Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]/[CH:2]=[C:3](/[C:5]([O:7][C@@H:8]1[C@:16]23[C@H:20]([C@@:21]([C@:25]45[O:30][C@@:29]4([CH3:31])[C@H:28]4[C@:32]6([OH:38])[C@H:36]([O:37][C@@H:26]5[CH2:27]4)[O:35][CH:34]=[CH:33]6)([CH3:24])[C@H:22]([OH:23])[C@H:14]4[C@H:15]2[C@:11]([C:44]([O:46][CH3:47])=[O:45])([CH2:12][O:13]4)[C@H:10]([O:48]C(C)=O)[CH2:9]1)[C@@:19]([OH:43])([C:39]([O:41][CH3:42])=[O:40])[O:18][CH2:17]3)=[O:6])\[CH3:4].CO.C[O-].[Na+].C(O)(=O)C>O>[CH3:1]/[CH:2]=[C:3](/[C:5]([O:7][C@@H:8]1[C@:16]23[C@H:20]([C@@:21]([C@:25]45[O:30][C@@:29]4([CH3:31])[C@@H:28]4[C@:32]6([OH:38])[C@H:36]([O:37][C@H:26]5[CH2:27]4)[O:35][CH:34]=[CH:33]6)([CH3:24])[C@H:22]([OH:23])[C@H:14]4[C@H:15]2[C@:11]([C:44]([O:46][CH3:47])=[O:45])([CH2:12][O:13]4)[C@H:10]([OH:48])[CH2:9]1)[C@@:19]([OH:43])([C:39]([O:41][CH3:42])=[O:40])[O:18][CH2:17]3)=[O:6])\[CH3:4]
Reactant: C/C=C(\C)C(=O)O[C@H]1C[C@@H](OC(C)=O)[C@@]2(C(=O)OC)CO[C@H]3[C@@H](O)[C@@](C)([C@]45O[C@@]4(C)[C@@H]4C[C@H]5O[C@@H]5OC=C[C@@]54O)[C@H]4[C@]1(CO[C@]4(O)C(=O)OC)[C@@H]32
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: C/C=C(\C)C(=O)O[C@H]1C[C@@H](O)[C@@]2(C(=O)OC)CO[C@H]3[C@@H](O)[C@@](C)([C@]45O[C@@]4(C)[C@H]4C[C@@H]5O[C@@H]5OC=C[C@@]54O)[C@H]4[C@]1(CO[C@]4(O)C(=O)OC)[C@@H]32

Procedure:
15.8 mg. azadirachtin A (2.2×10-5 mole) were dissolved in 100 μl. methanol. To this solution were added three times 100 μl. amounts of a methanolic solution of sodium methylate (0.6 g. sodium in 50 ml. methanol). After each addition of 100 μl. methylate solution, there was a pause of 2 minutes and then a testing with HPLC whether azadirachtin A was still present. After the disappearance of azadirachtin A, the reaction mixture was neutralised with acetic acid, diluted with water and extracted with chloroform. The purification from by-products took place by semipreparative HPLC on a 20 cm. RP-18 column of 9 mm. internal diameter, using the elution agent methanol/ water (2:3 v/v); detection at 215 nm; yield 2.4 mg. (15.2% of theory).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[CH:16]=[CH:15][C:14]4[CH2:18][CH2:19][CH2:20][CH2:21][C:13]=4[C:12]=3[NH:11][C:10](=[O:22])[C:9]2=[O:23])[CH:5]=[CH:6][CH:7]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([S:30]([Cl:33])(=[O:32])=[O:31])[CH:25]=1>>[ClH:33].[O:22]=[C:10]1[NH:11][C:12]2[C:13]3[CH2:21][CH2:20][CH2:19][CH2:18][C:14]=3[CH:15]=[CH:16][C:17]=2[N:8]([C:4]2[CH:3]=[C:2]([NH:1][S:30]([C:26]3[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=3)(=[O:32])=[O:31])[CH:7]=[CH:6][CH:5]=2)[C:9]1=[O:23]
Reactant: Nc1cccc(-n2c(=O)c(=O)[nH]c3c4c(ccc32)CCCC4)c1
Reactant: O=S(=O)(Cl)c1cccnc1
Product: Cl
Product: O=c1[nH]c2c3c(ccc2n(-c2cccc(NS(=O)(=O)c4cccnc4)c2)c1=O)CCCC3
Yield: 26 %

Procedure:
4-(3-Aminophenyl)-1,4,7,8,9,10-hexahydrobenzo[f]quinoxaline-2,3-dione (30 mg, 0.097 mmol) and 3-pyridinesulfonyl chloride (26 mg, 0.146 mmol) were used in a process similar to Example 9 to give the titled compound (a white crystal, 12 mg, yield 26%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH:10]1([O:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH:10]1([O:16][CH:17]2[CH2:18][CH2:19][N:20]([C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)[CH2:21][CH2:22]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: N#Cc1ccc(F)cc1
Reactant: C1CCC(OC2CCNCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(N2CCC(OC3CCCCC3)CC2)cc1
Yield: 53.9 %

Procedure:
A solution of 4-fluorobenzonitrile (1.50 g), 4-(cyclohexyloxy)piperidine (2.40 g) and potassium carbonate (3.3 g) in DMF (30 ml) was stirred at 90-95° C. for 6 hours. The reaction mixture was poured into water (100 ml) and extracted twice with a mixture of ethyl acetate and n-hexane (80 ml:30 ml). The extracts were combined, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (200 ml) eluting with a mixture of n-hexane and ethyl acetate (6:1 v/v-5:1 v/v). The fractions containing the desired compound were collected and evaporated under reduced pressure to give 4-[4-cyclohexyloxypiperidin-1-yl)benzonitrile (1.90 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1[S:9][CH2:10][C@@H:11]2[C@@H:16]([C:17]([F:20])([F:19])[F:18])[O:15][CH2:14][C@:12]2([C:21]2[CH:26]=[C:25]([N+:27]([O-])=O)[CH:24]=[CH:23][C:22]=2[F:30])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].O.O.[Sn](Cl)(Cl)(Cl)Cl>C(O)C>[C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1[S:9][CH2:10][C@@H:11]2[C@@H:16]([C:17]([F:18])([F:20])[F:19])[O:15][CH2:14][C@:12]2([C:21]2[CH:26]=[C:25]([NH2:27])[CH:24]=[CH:23][C:22]=2[F:30])[N:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc([N+](=O)[O-])ccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)ccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.9 %

Procedure:
tert-Butyl((4aS,5S,7aS)-7a-(2-fluoro-5-nitrophenyl)-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)carbamate (16.61 g) was dissolved in ethanol (250 mL) and tin chloride dihydrate (25.0 g) was added. After stirring at RT for 18 h, the solution was poured onto NaOH (2N aq., 300 mL) and celite° (˜50 g) was added. The resulting mixture was filtered through more celite° and extracted with EtOAc (2×500 mL). The combined organic portions were dried over MgSO4 and evaporated to afford the title compound (15.52 g). This material could be used crude but a portion was purified by silica gel column chromatography (20% to 50% EtOAc in hexanes) to afford pure material (recovery 79%). 1H NMR (400 MHz, CDCl3) δ ppm 1.53 (s, 9H), 2.77 (d, J=14.4 Hz, 1H), 3.09 (br. s., 1H), 3.46 (br. s., 1H), 3.62 (br. s., 2H), 3.87 (br. s., 1H), 4.61 (d, J=8.6 Hz, 1H), 4.71 (br. s., 1H), 6.61 (br. s., 2H), 6.85-6.95 (m, 1H)
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1.[I:14](O)(=O)(=O)=O.II>CO>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[I:14]
Reactant: [O-][I+3]([O-])([O-])O
Reactant: COC(=O)c1cc(N)c(F)c(Cl)n1
Agent: II
Solvent: CO
Product: COC(=O)c1nc(Cl)c(F)c(N)c1I
Reaction time: 0.17 h
Yield: 194 %

Procedure:
Methyl 4-amino-6-chloro-5-fluoropicolinate (2.2 g, 10.8 mmol) was dissolved in methyl alcohol (20 mL). The solution was treated with periodic acid (880 mg, 3.9 mmol) and iodine (2.2 g, 8.6 mmol) and then heated at reflux for 20 h. The mixture was cooled, and the volatiles were removed under vacuum. The residue was dissolved in EtOAc (50 mL) and then stirred with 10% NaHSO3 solution (20 mL) for 10 min. The organic phase was separated and washed with satd aq NaCl (10 mL), dried (Na2SO4) and evaporated. The residue was purified by silica gel chromatography (5-50% EtOAc-hexane gradient) to give the title compound as a light orange solid (2.5 g, 70%): mp 149-151° C.; ESIMS m/z 330 ([M]+); 1H NMR (400 MHz, CDCl3) δ 5.17 (s, 2H, NH2), 3.97 (s, 3H, OMe); 19F NMR (376 MHz, CDCl3) δ −135.79 (s).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH2:12](O)[CH2:13][OH:14].C(OCC)(OCC)OCC>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:10]([O:9][C:7]([CH:3]1[CH2:4][CH2:5][CH2:6][C:2]21[O:14][CH2:13][CH2:12][O:1]2)=[O:8])[CH3:11]
Reactant: OCCO
Reactant: CCOC(=O)C1CCCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(OCC)OCC
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCCC12OCCO2
Yield: 128.1 %

Procedure:
A mixture of ethyl 2-oxocyclopentanecarboxylate (Aldrich, 10.0 g, 64.0 mmol), ethylene glycol (18 mL, 323 mmol), triethyl orthoformate (21 mL, 126 mmol) and p-toluenesulfonic acid monohydrate (0.61 g, 3.21 mmol) in toluene (150 mL) was heated under reflux with removing distillate with a Dean-Stark apparatus for 1 h. The mixture was cooled and poured into NaHCO3 solution, and the organic layer was separated. The aqueous layer was extracted with diethyl ether, and the combined organic layers were washed with NaCl solution and dried over Na2SO4. Filtration and concentration gave 16.41 g of 2, as a pale yellow oil, which was used in the next reaction without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]3[C:12](=[CH:13][C:2]1=2)[CH:11]=[CH:10][CH:9]=[CH:8]3.C1C[O:17][CH2:16]C1.C([Li])CCC.CN(C)C=O>O.C(OCC)C>[S:1]1[C:5]([CH:16]=[O:17])=[CH:4][C:3]2[CH:6]=[C:7]3[C:12](=[CH:13][C:2]1=2)[CH:11]=[CH:10][CH:9]=[CH:8]3
Reactant: c1ccc2cc3sccc3cc2c1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: O=Cc1cc2cc3ccccc3cc2s1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
Naptho[2,3-b]thiophene (4, 4.00 g, 21.7 mmol., 1.00 equiv.) and THF (360 mL) were added to a 500 mL Schlenk flask. The mixture was cooled to −78° C. and n-butyllithium was added (2.5 M in hexanes, 9.6 mL, 24 mmol., 1.1 equiv.). The mixture was stirred at −78° C. for 15 minutes before removing the dry ice/acetone bath and stirring at ambient for 2 hours. The mixture was cooled back to −78° C. and N,N-dimethylformamide (2.0 mL, 26 mmol., 1.2 equiv.) was added. The mixture was left to warm slowly to room temperature while stirring for 16 hours. The solution was diluted with water (500 mL) and diethyl ether (500 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (250 mL). The combined organic layers were washed with brine (300 mL), dried with MgSO4 and concentrated. The crude material was purified by silica gel column chromatography (solid loading, dichloromethane) to give a yellow solid (3.69 g, 80% yield). 1H NMR (400 MHz, CDCl3) δ ppm 10.18 (s, 1H), 8.52 (s, 1H), 8.39 (s, 1H), 8.16 (s, 1H), 8.07-7.88 (m, 2H), 7.54 (dddd, J=21.45, 8.05, 6.69, 1.28 Hz, 2H).
Reaction SMILES: C([NH:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]3[C:26]([CH:27]=[O:28])=[C:25]([Cl:29])[N:24]=[C:23]3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:17]([Cl:36])[CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[Cl:36][C:17]1[CH:16]=[C:15]([C:10]2[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:20]=[CH:19][C:18]=1[CH2:21][N:22]1[C:26]([CH:27]=[O:28])=[C:25]([Cl:29])[N:24]=[C:23]1[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(Cn2c(-c3ccccc3)nc(Cl)c2C=O)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: NS(=O)(=O)c1ccccc1-c1ccc(Cn2c(-c3ccccc3)nc(Cl)c2C=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 111.5 %

Procedure:
1.5 g of 3′-chloro-4′-(4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl)-biphenyl-2-sulfonic acid tert-butylamide and 340 μl of anisole are dissolved in 10 ml of trifluoroacetic acid and the solution is stirred at RT for 24 h. The volatile constituents are removed in vacuo, the residue is taken up twice using 50 ml of toluene each time and the volatile constituents are again removed in vacuo. 1.5 g of a colorless foam are obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH2:8][CH:9]=O)[C:4]([CH3:11])=[N:3]1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[N:21][CH:22]=[CH:23][N:24]=2)=[CH:15][CH:14]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(Cl)[Cl:50]>>[ClH:50].[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20]([N:25]3[CH2:26][CH2:27][N:28]([CH2:9][CH2:8][C:5]4[C:4]([CH3:11])=[N:3][N:2]([CH3:1])[C:6]=4[CH3:7])[CH2:29][CH2:30]3)=[N:21][CH:22]=[CH:23][N:24]=2)=[CH:15][CH:14]=1
Reactant: ClCCl
Reactant: Fc1ccc(-c2nccnc2N2CCNCC2)cc1
Reactant: Cc1nn(C)c(C)c1CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1nn(C)c(C)c1CCN1CCN(c2nccnc2-c2ccc(F)cc2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 5 %

Procedure:
Combine (1,3,5-trimethyl-1H-pyrazol-4-yl)-acetaldehyde (0.35 g, 2.27 mmol) and 3′-(4-fluorophenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.71 g, 2.76 mmol) in DCM (10 mL) and stir at room temperature for 10 min. Add glacial acetic acid (0.21 mL, 3.44 mmol) followed by sodium triacetoxyborohydride (0.73 g, 3.44 mmol). Stir at room temperature for 2 hr. Concentrate, dissolve in methanol (5 mL) and load on a 10 g SCX column. Wash with methanol (2×50 mL). Elute with 2 M ammonia in methanol (2×30 mL). Concentrate the eluent and purify (silica gel chromatography, eluting with 45:45:10 hexanes:DCM:ethanol), to give the free base of the title compound (48 mg, 5%). Dissolve the free base (0.041 g, 0.104 mmol) in methanol and add a solution of ammonium chloride (0.006 g, 0.104 mmol) in a minimal volume of methanol. Shake for 18 hr. at room temperature and concentrate to give the title compound (50 mg, 95%). MS (ES): m/z=395 [M+H]+.
Reaction SMILES: I.[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8](=[NH:11])SC.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([CH2:27][NH2:28])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1.C(O)CCC>O.C(OCC)(=O)C>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2([CH2:27][NH:28][C:8]([NH:7][N:6]=[CH:5][C:4]3[C:12]([Cl:16])=[CH:13][CH:14]=[CH:15][C:3]=3[Cl:2])=[NH:11])[CH2:25][CH2:26]2)=[CH:22][CH:23]=1
Reactant: CSC(=N)NN=Cc1c(Cl)cccc1Cl
Reactant: NCC1(c2ccc(Cl)cc2)CC1
Agent: I
Solvent: O
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: N=C(NCC1(c2ccc(Cl)cc2)CC1)NN=Cc1c(Cl)cccc1Cl

Procedure:
A solution of 7.80 g. of methyl 3-(2,6-dichlorobenzylidene)thiocarbazimidate hydroiodide and 4.37 g. of 1-(p-chlorophenyl)cyclopropanemethylamine in 100 ml. of n-butanol and 25 ml. of water is heated at reflux for 24 hours. The solution is cooled, diluted with water to a final volume of 2 liters and allowed to stand. Filtration gives a tan solid which is dissolved in ethyl acetate and purified by silica gel column chromatography. Crystallization of the product from diethyl ether gives the desired final product as colorless crystals, m.p. 126°-128° C.
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]([F:21])([F:20])[C:9]1[CH:19]=[CH:18][C:12]([O:13][CH:14]2[CH2:17][NH:16][CH2:15]2)=[CH:11][CH:10]=1.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>O1CCCC1.O>[C:22]1([NH:28][C:29]([N:16]2[CH2:15][CH:14]([O:13][C:12]3[CH:11]=[CH:10][C:9]([C:8]([F:7])([F:20])[F:21])=[CH:19][CH:18]=3)[CH2:17]2)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: FC(F)(F)c1ccc(OC2CNC2)cc1
Reactant: O=C=Nc1ccccc1
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)N1CC(Oc2ccc(C(F)(F)F)cc2)C1
Reaction time: 16 h
Yield: 52 %

Procedure:
A stirred slurry of 6.2 g (0.02 mole) of 3-[4-(trifluoromethyl)phenoxy]azetidine oxalate and 2.62 g (0.022 mole) of phenyl isocyanate in 60 ml of tetrahydrofuran was treated with 5 ml of triethylamine and stirring continued for 16 hr. The reaction mixture was diluted with water until an oil separated. The tetrahydrofuran-water portion was decanted and the residue solidified on standing. Recrystallization from ethanol-water yielded 3.5 g (53.4%) of fine white crystals, m.p. 174.5°-176° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[C:10](=[O:13])([O-])[O-].[K+].[K+].C(Cl)(Cl)=O.[C:20]([C:24]1[CH:28]=[C:27]([NH2:29])[O:26][N:25]=1)([CH3:23])([CH3:22])[CH3:21]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10](=[O:13])[NH:29][C:27]2[O:26][N:25]=[C:24]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:28]=2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)c1cc(N)on1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(S)cc1
Agent: O=C(Cl)Cl
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(SC(=O)Nc2cc(C(C)(C)C)no2)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-Methoxy-benzenethiol (0.20 g, 1 eq) and potassium carbonate (0.47 g, 2.5 eq) in dry THF was allowed to stir at room temperature under argon for an hour. Then the stirred suspension was cooled to 0° C. and to it was added drop wise a solution of phosgene (0.17 g 1.2 eq). The reaction stirred at 0° C. for half an hour. Then 3-tert-Butyl-isoxazol-5-ylamine (0.20 g, 1 eq) in THF was added dropwise. The reaction was allowed to warm to room temperature and stirred overnight. The solvent was removed and extracted with ethyl acetate and water. The organic layer was dried over magnesium sulfate and solvent removed. It was purified by HPLC. Yield: 157 mg (36%), LC/MS [MH+] 307.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[Br:10]Br.[OH-].[K+]>C(Cl)(Cl)Cl>[Br:10][C:7]1[CH:8]=[C:2]([F:1])[C:3]([NH2:4])=[C:5]([F:9])[CH:6]=1
Reactant: BrBr
Reactant: Nc1c(F)cccc1F
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Nc1c(F)cc(Br)cc1F
Yield: 78.8 %

Procedure:
100 g of 2,6-difluoroaniline was dissolved in 180 ml of chloroform and 140 g of bromine was added dropwise. After one hour of reflux, the resulting solution was poured into a solution of 10% potassium hydroxide. The mixture was extracted with chloroform and the organic layer was washed with a solution of 10% potassium hydroxide in water. After the chloroform was removed by distillation, the residue was distilled under reduced pressure (bp 70° to 80° C. at 4 mmHg) and recrystallized with hexane to yield 127 g of 4-bromo-2,6-difluoroaniline.
Reaction SMILES: [CH3:1][N:2]([CH:4]=[N:5][C:6]1[NH:7][CH:8]=[CH:9][N:10]=1)[CH3:3].C(N(CC)CC)C.[C:18](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[C:18]([N:7]1[CH:8]=[CH:9][N:10]=[C:6]1[N:5]=[CH:4][N:2]([CH3:3])[CH3:1])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(C)C=Nc1ncc[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C=Nc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the crude 2-[dimethylamino)methylene]aminoimidazole (2) was added methylene chloride (750 mL), triethylamine (98 mL, 700 mmol) and trityl chloride (62.98 g, 226 mmol) (Aldrich). The reaction mixture was stirred at room temperature for 3 hrs. Solvent was removed in vacuo and the crude 3 was crystallized from methanol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.F[C:14]1[CH:27]=[CH:26][C:17]([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[C:18]([C:20]1[CH:25]=[CH:24][C:23]([N:10]2[CH2:9][CH2:8][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:12][CH2:11]2)=[CH:22][CH:21]=1)(=[O:19])[C:17]1[CH:26]=[CH:27][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(c1ccccc1)c1ccc(F)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(c1ccccc1)c1ccc(N2CCN(c3ccncc3)CC2)cc1
Yield: 26.2 %

Procedure:
A solution of N-(4-pyridyl)piperazine (815 mg), 4-fluorobenzophenone (1.2 g) and powdered potassium carbonate (912 mg) was stirred at 95° C. in DMSO (10 ml) overnight. The solution was poured into water (150 ml) and extracted with dichloromethane (3×50 ml). The dichloromethane extracts were combined, washed with water, dried (Na2SO4) and evaporated. The residue was purified by chromatography on alumina (ICN Alumina N 32-63) using 1% methanol in dichloromethane as eluant to give a solid. The solid was recrystallised from a mixture of ethyl acetate/isohexane to give 1-(4-benzoylphenyl)-4-(4-pyridyl)piperazine (450 mg) as a solid. m.p.136-137° C.
Reaction SMILES: [I:1][CH2:2][C:3]1([CH3:18])[CH2:7][C:6]2[C:8]([CH3:17])=[C:9]([NH:14]C=O)[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.Cl.C(=O)(O)[O-].[Na+]>CO.O.C(OCC)(=O)C>[I:1][CH2:2][C:3]1([CH3:18])[CH2:7][C:6]2[C:8]([CH3:17])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1
Reactant: Cc1c(C)c2c(c(C)c1NC=O)CC(C)(CI)O2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CI)O2
Yield: 91.8 %

Procedure:
To a solution of N-[2,3-dihydro-2-(iodomethyl)-2,4,6,7-tetramethylbenzofuran-5-yl]formamide (6.5 g) in methanol (40 mL) was added conc. hydrochloric acid (10 mL). The mixture was refluxed for 1.5 hours under nitrogen atmosphere, and poured into a suspension of sodium bicarbonate (12 g) in water and ethyl acetate The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate, treated with activated carbon, filtrated and evaporated in vacuo. The residue was crystallized from hexane to afford 5.5 g of the title compound. Yield 91%.
Reaction SMILES: [CH:1]1([C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)O)[CH2:3][CH2:2]1.[BrH:18]>C1(C)C=CC=CC=1>[Br:18][CH2:3][CH2:2][CH:1]=[C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CC1
Reactant: Br
Solvent: Cc1ccccc1
Product: BrCCC=C(c1ccccc1)c1ccccc1
Yield: 95 %

Procedure:
To a vigorously stirred solution of 250.g (1.1 mol) of cyclopropyl diphenyl carbinol in 2.5 liters of toluene at ambient temperature was added rapidly 3.1 liters of 48% aqueous hydrobromic acid. After stirring for several hours, the layers were separated, the organic phase was washed with 1 liter of water, 1 liter of 10% aqueous sodium bicarbonate, and dried over sodium sulfate. The resulting crude oil residue was subjected to high-vacuum short path distillation to give 300 .g (95%) of 4-bromo-1,1-diphenyl-l-butene as a clear oil.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[C@H:10]1[CH2:14][C@H:13]([F:15])[CH2:12][NH:11]1.Br[C:17]1[CH:22]=[CH:21][N:20]2[N:23]=[CH:24][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:19]2[CH:18]=1>>[F:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[C@H:10]1[CH2:14][C@H:13]([F:15])[CH2:12][N:11]1[C:17]1[CH:22]=[CH:21][N:20]2[N:23]=[CH:24][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:19]2[CH:18]=1
Reactant: CCOC(=O)c1cnn2ccc(Br)cc12
Reactant: Fc1ccc(F)c([C@H]2C[C@H](F)CN2)c1
Agent: Cl
Product: CCOC(=O)c1cnn2ccc(N3C[C@@H](F)C[C@@H]3c3cc(F)ccc3F)cc12

Procedure:
The title compound (Int-67) was prepared by the method similar to that for Int-84 using (2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidine hydrochloride (Int-47) and Ethyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate to afford as yellow solid.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=[C:6]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[CH2:5][C@@H:4]1[CH3:26]>CCO.[Pd]>[C:10](=[O:11])([O-:16])[NH2:9].[NH2:23][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:17]=1[C@H:6]1[CH2:7][C@@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])[C@H:3]([O:2][CH3:1])[C@@H:4]([CH3:26])[CH2:5]1
Reactant: CO[C@@H]1[C@@H](C)CC(c2ccncc2[N+](=O)[O-])=C[C@H]1NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CO[C@@H]1[C@@H](C)C[C@@H](c2ccncc2N)C[C@H]1NC(=O)OC(C)(C)C
Product: NC(=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 12 %
Yield: 15 %

Procedure:
To a solution of (+/−)-tert-butyl ((1R,5S,6R)-6-methoxy-5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-en-1-yl)carbamate (1.0 equiv.) in degassed EtOH (0.10 M) was added Pd/C (0.1 equiv.). The mixture was purged with H2, and allowed to to stir under an atm of H2 overnight at RT. The reaction was filtered through a pad of celite and the cake was washed with MeOH. The organics were concentrated and purified by ISCO SiO2 chromatography. Purification was completed via SFC (30% MeOH, 100 mL/min, AD column) to yield tert-butyl S,2S,3R,5S)-5-(3-aminopyridin-4-yl)-2-methoxy-3-methylcyclohexyl)carbamate (15% yield, 99% ee) and tert-butyl ((1R,2R,3S,5R)-5-(3-aminopyridin-4-yl)-2-methoxy-3-methylcyclohexyl)carbamate (12% yield, 99% ee). LC/MS (m/z)=336.3 (MH+), Rt=0.58 min.