Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:22][CH2:21][CH2:20][C@@H:19]3[CH3:23])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:24]#[N:25])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.O.[N:27]([Na])=[N+:28]=[N-:29]>CS(C)=O.Br[Zn]Br>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:22][CH2:21][CH2:20][C@@H:19]3[CH3:23])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:24]4[N:27]=[N:28][NH:29][N:25]=4)[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: C[C@H]1CCCN1c1nc2cc(C#N)ccc2nc1-c1ccc(F)cc1
Reactant: [N-]=[N+]=N[Na]
Agent: Br[Zn]Br
Solvent: CS(C)=O
Solvent: O
Product: C[C@H]1CCCN1c1nc2cc(-c3nn[nH]n3)ccc2nc1-c1ccc(F)cc1
Temperature: 125 °C
Reaction time: 24 h
Yield: 63 %

Procedure:
To a solution of (S)-2-(4-fluorophenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carbonitrile (100 mg, 0.30 mmol) in DMSO (10 mL) was added dibromozinc (33.8 mg, 0.15 mmol), water (10 mL), azidosodium (48.8 mg, 0.75 mmol) and water (5 mL). The resulting solution was stirred for 1 days at 125° C. and then quenched by the addition of water (100 mL), extracted with dichloromethane (3×30 mL). The organic layers were combined and dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue, which was purified via silica gel column chromatography (2% dichloromethane in methanol) to afford (S)-2-(4-fluorophenyl)-3-(2-methylpyrrolidin-1-yl)-6-(2H-tetrazol-5-yl)quinoxaline as a yellow solid (70.9 mg, 63%).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[N:25]=[C:24]([CH:26]([F:28])[F:27])[CH:23]=[C:22]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=4)[N:21]=3)[CH:17]=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:28][CH:26]([F:27])[C:24]1[CH:23]=[C:22]([C:29]2[CH:30]=[CH:31][C:32]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:34]=2)[N:21]=[C:20]([C:18]2[CH:17]=[CH:16][N:15]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:13][CH:12]=3)[CH:19]=2)[N:25]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)F)n3)ccn2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)F)n3)ccn2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 46.2 %

Procedure:
To a cooled and stirred solution of 5-{4-[4-difluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-thiophene-2-sulfonic acid tert-butylamide (0.24 g) in dichloromethane (5 ml) was added TFA (5 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by flash-chromatography on silica gel (ethyl acetate/hexane) and crystallization (dichloromethane) yielded the title compound as an off-white solid (0.1 g, 20%). MS (ISP) 513.3 [(M+H)+]; mp 242° C.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5](OC)=[C:6]([CH:8](O)[C:9]#CC2C=CC=CC=2)[CH:7]=1.[CH3:20][O:21][C:22]1[CH:29]=[C:28]([CH3:30])[C:27]([O:31][CH3:32])=[CH:26][C:23]=1[CH:24]=[O:25]>>[CH3:20][O:21][C:22]1[CH:29]=[C:28]([CH3:30])[C:27]([O:31][CH3:32])=[CH:26][C:23]=1[CH:24]([OH:25])[C:9]#[C:8][C:6]1[CH:7]=[CH:2][CH:3]=[CH:4][CH:5]=1
Reactant: COc1ccc(F)cc1C(O)C#Cc1ccccc1
Reactant: COc1cc(C=O)c(OC)cc1C
Product: COc1cc(C(O)C#Cc2ccccc2)c(OC)cc1C
Yield: 98 %

Procedure:
Following the procedure used to prepare 1-(5-fluoro-2-methoxy-phenyl)-3-phenyl-prop-2-yn-1-ol, 2,5-dimethoxy-4-methyl-benzaldehyde (1.00 g, 5.55 mmol) was reacted to give the title compound (1.54 g, 98%). 1H NMR (400 MHz, DMSO-d6): δ 7.42-7.34 (m, 5H), 7.16 (s, 1H), 6.86 (s, 1H), 5.98-5.94 (d, 1H), 5.77-5.74 (d, 1H), 3.77 (s, 3H), 3.76 (s, 3H), 2.16 (s, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].Cl[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[C:2]2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:18][CH:19]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccccc2n1Cc1ccc(F)cc1
Temperature: 60 °C
Reaction time: 20 h
Yield: 70.1 %

Procedure:
Ethyl 1H-indole-2-carboxylate (500 mg, 2.64 mmol) was dissolved in anhydrous DMF (8 ml), followed by 1-(chloromethyl)-4-fluorobenzene (0.380 ml, 3.17 mmol) and the addition of solid potassium carbonate (730 mg, 5.29 mmol). This was stirred at 60° C. for 20 h, at which time the reaction was allowed to cool to room temperature. Precipitate formed upon the addition of water (40 mL), was isolated over a filter, and dried under high vacuum overnight to give 550 mg of the title compound as a white solid which was recrystallized from diethyl ether. Rf=0.55 (33% EtOAc/Hex.)
Reaction SMILES: [Cl-].[C:2]1([NH+:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)N)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][C:17]1=O.C(O)C>O>[C:2]1([N:8]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:18]3[C:19]4[C:24]([CH2:16][C:17]2=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccccc2C1
Reactant: N[NH+](c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: c1ccc(-n2c3c(c4ccccc42)-c2ccccc2C3)cc1
Yield: 42.7 %

Procedure:
In a 0.25 l bulb were placed 10 g (45 mmol) of N,N-diphenylhydrazinium chloride, 6.0 g (45 mmol) of 2-indanone and 50 ml of ethanol. The thus obtained mixture was heated at reflux for 4 hours and it was poured into water; the residual mixture was extracted with CH2Cl2 (150 ml) and the solvent was evaporated. The wanted compound was isolated by passing the obtained mixture through a column of silicagel, eluting with benzene/hexane=1:2. The resulting solution was evaporated and treated with 10 ml of hexane, obtaining the precipitation of crystals. Said crystals were separated, washed with hexane (10 ml) and finally dried, thus yielding 5.4 g of N-phenyl-5,6-dihydroindeno[2,1-b]indole (yield=45%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:4][N:3]=1.[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O)#[N:17].C(=O)([O-])[O-].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:15][C:12]1[S:13][CH:14]=[C:10]([C:9]#[C:8][C:5]2[CH:6]=[CH:7][C:2]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[C:16]#[N:17])=[N:3][CH:4]=2)[N:11]=1
Reactant: Cc1nc(C#Cc2ccc(Cl)nc2)cs1
Reactant: N#Cc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nc(C#Cc2ccc(-c3ccccc3C#N)nc2)cs1
Temperature: 150 °C

Procedure:
2-chloro-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (1.0 mmol, 234 mg), 2-cyanophenylboronic acid (1.2 mmol, 176 mg), dichlorobis(triphenylphosphine)palladium(II) (0.05 mmol, 35 mg), and potassium carbonate (3.5 mmol, 500 mg) were added to deoxygenated DME:water (1:1, 5 mL) at room temperature. The reaction was heated for 5 min at 150° C. via microwave irradiation, then partitioned in a separatory funnel with EtOAc (100 mL) and water (30 mL). The organic layer was washed with one additional portion of water (20 mL) and the combined aqueous layers back extracted with EtOAc (50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was chromatographed on SiO2, eluting with a 0% to 60% EtOAc gradient in hexanes, to afford the title compound as a white solid, which was dissolved in ether and precipitated as the hydrochloride salt with 1M HCl in ether. MS (ESI) 301.4 (M+H+).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[O-].[Na+].CO.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CO>[C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:15][CH:16]=1)([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Temperature: 40 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To a solution of N-Boc-tyrosine (281 mg, 1.0 mmol) in methanol (0.5 mL) were added 28% sodium methoxide-methanol solution (0.42 mL, 2.1 mmol) and benzyl bromide (162 μL, 1.4 mmol), and the mixture was stirred at 40° C. for 3 hr. Then, water (2 mL) was added to make the system homogeneous, which system was analyzed by HPLC. As a result, the objective N-Boc-(O-benzyl)tyrosine (353 mg, conversion yield 95%) was confirmed.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1.[H-].[K+].[CH2:22]1OCCOCCOCCOCCOCCO[CH2:23]1.ICC>C1COCC1>[CH2:22]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][C:10]=2[CH3:12])[C:6]([CH:13]2[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]2)=[CH:7]1)[CH3:23]
Reactant: COc1cc(C)c2[nH]cc(C3CCN(C)CC3)c2c1
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCn1cc(C2CCN(C)CC2)c2cc(OC)cc(C)c21
Yield: 704.3 %

Procedure:
By a method similar to Preparation 26, using 5-methoxy-7-methyl-3-(1-methylpiperidin-4-yl)-1H-indole (5.81 mmole, 1.5 g) in THF (100 mL), 35% potassium hydride (5.81 mmole, 0.665 g), 18-crown-6 (0.58 mmole, 0.153 g), and iodoethane (5.81 mmole, 0.906 g, 0.464 mL) afforded 1.17 g (70%) of the title compound: mass spectrum (ion spray): m/z=287 (M+1); Calculated for C18H26N2O-0.1 H2O: C, 75.01; H, 9.16; N, 9.72. Found: C, 75.10; H, 9.01; N, 9.79.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([NH:21][CH3:22])[C@@H:17]2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].CCN(C(C)C)C(C)C.O>C(#N)C>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([N:21]([CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH3:22])[C@@H:17]2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:30])[F:31])[CH:8]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CN[C@@H]1CC[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O
Product: C[C@@H](O[C@H]1CC[C@@H](N(C)CC(=O)OC(C)(C)C)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 50 °C

Procedure:
To a solution of 250 mg of non-racemic 1-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-2-(S)-(4-fluorophenyl)-3-(R)-(methylamino)cyclopentane from Example 39 in 6 mL of acetonitrile was added 0.108 mL of t-butyl bromoacetate and 0.36 mL of DIPEA. The reaction was heated at 50° C. for 5 h and then poured into water and extract twice with ethyl acetate. The organic layers were washed with a portion of brine, combined, dried over sodium sulfate and evaporated. The residue was purified by flash chromatography eluting with 0 to 2.5% methanol in methylene chloride to give 294 mg of title compound as an oil. Mass spec (NH3 /CI): 564 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]([N:14]2[CH2:19][C@H:18]([CH3:20])[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:16][C@H:15]2[CH3:29])=[O:13])=[C:6]([CH:9]=1)[CH2:7][NH2:8].[O:30]=[C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33](=[O:40])[N:32]1[CH2:41][CH2:42][S:43](Cl)(=[O:45])=[O:44].C(N(CC)CC)C>C(Cl)Cl.C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]([N:14]2[CH2:19][C@H:18]([CH3:20])[N:17]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[CH2:16][C@H:15]2[CH3:29])=[O:13])=[C:6]([CH:9]=1)[CH2:7][NH:8][S:43]([CH2:42][CH2:41][N:32]1[C:31](=[O:30])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]1=[O:40])(=[O:44])=[O:45]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CN
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CNS(=O)(=O)CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.7 %

Procedure:
To a solution of (2R,5S)-5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzyl amine (0.060 g, 0.143 mmol) in methylene chloride (3 mL) was added 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonyl chloride (0.043 g, 0.150 mmol) and triethylamine (0.060 mL, 0.43 mmol) and the solution was stirred 1 hr at ambient temperature. The reaction was diluted with saturated aqueous sodium hydrogen carbonate and extracted with methylene chloride. The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (0.073 g, 77%).
Reaction SMILES: C(N[S:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11]2)(=[O:7])=[O:6])(C)C.[CH3:18][N:19]([CH:21](OC)OC)[CH3:20].[OH2:26]>CN(C=O)C>[CH3:18][N:19]([CH:21]=[C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[C:8]([S:5]([OH:6])(=[O:7])=[O:26])[CH:9]=2)[NH:13][C:12]1=[O:17])[CH3:20]
Reactant: O
Reactant: COC(OC)N(C)C
Reactant: CC(C)NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Solvent: CN(C)C=O
Product: CN(C)C=C1C(=O)Nc2ccc(S(=O)(=O)O)cc21

Procedure:
A solution of rpm281 (0.180 g, 0.708 mmol) and N,N-dimethylformamidedimethylacetal (0.125 g, 0.85 mmol, 1.2 eq) in DMF (2 ml) was stirred for 1 h at room temperature. Water (7 ml) was added and the product extracted with ethyl acetate (3×10 ml). The organic extracts were collected, dried over Na2SO4 and the solvent evaporated under reduced pressure to give a yellow solid, which was used in the next step without further purification.
Reaction SMILES: S(O)(C(F)(F)F)(=O)=O.C1(OC)C=CC=CC=1.[C:17]([C:19]1[CH:20]=[C:21]([C@H:26]2[CH2:30][C@H:29]([F:31])[CH2:28][N:27]2[C:32]2[CH:37]=[CH:36][N:35]3[N:38]=[CH:39][C:40]([C:41]([N:43](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)=[O:42])=[C:34]3[CH:33]=2)[CH:22]=[C:23]([F:25])[CH:24]=1)#[N:18]>C(Cl)Cl>[C:17]([C:19]1[CH:20]=[C:21]([C@H:26]2[CH2:30][C@H:29]([F:31])[CH2:28][N:27]2[C:32]2[CH:37]=[CH:36][N:35]3[N:38]=[CH:39][C:40]([C:41]([NH2:43])=[O:42])=[C:34]3[CH:33]=2)[CH:22]=[C:23]([F:25])[CH:24]=1)#[N:18]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)C(=O)c2cnn3ccc(N4C[C@@H](F)C[C@@H]4c4cc(F)cc(C#N)c4)cc23)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: N#Cc1cc(F)cc([C@H]2C[C@H](F)CN2c2ccn3ncc(C(N)=O)c3c2)c1
Temperature: -20 °C

Procedure:
A flask was charged with TfOH (136.4 g, 909 mmol) and DCM (505 mL) and cooled to −20° C. Anisole (45 g, 416 mmol) was added followed by a solution of 5-((2R,4S)-2-(3-cyano-5-fluorophenyl)-4-fluoropyrrolidin-1-yl)-N,N-bis(4-methoxybenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (I-53) (101 g, 166 mmol) in DCM (303 mL). The mixture was warmed to 20° C., and maintained for 15 hours. HPLC showed consumption of (I-53). The reaction was cooled to <0° C. and DCM (1 L) and an aqueous saturated K2CO3 (1 L) was added (aqueous layer pH=9-10). The aqueous layer was separated and extracted with DCM (500 mL). The rag layer was filtered through Celite and the two layers were separated. The organic layers were combined and concentrated to dryness. The resulting solid was triturated with TBME (250 mL) at 20° C. to yield 5-((2R,4S)-2-(3-cyano-5-fluorophenyl)-4-fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (X-10). Melting point: 140° C. (dec.). 1H NMR (400 MHz, CD3OD) δ 8.28 (d, J=8.0 Hz, 1 H), 8.23 (s, 1 H), 7.61-7.58 (m, 1 H), 7.48-7.42 (m, 1 H), 7.03 (d, J=2.4 Hz, 1 H), 6.52 (dd, J=2.8, 7.6 Hz, 1 H), 5.42 (d, J=52.4 1 H), 5.14 (dd, J=7.2, 9.6 Hz, 1 H), 4.21 (ddd, J=3.2, 12.0, 36.8 Hz, 1 H), 3.94 (ddd, J=2.0, 12.3, 23.8 Hz, 1 H), 2.98-2.85 (m, 1 H), 2.16 (dddd, J=3.6, 9.6, 14.0, 40.4 Hz, 1 H).
Reaction SMILES: [N+:1]([C:4]1[C:9](OC)=[CH:8][CH:7]=[CH:6][N:5]=1)([O-])=[O:2].[NH2:12][NH2:13].O>CN(C=O)C>[CH:7]1[CH:6]=[N:5][C:4]2[N:1]([OH:2])[N:12]=[N:13][C:9]=2[CH:8]=1
Reactant: COc1cccnc1[N+](=O)[O-]
Reactant: NN
Solvent: CN(C)C=O
Solvent: O
Product: On1nnc2cccnc21
Reaction time: 24 h
Yield: 52.1 %

Procedure:
To 13.58 g of 2-nitro-3-methoxypyridine was added 26.4 mL of 95% hydrazine, 10.4 mL of water and 15.3 mL of DMF. The mixture was carefully warmed to about 70° on a hot plate. Spontaneous warming then set in, the temperature rising to about 80° as the solid dissolved. The solution was set aside for 24 hr and then evaporated from a water bath with the aid of a water aspirator to remove excess hydrazine and water. The dark green residue was cooled in an ice bath, diluted with 50 mL of water and acidified to Congo Red with concentrated hydrochloric acid (ca. 17 ml). A yellow-straw-colored solid separated and was filtered and washed with a little cold water to give 6.25 g (52.1%) of HOAt upon recrystallization from 75 mL of water gave 5.46 g (45.5%) of nearly colorless crystals, mp 216°-217° 1H NMR (CDCl3-DMSO-d6) δ7.35 (dd, 1, β-H), 8.3 (dd, 1, γ-H), 8.66 (dd, 1, α-H); Jα,β=4.2 Hz, Jβ,γ=8.2 Hz, Jα, γ=1.6 Hz. Evaporation of the filtrate gave an additional 0.14 g of the pure hydroxy compound so the total yield was 5.6 g (46.7%).
Reaction SMILES: [Br:1][CH:2]1[O:6][C:5](=[O:7])[C:4]([CH3:8])=[C:3]1[O:9][CH3:10].[C:11]1([P:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1C=CC=CC=1>[Br-:1].[CH3:10][O:9][C:3]1[CH:4]([CH3:8])[C:5](=[O:7])[O:6][C:2]=1[P+:17]([C:18]1[CH2:23][CH:22]=[CH:21][CH2:20][CH:19]=1)([C:24]1[CH2:25][CH:26]=[CH:27][CH2:28][CH:29]=1)[C:11]1[CH2:16][CH:15]=[CH:14][CH2:13][CH:12]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC1=C(C)C(=O)OC1Br
Solvent: c1ccccc1
Product: COC1=C([P+](C2=CCC=CC2)(C2=CCC=CC2)C2=CCC=CC2)OC(=O)C1C
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Bromo-2,5-dihydro-4-methoxy-3-methyl-2-oxofuran (6.44 g) was dissolved in dry benzene (100 mls). Triphenylphosphine was added and the solution stirred overnight at room temperature. The solution was decanted from the orange gum, which was then triturated with ether to give a colourless crystalline solid. The ether was decanted and the salt dried under vacuum. The decanted solution was concentrated to a gum. Trituration of this with ether resulted in a second crop of the phosphonium salt. The combined crops gave the title compound as a colourless solid, (14 41 g, 99%), νmax (CH2Cl2) 1775, 1665, 1435, 1390 and 1330cm-1 ; δH (CDCl3) 1.74 (3H, m), 3.95 (3H, s) and 7.5-8.1 (16H, m); [mass spectrum: +ve ion (3NOBA, Na+) M+ -Br, 389].
Reaction SMILES: [CH:1]([N:4]([CH:32]([CH3:34])[CH3:33])[C:5](=[O:31])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([NH:22][O:23]CC3C=CC=CC=3)=[O:21])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)([CH3:3])[CH3:2].C(O)C>[Pd].C(OCC)(=O)C>[CH:32]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:31])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([NH:22][OH:23])=[O:21])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)([CH3:34])[CH3:33]
Reactant: CC(C)N(C(=O)COc1ccc(-c2ccc(C(=O)NOCc3ccccc3)cc2)cc1)C(C)C
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)N(C(=O)COc1ccc(-c2ccc(C(=O)NO)cc2)cc1)C(C)C
Reaction time: 8 h
Yield: 8.1 %

Procedure:
80 mg of the benzyl hydroxamate of Stage A were mixed with 50 mg of palladium on charcoal, 5 ml of ethanol and 40 ml of ethyl acetate, and the mixture was stirred for 8 hours under a hydrogen atmosphere. The reaction medium was filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica, eluting with a mixture of cyclohexane/ethyl acetate (50/50) then ethyl acetate and finally ethyl acetate/acetic acid 99/1. The product was finally crystallized from ethyl acetate to obtain 5.2 mg of the expected product.
Reaction SMILES: [C:1]([N:9]([CH2:20][CH2:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:10][CH2:11][NH:12]C(=O)OC(C)(C)C)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:35].CCOC(C)=O>CCOC(C)=O.CCCCCC>[ClH:35].[NH2:12][CH2:11][CH2:10][N:9]([CH2:20][CH2:21][CH:22]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCN(CCC(c1ccccc1)c1ccccc1)C(=O)c1ccccc1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: NCCN(CCC(c1ccccc1)c1ccccc1)C(=O)c1ccccc1
Reaction time: 1 h

Procedure:
To a suspension of tert-butyl {2-[benzoyl-(3,3-diphenylpropyl)amino]ethyl}carbamate (225 mg) in EtOAc (675 μL) was added 4M HCl/EtOAc (1.23 mL) at ambient temperature and the mixture was stirred at the same temperature for 1 hour. The resulting mixture was diluted with n-hexane (5.0 mL) and the precipitate was collected by filtration followed by washing with n-hexane (10 mL) to afford N-(2-aminoethyl)-N-(3,3-diphenylpropyl)benzamide hydrochloride (166 mg) as colorless crystals.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(Cl)Cl.C(N(CC)CC)C.[CH3:30][CH:31]([S:33](Cl)(=[O:35])=[O:34])[CH3:32]>O>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][S:33]([CH:31]([CH3:32])[CH3:30])(=[O:35])=[O:34])[N:13]=1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)S(=O)(=O)NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.8 %

Procedure:
The operation is carried out as in Stage 1 of Example 10 starting from 280 mg of the product obtained in Stage 1 of Example 7, 4 ml of methylene chloride, 0.2 ml of triethylamine and 172 mg of 1-methylethanesulphonic acid chloride in place of the 4-methyl-benzenesulphonic acid chloride then the reaction medium is agitated at ambient temperature for approximately 30 min. Then 2 ml of water is added, followed by extracting with 3×5 ml of methylene chloride, washing with 5 ml of saturated sodium chloride, drying, evaporating, impasting in 5 ml of ether then in 5 ml of pentane, separating, and drying. After chromatography on silica eluting with methylene chloride/CH3CN in a proportion of 70/30, 115 mg of expected product is thus obtained in the form of white crystals.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1.[CH2:30]([S:37]CC1C=CC=CC=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[Na]>CN(C)C=O>[CH2:30]([S:37][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CCO3)cc1
Reactant: c1ccc(CSCc2ccccc2)cc1
Agent: [Na]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CSCc4ccccc4)cc2)CCO3)cc1
Yield: 149.2 %

Procedure:
A solution of N-(4-chloromethylphenyl)-7—(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.15 g) and sodium benzyl sulfide (0.055 g) in dimethylformamide (10 ml) was stirred at room temperature over night. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized from ethyl acetate-hexane to give N-(4—(benzylthiomethyl)phenyl)-7—(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 86) (0.17 g) as colorless crystals.