Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[F:4][C:5]1[CH:10]=[CH:9][C:8]([C@@:11]2([CH2:15][N:16]3[CH:20]=[N:19][CH:18]=[N:17]3)[C@H:13]([CH3:14])[O:12]2)=[CH:7][CH:6]=1.C([S:24][C@H:25]1[CH2:30][O:29][C@@H:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:27][CH2:26]1)(=O)C>C(O)C>[F:4][C:5]1[CH:10]=[CH:9][C:8]([C@:11]([OH:12])([C@H:13]([S:24][C@H:25]2[CH2:26][O:27][C@@H:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:29][CH2:30]2)[CH3:14])[CH2:15][N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)=[CH:7][CH:6]=1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1
Reactant: CC(=O)S[C@H]1CO[C@@H](c2ccccc2)OC1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: C[C@@H](S[C@H]1CO[C@@H](c2ccccc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 72.2 %

Procedure:
1 ml (0.59 mmol) of a 4.8 M methanolic solution of sodium methoxide was added to a solution of 2.33 g (10 mmol) of (2R,3S)-2-(4-fluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane [prepared as described in Chem. Pharm. Bull., 43, 441-449 (1995)] and 2.38 g (10 mmol) of cis-5-(acetylthio)-2-phenyl-1,3-dioxane [prepared as descripted in Step 6(i) above] in 40 ml of ethanol. The resulting mixture was stirred at 80° C. for 5 hours. After cooling, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated and washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a silica gel (50 g) column using a 2:1 mixture of ethyl acetate and hexane as the eluant to afford 3.1 g (yield 72%) of the title compound as a brown foamy solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5](=[O:13])[N:6]([CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])[N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25]([S:30]([N:33]1[CH2:38][CH2:37][N:36]([C:39]([C:41]3[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=3)=[O:40])[CH2:35][CH2:34]1)(=[O:32])=[O:31])=[CH:24]2>COCCOC.O.C(O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25]([S:30]([N:33]1[CH2:34][CH2:35][N:36]([C:39]([C:41]3[CH:42]=[CH:43][C:44]([C:2]4[CH:3]=[CH:4][C:5](=[O:13])[N:6]([CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])[N:7]=4)=[CH:45][CH:46]=3)=[O:40])[CH2:37][CH2:38]1)(=[O:31])=[O:32])=[CH:24]2
Reactant: O=C(c1ccc(B(O)O)cc1)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Reactant: CN(C)CCn1nc(Cl)ccc1=O
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: CN(C)CCn1nc(-c2ccc(C(=O)N3CCN(S(=O)(=O)c4cc5cc(Cl)ccc5[nH]4)CC3)cc2)ccc1=O
Temperature: 150 °C
Yield: 60.7 %

Procedure:
6-Chloro-2-(2-dimethylamino-ethyl)-2H-pyridazin-3-one (76 mg, 0.38 mmol), cesium carbonate (122 mg, 0.38 mmol) and bis(triphenylphosphine)palladium II chloride (21.9 mg, 0.03 mmol) was added to a microwave vial. The vial was evacuated and filled with argon twice. 4-({4-[(5-Chloro-1H-indol-2-yl)sulphonyl]piperazin-1-yl}carbonyl)phenyl boronic acid (140 mg, 0.31 mmol) dissolved in 4 mL 1,2-di-methoxyethane/water/ethanol (7:3:2) was added and the vial was once again evacuated and filled with argon. The reaction mixture was heated at 150° C. for 100 seconds, filtrated and purified by preparative HPLC using a gradient of acetonitrile/5% acetonitrile-water phase containing 0.1M ammonium acetate, to give 107 mg of 6-{4-[4-(5-chloro-1H-indole-2-sulphonyl)-piperazine-1-carbonyl]-phenyl}-2-(2-dimethylamino-ethyl)-2H-pyridazin-3-one after evaporation and freeze drying over night (60% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([OH:6])=O.[O-:15][C:16]#[N:17].[K+].[OH-].[Na+].C(O)(C)C>C(O)(=O)C.O>[OH:15][C:16]1[N:17]=[C:4]([OH:6])[C:3]2[C:2](=[CH:10][CH:9]=[C:8]([O:11][CH3:12])[C:7]=2[O:13][CH3:14])[N:1]=1
Reactant: COc1ccc(N)c(C(=O)O)c1OC
Reactant: N#C[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC(C)O
Solvent: O
Product: COc1ccc2nc(O)nc(O)c2c1OC
Temperature: 60 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
2-Amino-5,6-dimethoxybenzoic acid (10.5 g, 53.2 mM) was dissolved in glacial acetic acid (100 ml) and potassium cyanate (10.8 g, 133.0 mM) in 120 ml H2O was added gradually and stirred for 2 hours at 60° C. After cooling the reaction mixture to 20° C., sodium hydroxide pellets (78.2 g, 196 mole) were added while maintaining the temperature below 60° C. The reaction mixture was then heated at 90° C. for 45 minutes. Upon cooling in an ice bath, the sodium salt of the product precipitated, was filtered, resuspended in H2O (120 ml), acidified (pH 3) with concentrated HCl, cooled, and filtered to give the crude product. Trituration with warm isopropanol afforded (60.8%) of a white solid, mp 266°-268° C.
Reaction SMILES: C(O[N:5]=[C:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([C:17](=[O:34])[C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:33])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])=[CH:20][CH:19]=2)[CH2:9][CH2:8][CH2:7]1)(=O)C>C(O)(=O)C.[Pt]=O>[NH2:5][CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([C:17](=[O:34])[C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:33])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])=[CH:20][CH:19]=2)[CH2:9][CH2:8][CH2:7]1
Reactant: CC(=O)ON=C1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3Cl)cc2)c2ccccc21
Agent: O=[Pt]
Solvent: CC(=O)O
Product: NC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3Cl)cc2)c2ccccc21
Yield: 44.9 %

Procedure:
To a solution of 5-acetyloxyimino-1-[4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.48 g) in acetic acid (20 ml) is added platinum oxide (0.05 g) and the mixture is subjected to catalytic reduction under hydrogen atmosphere. After completion of the reaction, the catalyst is removed by filtration, and the filtrate is concentrated. The resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=20:1→10:1), and recrystallized from ethanol/diethyl ether to give 5-amino-1-[4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.19 g) as colorless prisms, m.p. 176°-178° C.
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]([OH:13])(=[O:12])[C:9]([CH3:11])=[O:10].[CH2:14]([O:16][CH2:17][CH2:18]O)[CH3:15]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:8]([O:13][CH2:15][CH2:14][O:16][CH2:17][CH3:18])(=[O:12])[C:9]([CH3:11])=[O:10]
Reactant: CCOCCO
Reactant: CC(=O)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOCCOC(=O)C(C)=O
Temperature: 25 °C
Yield: 67.9 %

Procedure:
A toluene solution (1 L) contaning pyruvic acid (440 g, 5.0 mol), 2-ethoxyethanol (450 g, 5.0 mol) and p-toluenesulfonic acid monohydrate (2.5 g) was heated and refluxed for 16 hours under nitrogen flow. The reaction led to generation of water in the system. However, the water was removed using Dean-Stark trap. The resultant reaction solution was cooled down to room temperature, followed by removal of toluene using an evaporator under a reduced pressure. The residual was then purified using reduced pressure distillation (40 mmHg, 100 to 105° C.) to give 2-ethoxyethyl pyruvate (544 g, yield: 68%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:12][C:13]([C:15]2[CH:16]=[N:17][C:18]([O:22][CH3:23])=[C:19](Br)[CH:20]=2)=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[C:24]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)#[N:25].[F-].[K+].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>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].O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1([NH:12][C:13]([C:15]2[CH:16]=[N:17][C:18]([O:22][CH3:23])=[C:19]([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]([C:24]#[N:25])[CH:31]=3)[CH:20]=2)=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: COC(=O)C1(NC(=O)c2cnc(OC)c(Br)c2)CCCCCC1
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Product: COC(=O)C1(NC(=O)c2cnc(OC)c(-c3cccc(C#N)c3)c2)CCCCCC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
The compound of step 2 (300 mg, 0.779 mmol), 3-cyano-phenylboronic acid (171 mg, 1.17 mmol), tris(dibenzylideneacetone)dipalladium(0) (214 mg, 0.234 mmol), potassium fluoride (149 mg, 2.57 mmol) and tri-tert-butylphosphonium tetrafluoroborate (136 mg, 0.47 mmol) in a flask were thoroughly flushed with argon, dioxane (3 ml) was added and the mixture was stirred for 2 h at 50° C. The mixture was filtered over silica gel and evaporated to dryness. This residue was purified by RP HPLC (water/ACN gradient) to yield 200 mg of the title compound.
Reaction SMILES: [F:1][CH:2]([F:8])[CH2:3][O:4]C(=O)C.[CH2:9]([NH2:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(NC(=O)C(F)F)CC>C(#N)C>[CH2:9]([NH:21][C:3](=[O:4])[CH:2]([F:1])[F:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CC(=O)OCC(F)F
Reactant: CCCCCCCCCCCCN
Agent: CCCNC(=O)C(F)F
Solvent: CC#N
Product: CCCCCCCCCCCCNC(=O)C(F)F

Procedure:
One equivalent difluoroethylacetate and one equivalent dodecylamine stirred at room temperature in acetonitrile 16 hours. The solvent is removed to give a white wax, which is chromatographed on silica gel in CHCl3 /EtOAc (15:1), Rf =0.7. NMR (CDCl3, δ) 7.2 b-s (1H); 5.9 g (2H) J=26; 3.35 m (2H); 1.3 s (20H); 0.9 m (3H). Other compounds prepared this way, with similar NMR, acceptable Mass Spectra and TLC: N-propyl-difluoroacetamide.
Reaction SMILES: O[C:2]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]1C(OC(C)(C)C)=O.Cl>C(O)C>[NH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][N:5]=2)[CH:10]=[C:2]1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C1(O)Cc2cccnc2N1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc2cccnc2[nH]1
Temperature: 25 °C
Yield: 71.9 %

Procedure:
To a stirred solution of (RS) ethyl (2-hydroxy-1-tert-butoxycarbonyl-7-azaindoline-2-carboxylate) (0.6 g, 1.9 mmol) in ethanol (20 mL) was added dropwise concentrated hydrochloric acid (0.6 mL). The mixture was heated under reflux for 2 h, cooled to room temperature and partitioned between ether (30 mL) and aqueous sodium hydrogen carbonate solution (30 mL). The organic layer was washed (water, brine), dried (sodium sulfate) and concentrated in vacuo to give ethyl 7-azaindole-2-carboxylate as a white solid (0.26 g, 70%). mp 153–6° C. Found: C, 62.84; H, 5.34; N, 14.50%. C10H10N2O2 requires: C, 63.15; H, 5.30; N, 14.72%.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[O:15]1[C:19]2([CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]2)[O:18][CH2:17][CH2:16]1.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[CH2:26]([NH:33][CH:22]1[CH2:23][CH2:24][C:19]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:20][CH2:21]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NCc1ccccc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc(CNC2CCC3(CC2)OCCO3)cc1
Reaction time: 2 h
Yield: 101.1 %

Procedure:
Na(OAc)3BH 2.03 g (9.6 mmol) was added to a solution of 1,4-dioxa-spiro[4.5]decan-8-one 1.0 g (6.4 mmol) and benzylamine 0.69 g (6.4 mmol) in CH2Cl2 (20 ml) under nitrogen as inert gas and stirring was performed for 2 h at RT. After the addition of CH2Cl2 (80 ml), the organic phase was washed with aqueous saturated NaHCO3 solution. After drying of the separated organic phases over Na2SO4 and filtration, the solvent was removed by distillation and the product benzyl-(1,4-dioxa-spiro[4.5]dec-8-yl)-amine 1.6 g (100% of theoretical) was obtained.
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].[OH:6][C@H:7]1[CH2:33][CH2:32][C@@:31]2([CH3:34])[C@@H:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:30]2[C:29](=[O:35])[CH2:28][C@@:27]2([CH3:36])[C@H:13]3[CH2:14][C@@H:15]3[O:20][C@@:19]4([O:26][CH2:25][C@H:23]([CH3:24])[CH2:22][CH2:21]4)[C@@H:17]([CH3:18])[C@@H:16]32)[CH2:8]1.C(N(CC)CC)C.CC1C=CN=C(N)C=1C>ClCCl>[CH3:1][Si:2]([CH3:4])([CH3:3])[O:6][C@H:7]1[CH2:33][CH2:32][C@@:31]2([CH3:34])[C@@H:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:30]2[C:29](=[O:35])[CH2:28][C@@:27]2([CH3:36])[C@H:13]3[CH2:14][C@@H:15]3[O:20][C@@:19]4([O:26][CH2:25][C@H:23]([CH3:24])[CH2:22][CH2:21]4)[C@@H:17]([CH3:18])[C@@H:16]32)[CH2:8]1
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4C(=O)C[C@]3(C)[C@H]1[C@@H]2C
Reactant: C[Si](C)(C)Cl
Agent: Cc1ccnc(N)c1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O[Si](C)(C)C)CC[C@]5(C)[C@H]4C(=O)C[C@]3(C)[C@H]1[C@@H]2C
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.3 %

Procedure:
Trimethylsilylchloride (3.27 mL, 25.8 mmol) was added to a solution of (3β,5α,25R)3-hydroxy-spirostan-11-one (4.0 g, 9.3 mmol) and triethylamine (6.5 mL, 46 mmol) in dichloromethane (60 mL) at room temperature. One gram of dimethyl aminopyridine was added and the reaction was stirred at room temperature for 12 hours. The reaction was quenched with methanol (1 mL) and diluted with ethyl acetate, washed with water (5×) and brine (1×), dried (Na2SO4), filtered and concentrated in vacuo. The product was triturated with methanol, filtered and dried to afford 3.94 g (85%) product as a white solid. 1H NMR (250 MHz, CDCl3) 6 4.5 (q, 1H, J=6Hz); 3.45 (m, 2H); 2.35 (t, 1H, J=10 Hz); 2.4 (dt, 1H, J=12.2 Hz); 2.2 (s, 2H); 2.1-1.1 (m, 12H); 1.02 (s, 3H); 0.9 (d, 3H, J=7.0 Hz); 0.78 (d, 3H, J=7 Hz); 0.69 (s, 3H); 0.1 (s, 9H).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:4]=1[O:5][C@@H:6]1[CH2:10][N:9](CC2C=CC=CC=2)[CH2:8][C@H:7]1[OH:18].CCl.[CH2:26]([O:33][C:34](Cl)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[Cl:2][C:3]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:4]=1[O:5][C@@H:6]1[CH2:10][N:9]([C:34]([O:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:35])[CH2:8][C@H:7]1[OH:18]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O[C@@H]1CN(Cc2ccccc2)C[C@H]1Oc1cccc(Cl)c1Cl
Agent: CCl
Agent: Cl
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1C[C@@H](O)[C@H](Oc2cccc(Cl)c2Cl)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 8.5 g (0.023 mole) of trans-4-(2,3-dichlorophenoxy)-1-phenylmethyl-3-pyrrolidinol hydrochloride and 100 liters of methyl chloride was cooled and treated dropwise with a solution of 23 g (0.125 mole) of benzylchloroformate in 100 ml of methylene chloride. The mixture was stirred at ambient temperature for 48 hr and then washed successively with water, 2N hydrochloric acid, 5% sodium hydroxide and water. The methylene chloride layer was dried over anhydrous sodium sulfate and then subjected to vacuum distillation at 100°/1.0 mm. to remove the methylene chloride, excess benzylchloroformate and benzyl chloride. An NMR analysis of the pot residue indicated only the oxygen was substituted. An additional 25 ml. of benzylchloroformate and 100 ml. of methylene chloride was added to the residue and the solution stirred at ambient temperature for 48 hr. The mixture was purified as above to give 14.6 g. of residue which was chromatographed on 300 g. of silica gel. The chromatography gave 5.6 g. of the disubstituted compound (See Example 20) and 1.0 g. of the titled compound as a white solid, m.p. 130°-2° C. (recrystallized from benzene).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[S:11][C:10]([NH:12][C:13](=[O:22])[C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[F:21])=[N:9][C:8]=2[CH3:23])=[CH:4][CH:3]=1.O1C2C=CC(C3SC(NC(=O)C4C(F)=CC=CC=4F)=NC=3C)=CC=2OC1>>[F:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([F:20])[C:14]=1[C:13]([NH:12][C:10]1[S:11][C:7]([C:5]2[S:6][CH:2]=[CH:3][CH:4]=2)=[C:8]([CH3:23])[N:9]=1)=[O:22]
Reactant: Cc1nc(NC(=O)c2c(F)cccc2F)sc1-c1ccc(Br)s1
Agent: Cc1nc(NC(=O)c2c(F)cccc2F)sc1-c1ccc2c(c1)OCO2
Product: Cc1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccs1

Procedure:
Compound 60 was prepared from Compound 59 as described for the preparation of Compound 57.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]([C:16]2[CH:20]=[CH:19][NH:18][N:17]=2)[C:12]([NH:21]C(=O)C)=[N:11]1.Cl.[OH-].[K+].O>C(O)C.CO>[NH2:21][C:12]1[CH:13]([C:16]2[CH:20]=[CH:19][NH:18][N:17]=2)[C:14](=[O:15])[N:10]([C:3]2[C:4]([Cl:9])=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:11]=1
Reactant: CC(=O)NC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1c1cc[nH]n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Solvent: O
Product: NC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1c1cc[nH]n1
Temperature: 10 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
Next, 31 g (0.08 mol) of the 1-(2,4,6-trichlorophenyl)-3-acetylamino-4-pyrazolyl-5-oxo-2-pyrazoline in 600 ml of ethanol was heated under reflux while 55 ml of concentrated hydrochloric acid was added. Then, after 1 hour, the reaction mixture was cooled to about 10° C. and neutralized with a solution containing 39 g of potassium hydroxide in 400 ml of methanol. The resulting solution was added to 2.5 l of water to obtain 21.6 g (78%) of 3-amino-1-(2,4,6-trichlorophenyl)-4-pyrazolyl-5-oxo-2-pyrazoline.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:17][CH:16]=1)=[O:14])=[C:8]([C:30]1[C:35]([F:36])=[CH:34][C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH:7]=[CH:6]2.Cl.C(OCC)C.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl.CO>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)=[CH:17][CH:16]=1)=[O:14])=[C:8]([C:30]1[C:35]([F:36])=[CH:34][C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH:7]=[CH:6]2
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3c(F)cc(F)cc3F)ccc2c1
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2c(F)cc(F)cc2F)ccc2cc(O)ccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
Alternatively, dissolve [6-methoxy-2-(2,4,6-trifluoro-phenyl)-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (1.90 g, 3.67 mmol) in dichloromethane (10 ml). Add 2 M HCl in diethyl ether (4.0 mL, 80 mmol). Concentrate the slurry and dry in vacuo. Dilute the residue in dichloromethane (30 ml) and blanket with nitrogen. Cool the solution to 0° C. with an external ice bath. Add boron tribromide (1 mL, 11 mmol). After 60 minutes, pour the reaction mixture into a mixture of ice (20 g), methanol (10 mL) and saturated sodium bicarbonate solution (20 mL). Extract with dichloromethane (100 mL). Separate the layers, wash the organic layer with brine (20 mL), dry with magnesium sulfate, filter, and concentrate in vacuo. Purify the residue over silica gel, eluting the material with a step gradient of methanol/dichloromethane (0 to 10%), to give 1.6 g (87%) of the title compound: mass spectrum (ion spray) m/z=506.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:25][C:24]([O:26][C@H:27]3[CH2:32][O:31][C@H:30]([CH2:33][OH:34])[C@@H:29]([OH:35])[CH2:28]3)=[N:23][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=1.Br[C:37]1[CH:42]=[CH:41][C:40]([CH:43]([NH2:48])[C:44]([F:47])([F:46])[F:45])=[CH:39][CH:38]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>>[NH2:48][CH:43]([C:40]1[CH:41]=[CH:42][C:37]([C:11]2[CH:10]=[CH:9][C:8]([C:7]3[N:6]=[C:5]4[N:23]=[C:24]([O:26][C@H:27]5[CH2:32][O:31][C@H:30]([CH2:33][OH:34])[C@@H:29]([OH:35])[CH2:28]5)[NH:25][C:4]4=[CH:3][C:2]=3[Cl:1])=[CH:13][CH:12]=2)=[CH:38][CH:39]=1)[C:44]([F:45])([F:46])[F:47]
Reactant: CC1(C)OB(c2ccc(-c3nc4nc(O[C@H]5CO[C@H](CO)[C@@H](O)C5)[nH]c4cc3Cl)cc2)OC1(C)C
Reactant: NC(c1ccc(Br)cc1)C(F)(F)F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: NC(c1ccc(-c2ccc(-c3nc4nc(O[C@H]5CO[C@H](CO)[C@@H](O)C5)[nH]c4cc3Cl)cc2)cc1)C(F)(F)F
Temperature: 80 °C

Procedure:
A 10 mL reaction vial was charged with (2R,3S,5R)-5-((6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)-2-(hydroxymethyl)-tetrahydro-2H-pyran-3-ol (61.2 mg, 0.122 mmol), 1-(4-bromophenyl)-2,2,2-trifluoroethanamine (35 mg, 0.102 mmol), potassium phosphate tribasic (108 mg, 0.509 mmol), and [1,1′-[1,1′-Bis(Diphenyl-phosphino)-Ferrocene]Dichloropalladium (II) (14.89 mg, 0.020 mmol). The reaction vessel was evacuated and backfilled with N2 (×3), and degassed dioxane (339 μl) and water (339 μl) were added. The reaction was heated to 80° C. for 4 h, then diluted with water and EtOAc. The aqueous phase was extracted with EtOAc (×2); and the combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by mass directed reverse phase HPLC eluted with acetonitrile in water containing 0.1% formic acid. The desired fractions were combined and lyophilized to give the title compound as a white solid. LC-MS: calculated for C26H24ClF3N4O4 548.14 observed m/e: 549.14 (M+H)+ (Rt 1.55/4 min); 1H NMR δ (ppm) (CD3OD): 7.90 (d, 1H), 7.84 (s, 1H), 7.78 (s, 4H), 7.67 (d, 2H), 5.42 (q, 1H), 5.12 (septet, 1H), 4.35 (dd, 1H), 3.88 (d, 1H), 3.66-3.59 (m, 2H), 3.37 (t, 1H), 3.18-3.15 (m, 1H), 2.76-2.74 (m, 1H), 1.69 (q, 1H).
Reaction SMILES: C1(C2(C(O)=[O:13])CCCC2)C=CC=CC=1.[C:15]1([C@@H:21]([N:23]2[CH2:27][C@@H:26]3[CH:28](N)[CH2:29][CH2:30][C@@H:25]3[CH2:24]2)[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N1C[C@H]2C(N)CC[C@H]2C1)C1C=CC=CC=1>>[C:15]1([C@@H:21]([N:23]2[CH2:27][C@H:26]3[C:28](=[O:13])[CH2:29][CH2:30][C@H:25]3[CH2:24]2)[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Reactant: C[C@@H](c1ccccc1)N1C[C@H]2CCC(N)[C@H]2C1
Agent: NC1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Product: C[C@@H](c1ccccc1)N1C[C@@H]2CCC(=O)[C@@H]2C1

Procedure:
The title compounds were prepared by substituting (S)-2-phenylbutanoic acid for 1-phenylcyclopentanecarboxylic acid and (3aR,6aS)-2-((S)-1-phenylethyl)octahydrocyclopenta[c]pyrrol-4-amine for (3aS*,6aR*)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Examples 1 and 2.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([N:18]=[CH:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH:18][CH2:19][CH2:20][CH:21]([CH3:22])[CH3:23])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3ccccc3c2n1N=CCC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOCc1nc2cnc3ccccc3c2n1NCCC(C)C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
A solution of N-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)(3-methylbutylidene)amine (1.28 g, 4.13 mmol) in 25 mL of methanol was treated with NaBH4 (0.47 g, 12.39 mmol). After 1 h, the reaction was quenched with saturated NH4Cl solution and the mixture was concentrated under reduced pressure. The residue was partitioned between CHCl3 and saturated NaHCO3 solution and the phases were separated The organic portion was washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield N-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)(3-methylbutyl)amine (1.24 g) as a dark orange oil.