F)(F)C(F)(F)Br.[Cl-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[C:9]([CH3:16])=[N:10][N:11]2[C:15]([Br:23])=[CH:14][S:13][C:12]=12)([CH3:4])([CH3:3])[CH3:2]
Reactant: FC(F)(Br)C(F)(F)Br
Reactant: Cc1nn2ccsc2c1NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1nn2c(Br)csc2c1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
A tetrahydrofuran (40 mL) solution of tert-butyl(6-methylpyrazolo[5,1-b][1,3]thiazol-7-yl)carbamate (1.20 g, 4.74 mmol) was cooled to −78° C., and n-butyllithium (1.57 M, 6.64 mL, 10.4 mmol) was added dropwise thereto, and the mixture was stirred for 30 minutes. Then, 1,2-dibromotetrafluoroethane (619 μl, 5.21 mmol) was added to the mixture, and the reaction mixture was warmed to room temperature, and stirred at room temperature for one hour. To the reaction mixture, a saturated aqueous solution of ammonium chloride was added, and a substance of interest was extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by medium pressure silica gel column chromatography (n-heptane/ethyl acetate: 50% then 66%) to obtain 1.39 g (4.32 mmol) of the title compound.