Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][C:6]([O:8][C:9]1[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=1)[NH:12][C:13](=[O:18])[CH2:14][C:15](=[O:17])[CH3:16])=[O:7])[CH2:2][CH2:3][CH3:4].[CH:22]([O-])([O-])[O:23]C.[C:27]1(C)C=CC(S(O)(=O)=O)=CC=1.N1C2C(=CC=CC=2)C=CC=1>CO>[CH2:1]([NH:5][C:6]([O:8][C:9]1[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=1)[NH:12][C:13](=[O:18])[CH2:14][C:15]([O:23][CH3:22])([O:17][CH3:27])[CH3:16])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC([O-])[O-]
Reactant: CCCCNC(=O)Oc1cccc(NC(=O)CC(C)=O)c1
Solvent: CO
Solvent: c1ccc2ncccc2c1
Product: CCCCNC(=O)Oc1cccc(NC(=O)CC(C)(OC)OC)c1
Reaction time: 24 h

Procedure:
A mixture of 23.5 g of m-(n-butylcarbamoyloxy)-acetylacetanilide 15 g of methyl orthoformate, 75 ml of methanol and 0.5 g of p-toluene sulfonic acid was stirred for 24 hours and 1 ml of quinoline was then added. The solvent was evaporated and the residue was chromatographed over silica. Elution with an 8-2 methylene chloride-acetone mixture yielded 20 g of m-(n-butylcarbamoyloxy)-3,3-dimethoxy-butyranilide melting at 114°C. STEP B: m-(n-butylcarbamoyloxy)-3-methoxy-crotonanilide
Reaction SMILES: O[C:2]1[C:11]2[CH:12]=[C:13]([O:15][CH3:16])[CH:14]=[C:9]3[C:10]=2[N:5]([CH2:6][CH2:7][O:8]3)[C:4](=[O:17])[C:3]=1[C:18]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1)=[O:19].P(Cl)(Cl)([Cl:31])=O>>[Cl:31][C:2]1[C:11]2[CH:12]=[C:13]([O:15][CH3:16])[CH:14]=[C:9]3[C:10]=2[N:5]([CH2:6][CH2:7][O:8]3)[C:4](=[O:17])[C:3]=1[C:18]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1)=[O:19]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2c3c(c1)c(O)c(C(=O)N1CCc4ccccc41)c(=O)n3CCO2
Product: COc1cc2c3c(c1)c(Cl)c(C(=O)N1CCc4ccccc41)c(=O)n3CCO2
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 2,3-dihydro-7-hydroxy-9-methoxy-6-(1-indolinylcarbonyl)-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (3 g) and phosphorus oxychloride (2.2 ml) was stirred at 80° C. for 1 hour. The mixture was poured into ice-water and the precipitates were collected and washed with water to give yellow crystals of 2,3-dihydro-7-chloro-9-methoxy-6-(1-indolinylcarbonyl)-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (2.8 g).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C@H:12]([C:21](OC)=[O:22])[CH2:13][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:7]([N+:25]([O-:27])=[O:26])[CH:6]=1)(=[O:4])=[O:3].[BH4-].[Li+]>C1COCC1.CO.C(OCC)(=O)C>[OH:22][CH2:21][CH:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]([S:2]([NH2:1])(=[O:3])=[O:4])=[CH:6][C:7]=1[N+:25]([O-:27])=[O:26])[CH2:13][S:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc(NC(CO)CSc2ccccc2)c([N+](=O)[O-])c1
Reaction time: 3 h

Procedure:
A solution of Example 434A (1.42 g, 3.45 mmol) in THF (10 mL) and methanol (1 mL) at room temperature was slowly treated with lithium borohydride (100 mg), stirred for 3 hours, as diluted with ethyl acetate (100 mL), washed with water (45 mL) and brine (10 mL), dried (MgSO4), filtered, and concentrated to provide the desired product. MS (ESI(+)) m/e 384 (M+H).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH2:23])=[CH:17][CH:16]=1.Cl.[H][H]>[Pd].C(O)C>[F:13][C:14]([F:24])([F:25])[C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][NH:23][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4])=[CH:19][CH:20]=1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: NCCc1ccc(C(F)(F)F)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CNCCc1ccc(C(F)(F)F)cc1

Procedure:
Ethanol (40 ml) is added to a pressure shaker bomb. One part of glucose is dissolved in the solvent followed by one part of 2-(4-trifluoromethylphenyl)-ethylamine. Hydrochloric acid is added to a pH of about 8 to 9. Wet 50% palladium on carbon 0.1 of a part of glucose is added and the mixture is agitated at about 40 degrees centigrade under about 3 atm of hydrogen gas until hydrogen uptake ceases. The hydrogen is vented and the catalyst is removed by filtration and the filtrated is washed with ethanol and the washings are added to the filtrate. The pH of the solution is lowered to about pH=4 with additional hydrochloric acid and the solvents removed on a rotary evaporator under reduced pressure.
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.C(N(CC)CC)C.[NH2:20][C:21]1[CH:48]=[CH:47][C:24]([C:25]([N:27]2[CH2:32][CH2:31][N:30]([CH2:33][C:34]3[CH:35]=[C:36]([CH:44]=[CH:45][CH:46]=3)[C:37]([NH:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:29][CH2:28]2)=[O:26])=[C:23]([F:49])[C:22]=1[Cl:50].[CH:51]1([CH2:54][NH2:55])[CH2:53][CH2:52]1>ClCCl>[C:40]([NH:39][C:37](=[O:38])[C:36]1[CH:44]=[CH:45][CH:46]=[C:34]([CH2:33][N:30]2[CH2:29][CH2:28][N:27]([C:25](=[O:26])[C:24]3[CH:47]=[CH:48][C:21]([NH:20][C:1]([NH:55][CH2:54][CH:51]4[CH2:53][CH2:52]4)=[O:12])=[C:22]([Cl:50])[C:23]=3[F:49])[CH2:32][CH2:31]2)[CH:35]=1)([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)c(Cl)c3F)CC2)c1
Reactant: NCC1CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(NC(=O)NCC4CC4)c(Cl)c3F)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.4 %

Procedure:
To a stirred solution of bis(trichloromethyl) carbonate (0.128 mmol, 38.1 mg) in dichloromethane (6 mL) was added a mixture of triethylamine (0.867 mmol, 0.121 mL, 88 mg) and 3-((4-(4-amino-3-chloro-2-fluorobenzoyl)piperazin-1-yl)methyl)-N-tert-butylbenzamide (0.347 mmol, 155 mg) in dichloromethane (6 mL). The mixture was heated to reflux for 2 hours before being cooled to room temperature. Cyclopropylmethylamine (0.694 mmol, 0.060 mL, 49.3 mg) was added and the mixture stirred for 2 hours. After this time the reaction was concentrated under reduced pressure and purified by silica chromatography to yield the title compound (17 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+].[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:27]Cl>O.C(Cl)(Cl)Cl>[Cl:27][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[N:1]([C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:2][CH2:3]2
Reactant: ClCl
Reactant: c1ccc2c(c1)CCN2
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(c1ccccc1)N1CCc2cc(Cl)ccc21

Procedure:
A mixture of 714 g (6 moles) of indoline and 1500 ml of chloroform and 528 g (6.6 moles) of aqueous sodium hydroxide solution (50%) was stirred at 20° to 30° C. while adding 928 g (6.6 moles) of benzoyl chloride thereto and the mixture was stirred for one hour after which 300 ml of water and 351 g (3.3 moles) of sodium carbonate were added thereto. 468.5 g (6.6 moles) of chlorine were added to the mixture with vigorous stirring and water cooling over 51/2 hours to keep the temperature below 30° C. The mixture was stirred for 30 minutes and after the addition of 1500 ml of water, the mixture was stirred for 15 minutes. The decanted organic phase was evaporated to dryness under reduced pressure at 130° C. and the residue was taken up in 1200 ml of isopropanol. The mixture was heated with stirring until complete dissolution occured and the mixture was cooled and stirred at 20°-25° C. for one hour. The mixture was vacuum filtered to obtain 5-chloro-1-benzoyl-indoline melting at 135°- 136° C.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:19]1[CH2:20][O:21][C:22](=[O:26])[C:23]=1[CH:24]=C.I([O-])(=O)(=O)=[O:28].[Na+]>CC(C)=O.O>[CH:24]([C:23]1[C:22](=[O:26])[O:21][CH2:20][C:19]=1[N:3]1[CH2:4][CH2:5][C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)[C:2]1=[O:1])=[O:28]
Reactant: C=CC1=C(N2CCC3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)COC1=O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(C1=C(C=O)C(=O)OC1)C2=O
Reaction time: 0.08 h

Procedure:
tert-butyl 1-oxo-2-(5-oxo-4-vinyl-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate (1.6 g, 4.4 mmol) was dissolved in acetone (36 mL) and water (36 mL), then K2OsO4.2H2O was added and the mixture was stirred for ˜5 min. Solid sodium periodate (3.77 g, 17.6 mmol) was added in 4 portions during 1 hour and the reaction temperature was maintained below 40° C. using an ice-bath. The resulting mixture was stirred for 1 hour at room temperature. LCMS after 2 hours showed complete consumption of starting material. The suspension was filtered and the filtrate was concentrated to remove acetone. The aqueous layer was extracted with DCM (3×). Combined organic layers were washed with 10% Na2S2O3 solution (2×), dried over anhydrous Na2SO4, filtered, concentrated to obtain the title compound, which was taken to the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N+:13]([O-])([OH:15])=[O:14]>>[N+:13]([C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=[CH:7][C:8]=1[O:11][CH3:12])([O-:15])=[O:14]
Reactant: COc1ccc(C(C)(C)C)cc1
Reactant: O=[N+]([O-])O
Product: COc1ccc(C(C)(C)C)cc1[N+](=O)[O-]

Procedure:
reacting 4-tert-butylanisole with nitric acid to produce 2-nitro-4-tertbutylanisole;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][CH:4]=1.[Cl:14][S:15](O)(=[O:17])=[O:16]>C(Cl)(Cl)(Cl)Cl>[Cl:14][S:15]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:3]=1[O:2][CH3:1])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:17])=[O:16]
Reactant: O=S(=O)(O)Cl
Reactant: CCOC(=O)c1ccc(OC)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(OC)c(S(=O)(=O)Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of ethyl 4-methoxybenzoate (10.25 g, 57 mmol) in CCl4 (40 ml) is cooled to −15° C. and treated dropwise with chlorosulfonic acid (10.4 ml, 156 mmol) in the course of 15 min, the temperature rising to −10° C. After addition is complete, the reaction mixture is warmed to RT with stirring in the course of 30 min and then stirred at 40-50° C. for 1.5 h. The heating is removed and the reaction mixture is stirred at RT in a gentle stream of argon for 64 h to complete the chlorination. The reaction mixture is added to a suspension of ice (25 g) in CCl4 (50 ml) with ice-cooling and vigorous stirring. It is stirred vigorously for 3 min. The organic phase is separated off and the aqueous phase is extracted 3 times with further CH2Cl2 (150 ml). The combined organic extracts are washed with saturated NaCl solution, dried over Na2SO4 sicc. and concentrated: a crystalline, white residue of a mixture of ester and free acid in the ratio 1:1 remains, which is dried on an oil pump, yield 6.7 g (42%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[H-].[Na+].[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17](F)[C:14]=1[C:15]#[N:16]>CN(C)C=O>[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([O:6][CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([Br:1])[CH:3]=2)[C:14]=1[C:15]#[N:16]
Reactant: OCc1cccc(Br)c1
Reactant: N#Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(F)cccc1OCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Bromobenzyl alcohol (1.45 mg; 7.9 mmol) in dimethylformamide was added to a cooled (0° C.) slurry of sodium hydride (316 mg; 7.9 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature, stirred for 30 min. The reaction mixture was then added to a cooled (0° C.) solution of 2,6-difluorobenzonitrile in dimethylformamide, stirred for 2 hours at room temperature. The reaction mixture was poured on crushed ice-water, stirred, filtered, washed with water and dried to afford 1.81 grams of 2-fluoro-6-(3-bromophenylmethoxy)benzonitrile.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:10][C@H:9]([NH2:11])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](N1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[N:17]=[CH:16]1)([O-])=O>>[N+:20]([C:18]1[N:17]=[CH:16][N:11]([C@H:9]2[CH2:8][C@@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:10]2)[CH:19]=1)([O-:22])=[O:21]
Reactant: N[C@H]1C[C@@H](c2ccccc2)C1
Reactant: O=[N+]([O-])c1cn([N+](=O)[O-])cn1
Product: O=[N+]([O-])c1cn([C@H]2C[C@@H](c3ccccc3)C2)cn1
Yield: 46 %

Procedure:
This reaction was carried out using the procedure for Preparation 1 with cis-3-phenylcyclobutylamine (J. Med. Pharm. Chem. 1960, 2, 687–691; ACIEE 1981, 20, 879–880) and 1,4-dinitroimidazole to afford 46 mg (46% yield) of 4-nitro-1-(cis-3-phenyl-cyclobutyl)-1H-imidazole; 1H NMR (300 MHz, CDCl3) δ 7.9 (s, 1H), 7.55 (s, 1H), 7.4–7.2 (m, 5H), 4.73 (m, 1H), 3.48 (m, 1H), 3.12 (m, 2H), 2.54 (m, 2H); MS (AP/CI): 244 (M+H)+.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C@@H:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH2:11]4)[C@@H:6]1[CH2:5][CH:4]=[CH:3]2.[BH4-].[Na+]>C1COCC1.CO>[CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C@@H:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C@H:12]([OH:20])[CH2:11]4)[C@@H:6]1[CH2:5][CH:4]=[CH:3]2
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C=CC[C@@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@]12CC[C@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C=CC[C@@H]12

Procedure:
This synthesis is depicted in FIG. 1. Ketone 1 (500 mg, 1.84 mmol) Was reduced with sodium borohydride (d, 75 mg, 2 mmol) in THF/MeOH 5:1 (18 ml) at RT (2 h). The crude product was chromatographed on silica gel (60 g) using toluene/ethyl acetate 2:1. After traces of the axial alcohol 2 (9 mg, 2%) were observed, the pure equatorial alcohol 3 (388 mg, 77%) was eluted. An analytical sample was recrystallized from MeOH/water. M.p. 124°-125°, [a]D =+14.2° (c=1.12) ([2]: m.p. 125°-127°, [a]D17 =+11.2° (c=0.76)). --IR. (CDCl3): 3620m, 3430w, 1590w. --1H-NMR. (360 Mhz): 0.77 (s, 3 H); 0.85 (s, 3 H); 3.60 t×t, J=11 and 5, 1 H); 5.70 (m, 1 H); 5.84 (m, 1 H).
Reaction SMILES: [Li].[CH3:2]I.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:12]23[CH2:21][CH:16]([N:17]([CH3:20])[C:18]2=O)[CH2:15][CH2:14][CH2:13]3)[CH:9]=[CH:10][CH:11]=1.O>CCOCC.C1C=CC=CC=1>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:12]23[CH2:21][CH:16]([N:17]([CH3:20])[C:18]2=[CH2:2])[CH2:15][CH2:14][CH2:13]3)[CH:9]=[CH:10][CH:11]=1
Reactant: COc1cccc(C23CCCC(C2)N(C)C3=O)c1
Reactant: CI
Agent: [Li]
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: O
Product: C=C1N(C)C2CCCC1(c1cccc(OC)c1)C2
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
0.17 g of lithium is added to 8 ml of absolute ether in a nitrogen atmosphere, and a solution of 1.6 g of methyl iodide in 3 ml of absolute ether is added dropwise thereto at 0° to -5°C. The mixture is stirred at the same temperature for 30 minutes. Then, a solution of 1.0 g of 1-(3-methoxyphenyl)-6-methyl-6-azabicyclo[3,2,1]octane-7-one in 30 ml of benzene is added dropwise to the mixture at room temperature for 5 minutes. The mixture is refluxed for 3 hours. Water is added to the mixture under ice-cooling, and the aqueous mixture is extracted with ether. The ether extract is washed with water, dried and then evaporated to remove solvent, whereby 1.0 g of 1-(3-methoxyphenyl)-6-methyl-7-methylidene-6-azabicyclo[3,2,1]octane is obtained. The product thus obtained is dissolved in 60 ml of ethanol. 300 mg of sodium borohydride are added to the ethanol solution at 10° to 15°C. Then, the mixture is stirred at room temperature for 20 hours. After the reaction, the mixture is concentrated under reduced pressure. Water is added to the residue, and the aqueous mixture is extracted with chloroform. The chloroform extract is washed with water, dried and then evaporated to remove solvent. Methanolic hydrogen bromide is added to the residue in ether, and the crystalline precipitate is collected by filtration. The precipitate is recrystallized from a mixture of ethanol, acetone and ether. 1.1 g of 1-(3-methoxyphenyl)-6,7-dimethyl-6-azabicyclo[3,2,1]octane hydrobromide are obtained. M.p. 175° - 177°C.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:18][C:19]1[CH:44]=[CH:43][C:22]2[C:23]([N:26](C(OCC(Cl)(Cl)Cl)=O)[C:27](OCC(Cl)(Cl)Cl)=[O:28])=[N:24][O:25][C:21]=2[CH:20]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[F:18][C:19]1[CH:44]=[CH:43][C:22]2[C:23]([NH:26][C:27]([N:15]3[CH2:16][CH2:17][N:12]([C:10]4[S:9][N:8]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[N:11]=4)[CH2:13][CH2:14]3)=[O:28])=[N:24][O:25][C:21]=2[CH:20]=1
Reactant: O=C(OCC(Cl)(Cl)Cl)N(C(=O)OCC(Cl)(Cl)Cl)c1noc2cc(F)ccc12
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1noc2cc(F)ccc12)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 70 °C
Reaction time: 5 h
Yield: 32 %

Procedure:
A mixture of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (492 mg, 2.00 mmol), bis(2,2,2-trichloroethyl) (6-fluoro-1,2-benzisoxazol-3-yl)imidodicarbonate (502 mg, 1.00 mmol), diisopropylethylamine (0.174 ml, 1.00 mmol) and dimethyl sulfoxide (5 ml) was stirred at 70° C. for 5 hours. The reaction mixture was poured to water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of tetrahydrofuran and ethyl acetate to yield 136 mg (32.1%) of the desired product.
Reaction SMILES: CO[N:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]1[C:13]([F:16])([F:15])[F:14].[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18]>C(OCC)C>[C:17]([NH:21][C:8]1[N:7]=[C:6]2[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[NH:3][C:11]2=[CH:10][C:9]=1[Cl:12])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)N
Reactant: COn1c(C(F)(F)F)nc2ncc(Cl)cc21
Solvent: CCOCC
Product: CC(C)(C)Nc1nc2nc(C(F)(F)F)[nH]c2cc1Cl
Reaction time: 192 h

Procedure:
1-Methoxy-6-chloro-2-(trifluoromethyl)-1H-imidazo [4,5-b] pyridine (2.0 grams) was mixed with tert-butylamine (5 milliliters) in 10 milliliters of diethyl ether. The reaction mixture was permitted to stand for eight days; then solvent was evaporated and the residue taken up in 8 milliliters of chloroform, permitted to stand for two hours, and filtered to separate the desired 5-tert-butylamino-6-chloro-2-(trifluoromethyl)-1H-imidazo [4,5-b] -pyridine, m.p., 252° -4° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:11][N:12]3[CH:16]=[C:15]([CH2:17][OH:18])[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13]3)[CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[S:35](Cl)(=[O:37])=[O:36]>C1COCC1.CS(C)=O>[OH:18][CH2:17][C:15]1[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13][N:12]([CH2:11][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[CH2:3][C@H:2]([NH:1][S:35]([C:31]2[O:30][CH:34]=[CH:33][CH:32]=2)(=[O:37])=[O:36])[CH2:10]3)[CH:16]=1
Reactant: O=S(=O)(Cl)c1ccco1
Reactant: N[C@H]1Cc2ccc(Cn3cc(CO)c(C(F)(F)F)n3)cc2C1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(N[C@H]1Cc2ccc(Cn3cc(CO)c(C(F)(F)F)n3)cc2C1)c1ccco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
(S)-(1-((2-amino-2,3-dihydro-1H-inden-5-yl)methyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)methanol (0.08 mmol, 25 mg) was dissolved in THF (1 mL) and triethylamine (0.25 mmol, 35 μL, 25 mg) followed by furan-2-sulfonyl chloride (0.084 mmol, 14.05 mg) and the solution stirred at room temperature overnight. The reaction was concentrated before partitioning between dichlormethane (3 mL) and 1N HCl (3 mL). The organic layer was collected and dried using a hydrophobic frit and concentrated under a stream of nitrogen to give a brown residue which was dissolved in DMSO (1 mL) and purified on preparative basic HPLC to give (S)—N-(5-((4-(hydroxymethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2,3-dihydro-1H-inden-2-yl)furan-2-sulfonamide (14.3 mg, 0.032 mmol, 40.5%) MS (ESI): m/z [M+H]+ 442.2
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O)C.[BH4-].[Na+]>CN(C=O)C>[CH2:22]([N:7]1[CH2:8][CH2:9][C:4]2[CH:3]=[C:2]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[NH:1][C:5]=2[CH2:6]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cc2ccncc2n1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)c1cc2c([nH]1)CN(Cc1ccccc1)CC2
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 1-tert-butyl 2-ethyl 1H-pyrrolo[2,3-c]pyridine-1,2-dicarboxylate (1.0 eq) in DMF was added benzyl bromide (1.0 eq.) and heated to 80° C. for 4 hrs. Reaction mixture was evaporated to dryness. The product obtained was dissolved aqueous ethanol and NaBH4 (1.5 eq.) was added at 0° C. and stirred for 4 hrs. Reaction was quenched with water, extracted with dichloromethane, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded ethyl 6-benzyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate.
Reaction SMILES: [I:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH:12]1[CH:17]=[CH:16][C:15]([P:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:14][CH:13]=1>CC#N>[I-:1].[C:25]1([P+:18]([C:15]2[CH:14]=[CH:13][CH:12]=[CH:17][CH:16]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: ICCCCc1ccccc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: [I-]
Product: c1ccc(CCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 62.2 %

Procedure:
A solution of (4-iodobutyl)benzene (1.04 g, 4.0 mmol) and Ph3P (1.05 g, 4.0 mmol) in CH3CN (20 mL) was stirred for 48 h and then washed with hexane. The solvent was removed to afford triphenyl(4-phenylbutyl)phosphonium iodide (1.30 g, 62%) as a white foam, which was used in the following step without purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[SH:14].Br[CH2:16][C:17]1[CH:21]=[CH:20][S:19][C:18]=1[C:22](=[O:27])[C:23]([O:25][CH3:26])=[O:24]>CC(C)=O>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14][CH2:16][C:17]1[CH:21]=[CH:20][S:19][C:18]=1[C:22](=[O:27])[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)C(=O)c1sccc1CBr
Reactant: Sc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C(=O)c1sccc1CSc1ccccc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 68.3 %

Procedure:
2.62 g (19 mmol) of potassium carbonate and 2.74 g (19 mmol) of 2-chlorothiophenol are added to a solution of 5 g (19 mmol) of methyl 3-bromomethylthien-2-ylglyoxylate in 50 ml of acetone, the mixture is stirred for 72 hours at room temperature and filtered and the filtrate is evaporated down. The residue is taken up in methylene chloride, and the solution is washed with Na2CO3 solution, dried and evaporated down. The crude product is recrystallized from methanol. 4.24 g (68%) of the abovementioned compound are obtained.