Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([N:14]=[N+]=[N-])[C@H:10]([OH:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH2:14])[C@H:10]([OH:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N=[N+]=[N-])[C@H](O)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](O)C1

Procedure:
To a stirred solution of (±)-trans-4-azido-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (10 mmol, 2.42 g) in methanol (25 mL) was added 10% palladium on carbon (0.5 g, wet), and the resultant reaction mixture was subjected to hydrogenation using a balloon full of hydrogen for 8 h. The catalyst was filtered through a pad of celite, and the pad was with methanol (25 mL). The combined filtrate was concentrated under reduced pressure to provide (±)-trans-4-amino-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]2[S:9][CH:10]=[C:11]([Cl:12])[C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl.[Cl:14]/[CH:15]=[CH:16]/[CH2:17][NH:18][CH3:19].C(=O)([O-])[O-].[K+].[K+].ClCCl>CS(C)=O>[Cl:12][C:11]1[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][N:18]([CH2:17]/[CH:16]=[CH:15]/[Cl:14])[CH3:19])[C:8]=2[S:9][CH:10]=1
Reactant: Clc1csc2c(CBr)cccc12
Reactant: CNC/C=C/Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CN(C/C=C/Cl)Cc1cccc2c(Cl)csc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
To a solution of 2.62 g-(10 mmol) of 7-bromomethyl-3-chlorobezo(b]thiophene in 10 ml of dimethyl sulfoxide were added 1.7 g (12 mmol) of (E)-N-(3-chloro-2-propenyl)methylamine hydrochloride and 2.07 g (15 mmol) of ground potassium carbonate. The mixture was stirred for 16 hours at room temperature, and poured into 150 ml of dichloromethane. The organic layer was washed with 100 ml×2 of water and 50 ml of saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (n-heptane). The desired fractions were put together and concentrated under reduced pressure to obtain 2.12 g (yield: 74%) of the above identified compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:28]2[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]2)[CH:16]=1
Reactant: CN1CCNCC1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Solvent: C1CCOC1
Product: CN1CCN(Cc2cccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)c2)CC1
Temperature: 70 °C
Yield: 65.9 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-3-((4-methylpiperazin-1-yl)methyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.050 g; 0.144 mmol) and N-methylpiperazine (0.0554 mL; 0.5 mmol) in THF (3 mL). The mixture was heated at 70° C. for 5 hours. Flash chromatography on silica gel (eluent 10 to 15% methanol in dichloromethane) furnished 0.039 g (66%) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6]>C1COCC1>[Br:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH2:5][OH:6])[CH:8]=[CH:9][CH:10]=1
Reactant: COc1c(Br)cccc1C(=O)O
Solvent: C1CCOC1
Product: COc1c(Br)cccc1CO
Temperature: 0 °C
Reaction time: 15 h

Procedure:
In a 250 ml round bottom flask, 3-bromo-2-methoxybenzoic acid (4.0 g, 17 mmol, 1.0 eq) was dissolved in THF (100 mL). The solution was cooled to 0° C. To above solution was added dropwise borane/THF complex (1 N, 17.3 mL, 17.3 mmol). The solution was warmed to r.t. and let stirred at r.t for 15 hr. The reaction was quenched with addition of aqueous ammonium chloride and concentrated. The mixture was diluted with EtOAc, washed with 1 N HCl followed by aqueous sodium bicarbonate solution, brine and water. The organic phase was dried over MgSO4, filtered and concentrated. The crude product was used without purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9]OS(C)(=O)=O)=[CH:3][CH:2]=1.[CH3:15][S-:16].[Na+]>CO>[CH3:15][S:16][CH2:9][CH2:8][CH2:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1
Reactant: C[S-]
Reactant: CS(=O)(=O)OCCCc1ccncc1
Agent: [Na+]
Solvent: CO
Product: CSCCCc1ccncc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.4 %

Procedure:
To a solution of methanesulfonic acid 3-pyridin-4-yl-propyl ester (6.5 g, 30.19 mmol) in methanol (150 mL) was added sodium thiomethoxide (6.35 g, 90.57 mmol, Aldrich). The mixture was stirred at room temperature for 1 h then concentrated in vacuo. The residue was diluted with ethyl acetate and washed with water (2×), brine (1×), dried over anhydrous sodium sulfate and concentrated to give 4-(3-methylsulfanyl-propyl)-pyridine as dark brown oil (2.24 g).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[C:8]=2[CH:9]=1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][NH:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:8]=2[CH:9]=1)=[O:4]
Reactant: CNC(=O)c1cc2c(N3CCN(C(=O)OC(C)(C)C)CC3)cccc2o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)c1cc2c(N3CCNCC3)cccc2o1

Procedure:
tert-Butyl 4-(2-(methylcarbamoyl)benzofuran-4-yl)piperazine-1-carboxylate (5.8 g, 16.1 mmol) was stirred in dichloromethane (50 mL) and trifluoroacetic acid (12.4 mL, 161.4 mmol) at rt for 4 h. The solvent was removed by rotary evaporation. The residue was dissolved in dichloromethane and 20 mL of 7 N NH3 in methanol was added. The mixture was evaporated onto silica gel, which was added to a silica gel column and eluted with 0-10% methanol (7 N NH3) in dichloromethane. The collected fractions were combined and the solvent was removed by rotary evaporation to give the title compound. Yield: 3.66 g, 87%. MS m/z 260.6 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16]O)=[CH:12][CH:11]=2)[C:4](=[O:18])[CH:3]=1.P(Br)(Br)[Br:20]>C(Cl)Cl>[Br:20][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][N:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][C:4]2=[O:18])=[CH:11][CH:12]=1
Reactant: O=c1cc(O)ccn1CCc1ccc(CO)cc1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: O=c1cc(O)ccn1CCc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2.45 g (10.0 mmol) 4-hydroxy-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (preparation 2.b) in 25 mL DCM is added 470 μL (5.00 mmol) phosphorus tribromide at 0° C. The mixture is stirred overnight at RT and then poured into ice water. The precipitate is collected, washed with DCM and dried.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[CH3:21])(=[O:13])=[O:12])[CH2:7][CH2:6]1)=[O:4].C1C(=O)N([Br:31])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:31][CH2:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[S:11]([N:8]1[CH2:7][CH2:6][N:5]([C:3](=[O:4])[C:2]([F:1])([F:22])[F:23])[CH2:10][CH2:9]1)(=[O:12])=[O:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)cc1S(=O)(=O)N1CCN(C(=O)C(F)(F)F)CC1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(N1CCN(S(=O)(=O)c2cc(F)ccc2CBr)CC1)C(F)(F)F

Procedure:
A mixture of Intermediate 2 (37.5 g, 105.9 mmol), NBS (19.4 g, 105.9 mmol) and AIBN (0.45 g, 2.8 mmol) in carbon tetrachloride (500 mL) was refluxed for 4 h. The mixture was cooled, concentrated and purified over silica gel eluting with EtOAc to give the title compound contaminated with starting material and dibrominated side-product as amber oil (41.0 g). LCMS (M+H) calcd for C13H14F4N2O3SBr: 433.97; found: 433.01.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.BrCC(OCC)=O.[Zn]>[NH2:2][C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: N#Cc1cccnc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C=C(N)c1cccnc1
Reaction time: 0.83 h
Yield: 78.4 %

Procedure:
In an atmosphere of argon, activated zinc powder (4.88 g, 0.07 g atom) was suspended in anhydrous tetrahydrofuran (THF) (25.0 ml) to which was subsequently added dropwise several drops of ethyl bromoacetate while heating under reflux. When color of the reaction solution became green, 3-cyanopyridine (1.59 g, 15.0 mmol) was added to the solution, ethyl bromoacetate (6.0 ml, 51.4 mmol) was added dropwise thereto spending 50 minutes and then the mixture was heated under reflux for 15 minutes. After cooling, the reaction solution was diluted with THF, mixed with 50% potassium carbonate aqueous solution (15.0 ml) and then stirred for 30 minutes. After standing, the organic layer was collected and extracted three times with THF in the same manner and then the thus obtained organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by a silica gel column chromatography (ethyl acetate:hexane=2:1-4:1) to obtain the title compound (2.26 g, 72.3%) as pale yellow oil.
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].N1C=CN=C1.[CH:11]1([C@@:17]([OH:27])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18](=[O:20])[CH3:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.CCOCC>CN(C=O)C>[CH:21]1([C@:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)([O:27][Si:2]([CH3:4])([CH3:3])[CH3:1])[C:18](=[O:20])[CH3:19])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C[Si](C)(C)Cl
Reactant: CC(=O)[C@](O)(c1ccccc1)C1CCCCC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(=O)[C@](O[Si](C)(C)C)(c1ccccc1)C1CCCCC1
Temperature: 85 °C
Yield: 68.7 %

Procedure:
To a solution of 12 ml (95 mmoles) of trimethylsilyl chloride and 11.6 g (172 mmoles) of imidazole in 100 ml of DMF was added 20 g (86 mmoles) of (R)-1-cyclohexyl-1-hydroxy-1-phenyl-2-propanone. This mixture was heated to 85° C. overnight. The next day, the mixture was cooled and poured onto a mixture of 100 ml of petroleum ether and 100 ml of ether. This was extracted with water. The organic layer was separated, dried, and the solvent removed. The residue was chromatographed on silica gel with hexane as the eluent to give 18.0 g of clear oil. IR 2950, 1730 cm-1NMR (CDCl3) δ7.4(m, 5H), 2.3(t, 1H), 2.1(s, 3H), 1.9-1.0(m, 10H), 0.3(s, 9H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([N:29]([CH3:31])[CH3:30])=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][C:10]=2[C:25]([F:28])([F:27])[F:26])=[O:5])C.[OH-].[Na+]>C(O)C>[Cl:24][C:12]1[CH:13]=[C:14]2[C:9](=[C:10]([C:25]([F:28])([F:26])[F:27])[CH:11]=1)[N:8]=[C:7]([N:29]([CH3:30])[CH3:31])[C:6]([C:4]([OH:5])=[O:3])=[C:15]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23]
Reactant: CCOC(=O)c1c(N(C)C)nc2c(C(F)(F)F)cc(Cl)cc2c1Cc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)c1nc2c(C(F)(F)F)cc(Cl)cc2c(Cc2ccccc2Cl)c1C(=O)O

Procedure:
The title compound was prepared in analogy to example 12 step B from a mixture of 6-chloro-4-(2-chloro-benzyl)-2-dimethylamino-8-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (50 mg, 0.106 mmol) and 1N NaOH in ethanol. Pale yellow solid (22 mg, 47%). LC-MS (ESI): 441 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[CH:6]=O.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[CH:6]=[N:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: Nc1ccccc1
Solvent: CO
Product: COc1cc(C=Nc2ccccc2)cc(OC)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,5-Dimethoxy-4-hydroxybenzaldehyde (1 g, 5.46 mmol) was dissolved in methanol (50 ml) and aniline (560 mg, 6.01 mmol, 0.35 ml, neat liquid) was added to the solution by syringe. The resultant reaction mixture was stirred overnight at room temperature under nitrogen then taken to dryness in vacuo. The yellow crystals thus obtained were triturated with hot ether, allowed to cool, filtered and the collected solid was washed with ether to yield the title product: 1H NMR (300 MHZ, CDCl3) δ , 8.33 (S, 1H), 7.42-7.39 (m, 2H), 7.21-7.18 (m, 5H), 5.84 (S, 1H), 3.98 (S, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[CH2:22]([CH2:24][NH2:25])[OH:23]>C(Cl)Cl.CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([NH:25][CH2:24][CH2:22][OH:23])=[O:8])#[N:2]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Reactant: NCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(C(=O)NCCO)cc1C#N
Temperature: 50 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
To a stirring suspension of 3-cyano-4-isopropoxybenzoic acid (1.0 g, 4.8 mmol) in DCM (20 mL) was added oxalyl chloride (3.7 g, 29.2 mmol) followed by two drops DMF. The reaction mixture was stirred at 50° C. for 2 h. The mixture was concentrated and the residue re-dissolved in DCM (10 mL). Ethanolamine (0.6 g, 9.7 mmol) and TEA (1.45 g, 14.4 mmol) were added and the reaction mixture was stirred overnight at room temperature. The resulting solid was filtered, washed with water, and dried to afford 1.0 g (83%) of 3-cyano-N-(2-hydroxyethyl)-4-isopropoxybenzamide which was used in the next step without purification. LCMS-ESI (m/z) calculated for C13H16N2O3: 248.3; found 249.0 [M+H]+, tR=2.41 min. 1H NMR (400 MHz, CDCl3) δ 8.02-7.79 (m, 2H), 6.97-6.87 (m, 1H), 6.71 (s, 1H), 4.65 (dt, J=12.1, 6.1 Hz, 1H), 3.82-3.70 (m, 2H), 3.56 (dd, J=10.2, 5.5 Hz, 2H), 1.96 (d, J=10.0 Hz, 1H), 1.40-1.29 (m, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:15]1CCOCC1.ClC(OCC(C)C)=O.[OH-].[NH4+]>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH3:13])[C:10]([NH2:15])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCOCC1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(N)=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of (2S)-2-[(tert-butoxycarbonyl)amino]propanoic acid (1 g, 0.005 mol) in THF at 0° C. was added 4-methylmorpholine (0.588 g, 0.00581 mol) followed by dropwise addition of isobutyl chloroformate (0.794 g, 0.00581 mol) over 2 min. The reaction was stirred at 0° C. for 30 min. after which a solution of 30 wt. % ammonium hydroxide (12.0 mL, 0.0925 mol) was quickly poured into the reaction. The reaction was warmed to room temperature and stirred for 5 h. The reaction mixture was concentrated. Water was added and the mixture extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to afford the crude product which was directly used in the next step reaction without further purification (800 mg, 80%). 1H-NMR (300 MHz, DMSO-d6): 12.40 (s, 1H), 7.10 (d, J=7.0 Hz, 1H), 3.88 (m, 1H), 1.35 (s, 9H), 1.20 (d, J=7.3 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1([O:20][C:21]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=O)C=CC=CC=1>>[Br:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:21]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:20])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(N2CCNCC2)cn1
Reactant: CCOC(=O)COC(=O)Oc1ccccc1
Product: CCOC(=O)COC(=O)N1CCN(c2ccc(Br)nc2)CC1

Procedure:
The process is performed as described in Example 1 (step 1.2.). Starting with 3.57 g (14.76 mmol) of 1-(6-bromo-3-pyridyl)piperazine, obtained in step 7.3., and 3.97 g (17.71 mmol) of ethyl [(phenyloxycarbonyl)oxy]acetate, prepared in step 1.1. of Example 1, and after chromatography on silica gel, eluting with a 99/1 and then 98/2 mixture of dichloromethane and methanol, 3.75 g of product are obtained in the form of a yellow oil that crystallizes at room temperature.
Reaction SMILES: CC1C=CC(S(O[CH:12]2[CH2:40][CH2:39][C:15]3([O:19][N:18]=[C:17]([C:20]4[C:21]([NH:32][CH:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[C:22]5[C:28](C)=[N:27][N:26]([CH2:30][CH3:31])[C:23]5=[N:24][CH:25]=4)[CH2:16]3)[CH2:14][CH2:13]2)(=O)=O)=CC=1.[N-:41]=[N+:42]=[N-:43].[Na+].O>CN(C)C=O>[N:41]([CH:12]1[CH2:40][CH2:39][C:15]2([O:19][N:18]=[C:17]([C:20]3[CH:25]=[N:24][C:23]4[N:26]([CH2:30][CH3:31])[N:27]=[CH:28][C:22]=4[C:21]=3[NH:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[CH2:16]2)[CH2:14][CH2:13]1)=[N+:42]=[N-:43]
Reactant: [N-]=[N+]=[N-]
Reactant: CCn1nc(C)c2c(NC3CCCCC3)c(C3=NOC4(CCC(OS(=O)(=O)c5ccc(C)cc5)CC4)C3)cnc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1ncc2c(NC3CCCCC3)c(C3=NOC4(CCC(N=[N+]=[N-])CC4)C3)cnc21
Temperature: 65 °C
Reaction time: 8 h

Procedure:
3-[4-(Cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridin-5-yl]-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl 4-methylbenzenesulfonate (0.00090 mole) (example 39) is taken in dimethylformamide. Sodium azide (0.0027 mole) is added. The reaction mixture is stirred at 60-70° C. overnight. It is cooled and water is added and extraction is done with ethyl acetate. The organic layer is washed with brine, dried and concentrated under reduced pressure to give crude compound, which is purified by column chromatography.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)=[CH:16][C:15]([C:28]([F:31])([F:30])[F:29])=[N:14]2)=[CH:9][CH:8]=1>ClCCl>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:17]([C:18]3[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=3)=[CH:16][C:15]([C:28]([F:29])([F:30])[F:31])=[N:14]2)=[CH:11][CH:12]=1
Reactant: COc1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(S(C)(=O)=O)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(O)cc2)cc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 67.4 %

Procedure:
Boron tribromide (1M in dichloromethane; 11 ml) was added to an ice-cooled solution of 1-(4-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole (1.4 g) in dichloromethane (30 ml). The mixture was stirred at 5° C. for 2 hours and concentrated in vacuo. The residue was triturated in dilute hydrochloric acid. The obtained powder was recrystallized from ethanol to give colorless crystals of 1-(4-hydroxyphenyl)-5-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole (0.91 g).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:17]([O:19][C:20](=[O:29])[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23](Br)[CH:22]=1)[CH3:18]>[Cu]I>[CH2:17]([O:19][C:20](=[O:29])[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([N:7]2[C:8]([NH2:10])=[CH:9][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6]2)[CH:22]=1)[CH3:18]
Reactant: CC(C)(C)c1cc(N)[nH]n1
Reactant: CCOC(=O)c1cc(Cl)cc(Br)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1cc(Cl)cc(-n2nc(C(C)(C)C)cc2N)c1
Yield: 19.2 %

Procedure:
3-(Tert-butyl)-1H-pyrazol-5-amine (1.10 g, 7.90 mmol), potassium carbonate (2.29 g, 16.6 mmol), and copper (I) iodide (75.0 mg, 1.58 mmol) were weighed into a microwave vial and purged with argon. 3-Bromo-5-chloro-benzoic acid ethyl ester (2.50 g, 9.49 mmol) was then added, followed by trans-N,N′-dimethylcyclohexane-diamine (225 mg, 1.58 mmol) and the reaction vessel purged with argon. The reagents were then solvated with toluene (8 mL), and then degassed with argon, sealed and subjected to microwave irradiation (135° C., 6 h). The reaction mixture was filtered through Celite, concentrated in vacuo and purified by FCC, eluting with 0-10% EtOAc/cyclohexane, to afford the title compound (489 mg, 19%). LCMS (Method 3) Rt 4.26 min, 322.1 [MH+].
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]([F:16])[CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[S:19][C:20]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([OH:35])([CH3:34])[CH3:33])=[CH:28][C:27]=2[F:36])=[CH:21][C:22]=1[C:23]([NH2:25])=[O:24]>>[F:36][C:27]1[CH:28]=[C:29]([C:32]([OH:35])([CH3:33])[CH3:34])[CH:30]=[CH:31][C:26]=1[C:20]1[S:19][C:18]([NH:17][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]([F:16])[CH2:9][N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:7]=2)=[C:22]([C:23]([NH2:25])=[O:24])[CH:21]=1
Reactant: FC(CN1CCOCC1)c1cccc(Br)n1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(C(F)CN4CCOCC4)n3)s2)c(F)c1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using 4-[2-(6-bromopyridin-2-yl)-2-fluoroethyl]morpholine (80 mg, 0.28 mmol) and 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (81 mg, 0.28 mmol) as the starting materials.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:47][C:48]([F:55])([F:54])[CH:49]1[CH2:53][CH2:52][CH2:51][NH:50]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:50]4[CH2:51][CH2:52][CH2:53][CH:49]4[C:48]([F:55])([F:54])[F:47])=[O:43])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: FC(F)(F)C1CCCN1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N2CCCC2C(F)(F)F)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 2-trifluoromethyl-pyrrolidine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C41H49F3Cl2N5O3 [(M+H)+] 786.3159, observed 786.3157.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]([NH:14][S:15]([C:18]([F:21])([F:20])[F:19])(=[O:17])=[O:16])[CH2:12][CH3:13])[CH2:7][CH2:6]2)[O:4]CC1.Cl>CC#N>[F:20][C:18]([F:19])([F:21])[S:15]([NH:14][CH:11]([CH:8]1[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]1)[CH2:12][CH3:13])(=[O:16])=[O:17]
Reactant: CCC(NS(=O)(=O)C(F)(F)F)C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC#N
Product: CCC(NS(=O)(=O)C(F)(F)F)C1CCC(=O)CC1

Procedure:
A solution of N-(1-1,4-dioxaspiro[4.5]decan-8-ylpropyl)-1,1,1-trifluoromethanesulfonamide (as prepared in the previous step, 47 mg, 0.14 mmol, 1.00 equiv) in CH3CN (5 mL) and HCl (2M, 1 mL) was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was diluted with 10 mL of aq. sodium bicarbonate (1M). The resulting solution was extracted with 2×20 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum to give the title compound as a yellow oil.