Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[C:10]2[C:5](=[N:6][C:7]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[C:8]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[CH:9]=2)[NH:4][N:3]=1.N([O-])=O.[Na+].C(=O)(O)[O-].[Na+].N.[BrH:34]>O>[Br:34][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[C:8]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[CH:9]=2)[NH:4][N:3]=1
Reactant: Br
Reactant: Nc1n[nH]c2nc(-c3ccc(F)cc3)c(-c3ccncc3)cc12
Agent: N
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: O
Product: Fc1ccc(-c2nc3[nH]nc(Br)c3cc2-c2ccncc2)cc1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 21 %

Procedure:
To a solution of 3-amino-6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (0.20 g, 0.7 mmol, obtained in example 70) in 48% HBr (1 mL) at 0° C., a solution of NaNO2 (0.05 g, 0.7 mmol) in water (0.1 mL) was added dropwise over a period of 15 minutes maintaining the temperature at 0-5° C. The mixture was stirred for 15 min at this temperature. Then, a solution of CuBr (0.24 g, 1.7 mmol) in 48% HBr (1 mL) was added slowly at 0° C. The resulting solution was stirred for 3 h at 0° C. It was allowed to reach room temperature, neutralized at pH=7 with saturated sodium bicarbonate and a 30% aqueous NH3. It was filtered and the solid was washed with a mixture of CH2Cl2 and water. The organic phase was washed with 1 N NaOH and the aqueous phase extracted with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using CHCl3-MeOH mixtures of increasing polarity as eluent, to afford 50 mg of the title compound (yield: 21%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Cl)[N:7]=1.Cl.[NH2:12][C@@H:13]([C:18]([NH2:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16].CCN(C(C)C)C(C)C>C(C#N)(C)=O.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:12][C@H:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:18]([NH2:20])=[O:19])[CH:5]=[N:4][C:3]=1[C:9]#[N:10]
Reactant: N#Cc1ncc(Cl)nc1Cl
Reactant: CC(C)C[C@@H](N)C(N)=O
Agent: CC(=O)C#N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H](Nc1cnc(C#N)c(Cl)n1)C(N)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.3 %

Procedure:
To a mixture of 3,5-dichloropyrazine-2-carbonitrile (100 mg, 0.57 mmol) and D-leucinamide HCl salt (104 mg, 0.625 mmol) in AcCN (2 mL) was added DIPEA (0.223 mL, 1.254 mmol). After stirring at room temperature for 4 h, it was diluted with EtOAc, washed with sat. NaHCO3, organic layer was separated and washed with brine, dried and concentrated to give (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)-4-methylpentanamide (150 mg).
Reaction SMILES: Br[C:2]1[C:3]([N:10]([CH2:17][CH:18]2[CH2:22][O:21][C:20](=[O:23])[O:19]2)[C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[C:24]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:27])[CH:25]=[CH2:26].O>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(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]>[CH3:13][C:12]([CH3:15])([CH3:14])[C:11]([N:10]([CH2:17][CH:18]1[CH2:22][O:21][C:20](=[O:23])[O:19]1)[C:3]1[C:2](/[CH:26]=[CH:25]/[C:24]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:27])=[CH:7][CH:6]=[C:5]([O:8][CH3:9])[N:4]=1)=[O:16]
Reactant: C=CC(=O)OCCCC
Reactant: COc1ccc(Br)c(N(CC2COC(=O)O2)C(=O)C(C)(C)C)n1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CCCCOC(=O)/C=C/c1ccc(OC)nc1N(CC1COC(=O)O1)C(=O)C(C)(C)C
Temperature: 80 °C
Yield: 96.2 %

Procedure:
A mixture of N-[3-bromo-6-(methyloxy)-2-pyridinyl]-2,2-dimethyl-N-[(2-oxo-1,3-dioxolan-4-yl)methyl]propanamide (5.722 g, 14.722 mmol), Pd(PtBu3)2 (151 mg, 0.296 mmol), Pd2(dba)3 (135 mg, 0.149 mmol), in 1,4-dioxane (40 ml) was treated with N,N′-dicyclohexylmethylamine (3.48 ml, 16.265 mmol) and n-butyl acrylate (2.54 ml, 17.743 mmol) and the mixture was then heated at 80° C. for 1 h. The reaction was then cooled, treated with water (200 ml), extracted with DCM (3×200 ml). The organic extracts were dried (MgSO4), and evaporated and chromatographed (0-50% ethyl acetate:Hexane) to give the product as a yellow oil (6.156 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([NH:10][N:11]([CH2:13][C:14]([OH:16])=O)[CH3:12])=[O:9])=[CH:4][CH:3]=1.[NH2:19][C@H:20]([C:33]([N:35]([CH2:45][C:46]1[C:47]2[CH:54]=[CH:53][CH:52]=[CH:51][C:48]=2[S:49][CH:50]=1)[C@@H:36]([CH3:44])[CH:37]([O:41][CH2:42][CH3:43])[O:38][CH2:39][CH3:40])=[O:34])[CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29]>>[S:49]1[CH:50]=[C:46]([CH2:45][N:35]([C@@H:36]([CH3:44])[CH:37]([O:38][CH2:39][CH3:40])[O:41][CH2:42][CH3:43])[C:33](=[O:34])[C@@H:20]([NH:19][C:14](=[O:16])[CH2:13][N:11]([CH3:12])[NH:10][C:8](=[O:9])[NH:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:18][CH:17]=2)[CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[C:47]2[CH:54]=[CH:53][CH:52]=[CH:51][C:48]1=2
Reactant: CN(CC(=O)O)NC(=O)NCc1ccc(Cl)cc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)CN(C)NC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(4-chlorobenzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-7) 78 mg (0.29 mmol) was coupled with tert-butyl (S)-5-amino-6-((benzo[b]thiophen-3-ylmethyl)-((S)-1,1-diethoxypropan-2-yl)amino)-6-oxohexylcarbamate IV-15) 100 mg (0.19 mmol) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:20](=[O:21])[C:11]3=[CH:12][NH:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24]I>O1CCCC1>[CH3:24][N:13]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[C:10]2=[N:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:20](=[O:21])[C:11]2=[CH:12]1
Reactant: CI
Reactant: O=c1c2c[nH]c3ccccc3c-2nn1-c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c2ccccc21
Temperature: 25 °C

Procedure:
The mixture of 5.0 g of 2-(p-chlorophenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one, 0.81 g of 50% sodium hydride in mineral oil and 100 ml of anhydrous tetrahydrofuran is refluxed for 2 hours. It is cooled to room temperature, combined with 3.0 g of methyl iodide while stirring and another 1.0 g thereof is added after one hour. The mixture is stirred overnight at room temperature, filtered and the residue recrystallized from tetrahydrofuran-heptane, to yield the 5-methyl-2-(p-chlorophenyl)-pyrazolo[4,3-c]quinolin-3-one melting at 322°-323°.
Reaction SMILES: [Br:1][CH:2]([CH2:7][CH2:8][Br:9])[C:3](OC)=[O:4].[CH3:10][NH2:11]>C(Cl)(Cl)Cl>[CH3:10][NH:11][C:3](=[O:4])[CH:2]([Br:1])[CH2:7][CH2:8][Br:9]
Reactant: CN
Reactant: COC(=O)C(Br)CCBr
Solvent: ClC(Cl)Cl
Product: CNC(=O)C(Br)CCBr

Procedure:
Methyl 2,4-dibromobutyrate (50 gm, 0.192 mole) was mixed with 40 wt % methylamine in aqueous solution (20.0 ml, 7.22 gm, 0.232 mole) with stirring and cooling in an ice bath. The reaction mixture was stirred for 16 hours at 5° C., chloroform (100 ml) was then added and the organic layer washed with water. The organic extract was dried over magnesium sulfate, filtered and the solvent removed. The crude product was purified by column chromatography (silica gel, gradient elution hexane/chloroform to chloroform/ethylacetate) to yield an off-white solid, (25.4 gm, 51.7%): m.p. 42°-47° C. The compound was used in the next step without further purification. A small portion was further purified for elemental analysis; m.p. 48°-49° C. IR(KBr) 3450, 1660, 1570, 1415, 1240 and 1210 cm-1 ; H-NMR (CDCl3) δ 2.48 (m, 1H, --CH2 -CHBr--), 2.79(m, 1H, --CH2 -CHBy--), (d, 3H, --NH2 -CH3 --), 3.55 (t, 2H, Br--CH2 --CH2), 4.54 (dd, 1H, --CHBr--); 6.39 (s, broad, 1H, --NH--CH3), C--NMR, decoupled (CDCl3) 26.83, 30.27, 37.60, 48.26, 168.65 ppm. Anal. calcd. for C5H9NBr2O (258.949): C, 23.19; H, 3.50; N, 5.41. Found: C, 23.53; H, 3.44; N, 5.29%.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[CH3:3].[CH3:15][S:16][C:17](SC)=[CH:18][N+:19]([O-:21])=[O:20]>C(#N)C>[CH3:3][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:17]([S:16][CH3:15])=[CH:18][N+:19]([O-:21])=[O:20])[N:9]=1)[CH3:1]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: CN(C)Cc1nc(CSCCN)cs1
Solvent: CC#N
Product: CSC(=C[N+](=O)[O-])NCCSCc1csc(CN(C)C)n1
Yield: 53.1 %

Procedure:
With 2 ml of acetonitrile were mixed 1 g of 2-{[2-(dimethylamino)methyl-4-thiazolyl]methylthio}ethylamine and 1.4 g of 1,1-bis(methylthio)-2-nitroethene, and the resulting mixture was subjected to reaction under reflux for 2 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and 5 ml of ethanol was added to the resulting residue, after which the insolubles were removed by filtration. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography (Wako Silica Gel C-200, eluent; chloroform:ethanol=20:1 by volume) to obtain 0.8 g (yield 53%) of oily 1-{2-[[2-(dimethylamino)methyl-4-thiazolyl]methylthio]ethylamino}-1-methylthio-2-nitroethene.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.CON(C)[C:11]([C:13]1[N:14]=[C:15]([CH3:18])[S:16][CH:17]=1)=[O:12]>C1COCC1>[CH3:7][N:6]1[C:2]([C:11]([C:13]2[N:14]=[C:15]([CH3:18])[S:16][CH:17]=2)=[O:12])=[CH:3][N:4]=[CH:5]1
Reactant: Cn1cncc1Br
Reactant: CON(C)C(=O)c1csc(C)n1
Solvent: C1CCOC1
Product: Cc1nc(C(=O)c2cncn2C)cs1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a flask containing 5-bromo-1-methyl-1H-imidazole (345 mg, 2.14 mmol) was added THF (8 mL) and the solution was cooled to 0° C. To this clear homogeneous solution was added isopropylmagnesium chloride-LiCl complex (1.3 M, 2.0 mL, 2.6 mmol) which resulted in a white suspension. The reaction was stirred at 0° C. for 30 min, then a THF (2 mL) solution of N-methoxy-N,2-dimethylthiazole-4-carboxamide (250 mg, 1.34 mmol, Intermediate 38, step a) was introduced and the mixture became more viscous and was allowed to warm to room temperature. After 3 hours the mixture was quenched with saturated NH4Cl solution and extracted with EtOAc (4×50 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. Flash chromatography on silica gel (20-40% EtOAc-DCM increasing gradient to 5% MeOH-DCM) provided the title compound as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[CH:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]1=[O:18].[C:19]1(=[O:25])[O:24][C:22](=[O:23])[CH2:21][CH2:20]1>>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:18])[N:11]([C:19](=[O:25])[CH2:20][CH2:21][C:22]([OH:24])=[O:23])[C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Cc1cc(C)c(C=C2C(=O)Nc3ccccc32)[nH]1
Reactant: O=C1CCC(=O)O1
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)CCC(=O)O)c3ccccc32)[nH]1

Procedure:
The title compound was prepared from 3-(3,5-dimethyl-1H-pyrrol-2-ylmethylidene)-1,3-dihydro-indol-2-one and succinic anhydride (modification of procedure used to prepare (3Z)-1-acetyl-3-[(3,5-dimethyl-4-1H-pyrrol-2-yl)-methylidene]-1,3-dihydro-2H-indol-2-one).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+].Br[C:21]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:22]=1[C:23]([OH:25])=[O:24]>O>[Cl:1][C:2]1[CH:3]=[C:4]([S:8][C:21]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:22]=2[C:23]([OH:25])=[O:24])[CH:5]=[CH:6][CH:7]=1
Reactant: Sc1cccc(Cl)c1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Sc2cccc(Cl)c2)c(C(=O)O)c1
Temperature: 150 °C
Yield: 67.9 %

Procedure:
To a mixture of 3-chlorothiophenol (20 g, 0.138 mol), and cupric acetate (1.8 g) and DMF (200 mL) was added K2CO3 (23 g). The mixture was heated to 150° C. for 15-20 minutes, then 2-bromo-5-methoxybenzoic acid (35.8 g, 0.155 mol) was added in portions. The mixture was heated overnight, poured into water (600 mL), filtered and the filtrate was treated with charcoal, filtered and diluted with HCl. The resulting precipitate was collected by filtration, washed with water, and dried at 50° C. in vacuo over P2O5 to afford 27.6 g of 2-[(3-chlorophenyl)thio]-5-methoxybenzoic acid.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[N:18]=[C:19]=[S:20].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:3]1[CH2:4][C:5](=[O:7])[N:18]([C:9]2[CH:10]=[CH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=2)[C:19]1=[S:20])[CH3:2]
Reactant: CCNCC(=O)O
Reactant: S=C=Nc1ccc2ccccc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN1CC(=O)N(c2ccc3ccccc3c2)C1=S
Yield: 34.6 %

Procedure:
The title compound was prepared by the procedure described in Example 19 using 9.2 g of N-ethyl glycine, 9.3 g of 2-naphthyl-isothiocyanate, 10.1 g of triethylamine, and 150 mL of methylene chloride. Purification was achieved through crystallization from ethanol. Title compound (4.7 g) was obtained as a light pink solid, m.p. 156°-159° C. Anal. Calcd. for. C15H14N2O S: C, 66.64; H, 5.22; N, 10.36 Found: C, 66.69; H,5.24; N, 10.42. Mass spectrum (EI, M.+) m/z 270.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]2[C@H:12]([CH:13]=[O:14])[O:11][C:10]([CH3:16])([CH3:15])[N:9]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:24]1(Br)[CH2:26][CH2:25]1.[Mg].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH:1]1([CH2:7][C@H:8]2[C@H:12]([C@H:13]([CH:24]3[CH2:26][CH2:25]3)[OH:14])[O:11][C:10]([CH3:16])([CH3:15])[N:9]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H](C=O)OC1(C)C
Reactant: BrC1CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H]([C@@H](O)C2CC2)OC1(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.8 %

Procedure:
A solution of 3.21 g (9.8 mmol) of tert-butyl (4S,5R)-4-(cyclohexylmethyl)-5-formyl-2,2-dimethyl-3-oxazolidinecarboxylate (WO 87/05302) in 25 ml of tetrahydrofuran is added dropwise at about 15° to a solution of the Grignard compound prepared from 3.94 ml (49 mmol) of cyclopropyl bromide and 1.2 g (0.049 gram atom) of magnesium shavings in 22 ml of tetrahydrofuran and the reaction mixture is subsequently stirred at room temperature under argon for 16 hours. Thereafter, the reaction mixture is poured into 40 ml of an ice-cold, saturated ammonium chloride solution and extracted twice with 50 ml of ethyl acetate each time. The ethyl acetate extracts are washed with 40 ml of ice-cold, saturated ammonium chloride solution, combined, dried over sodium sulphate and evaporated. For purification, the residue (4.33 g) is chromatographed over a column of 110 g of silica gel, prepared with toluene and 1% triethylamine, using a 95:5 mixture of toluene and ethyl acetate as the eluent. There are obtained 1.9 g of tert-butyl (4S,5R)-4-(cyclohexylmethyl)-5-[(S)-cyclopropylhydroxymethyl]-2,2-dimethyl-3-oxazolidinecarboxylate, MS: 368 (M+H)+, and 0.5 g of tert-butyl (4S,5R)-4-(cyclohexylmethyl)-5-[(R)-cyclopropylhydroxymethyl]-2,2-dimethyl-3-oxazolidinecarboxylate, MS: 368 (M+H)+, both as a colourless oil.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:9]([OH:11])=O.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.O>C1(C)C(C)=CC=CC=1>[OH:25][C:22]1[CH:23]=[CH:24][C:19]([N:18]2[CH:2]3[C:3]([CH2:4][CH2:5][CH2:6][CH2:7]3)=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]2=[O:11])=[CH:20][CH:21]=1
Reactant: O=C1CCCCC1C(C(=O)O)c1ccccc1
Reactant: Nc1ccc(O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C1C(c2ccccc2)=C2CCCCC2N1c1ccc(O)cc1
Yield: 82 %

Procedure:
92.8 g of 2-(2-oxo-cyclohexyl)-2-phenyl acetic acid and 44 g of 4-aminophenol in 800 cm3 of xylene were stirred and heated under reflux, as indicated in Example 1a), until the water formed in the reaction has been totally eliminated. This took 2 hours (volume collected: 14.2 cm3 ; theoretical: 14.4 cm3). After the distillation of 400 cm3 of solvent, the residue was cooled. The precipitate produced was collected and recrystallized from methylcellosolve to give 100 g (82%) of 1-(4-hydroxyphenyl)-2-oxo-3-phenyl-2,4,5,6,7,7a-hexahydro-indole (m.p. 241° C).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[CH3:30][C:31]1[CH:32]=[C:33](O)[CH:34]=[CH:35][CH:36]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:29][C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([CH3:30])[CH:36]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: Cc1cccc(O)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Br)cc3)CC2)c1
Product: Cc1cccc(OC(CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccc(Br)cc2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 3-methylphenol: ESMS m/e: 549.1 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([OH:16])=O.[NH2:17][C@H:18]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:19]1>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][CH2:23][N:20]2[CH2:21][CH2:22][C@H:18]([NH:17][C:14](=[O:16])[CH2:13][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:19]2)=[CH:26][CH:27]=1
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Reactant: O=C(O)Cc1ccccc1-c1ccccn1
Product: O=C(Cc1ccccc1-c1ccccn1)N[C@H]1CCN(CCc2ccc(F)cc2)C1

Procedure:
2-(2-Pyridyl)phenylacetic acid and (S)-3-amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine were reacted under the same conditions as in Example 23 to give (S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-2-(2-pyridyl)phenylacetamide.
Reaction SMILES: [F:1][CH:2]([F:13])[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]([N+:10]([O-])=O)[CH:4]=1.Cl.C(=O)(O)[O-].[Na+]>CO.O.[Fe]>[F:13][CH:2]([F:1])[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]([CH:4]=1)[NH2:10]
Reactant: O=[N+]([O-])c1cc(C(F)F)ccc1F
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CO
Product: Nc1cc(C(F)F)ccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a solution of 4-(difluoromethyl)-1-fluoro-2-nitrobenzene (0.200 g, 1.04 mmol) in methanol (10 mL) was added iron powder (0.500 g, 8.92 mmol). The reaction mass was cooled at 0° C. followed by drop-wise addition of conc. HCl (3.0 mL). The reaction mass was stirred at RT for 1 h. The reaction mass was diluted with water and basified with sodium bicarbonate, extracted with DCM. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated to afford 0.150 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 5.44 (s, 2H), 6.67 (m, 1H), 6.86 (s, 1H), 6.93 (d, J=8.1 Hz, 1H), 7.05-7.12 (m, 1H); MS [M+H]+: 160.13.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[NH2:11][C:12]1[N:16](C(OC(C)(C)C)=O)[N:15]=[C:14]([CH2:24][CH2:25][C:26]2[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=2)[CH:13]=1.[CH2:36]1[CH:41]2[CH2:42][CH2:43][CH2:44][CH2:45][N:40]2[CH2:39][CH2:38][N:37]1[C:46]1[CH:55]=[CH:54][C:49]([C:50](OC)=[O:51])=[CH:48][CH:47]=1>C1COCC1>[CH2:36]1[CH:41]2[CH2:42][CH2:43][CH2:44][CH2:45][N:40]2[CH2:39][CH2:38][N:37]1[C:46]1[CH:55]=[CH:54][C:49]([C:50]([NH:11][C:12]2[NH:16][N:15]=[C:14]([CH2:24][CH2:25][C:26]3[CH:27]=[C:28]([O:34][CH3:35])[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=3)[CH:13]=2)=[O:51])=[CH:48][CH:47]=1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Reactant: COC(=O)c1ccc(N2CCN3CCCCC3C2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCN5CCCCC5C4)cc3)[nH]n2)cc(OC)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 9.3 %

Procedure:
A 1M solution of NaHMDS in THF (1.13 ml, 1.05 mmol) was added to a stirred solution of tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (244 mg, 0.7 mmol) and methyl 4-(1,3,4,6,7,8,9,9a-octahydropyrido[2,1-c]pyrazin-2-yl)benzoate (231 mg, 0.84 mmol) in THF (5 ml) at 0° C. under nitrogen, over 5 minutes. The reaction mixture was stirred for an additional 5 minutes at 0° C., then stirred at 20° C. for 18 h. An additional amount of tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (80 mg, 0.23 mmol) was added with 1M NaHMDS in THF (1.13 ml, 1.13 mmol). The reaction mixture was stirred for an additional 3 h. The reaction mixture was quenched with saturated ammonium chloride (20 ml) and extracted with ethyl acetate (3×20 ml). The extracts were washed with saturated brine solution (15 ml), dried (MgSO4) and evaporated to give crude product. The crude product was purified by reverse phase prep. HPLC (basic) using a 38-58% gradient of acetonitrile in water containing 1% 0.880 ammonium hydroxide. The clean fractions were taken and evaporated to afford the title compound as a white solid (32 mg, 9%); 1H NMR (500.13 MHz, DMSO-d6) δ 1.25 (1H, s), 1.62 (2H, t), 1.72 (1H, d), 1.93-1.95 (2H, m), 2.19-2.20 (1H, m), 2.44 (1H, s), 2.81 (3H, q), 2.87 (4H, s), 3.28 (1H, s), 3.69 (1H, s), 3.72 (6H, s), 3.77 (1H, d), 6.33 (1H, t), 6.42 (2H, d), 6.44 (1H, s), 6.96 (2H, d), 7.89 (2H, d), 10.29 (1H, s), 12.07 (1H, s). MS: m/z 490 (MH+).
Reaction SMILES: COC1C=C(C)C(S(N2CCCC2COCC(O)=O)(=O)=O)=C(C)C=1.N1C=CC=C(C2(O)CCNCC2)C=1.C(=O)(O)[O-].[Na+].[OH:43][C:44]1([C:73]2[CH:74]=[N:75][CH:76]=[CH:77][CH:78]=2)[CH2:49][CH2:48][N:47]([C:50](=[O:72])[CH2:51][O:52][CH2:53][CH:54]2[CH2:58][CH2:57][CH2:56][N:55]2[S:59]([C:62]2[C:67]([CH3:68])=[CH:66][C:65]([O:69][CH3:70])=[CH:64][C:63]=2[CH3:71])(=[O:61])=[O:60])[CH2:46][CH2:45]1.[Cl:79][Si](C)(C)C>C(Cl)Cl.C(C(C)=O)C.C(OCC)C.C(OCC)C>[ClH:79].[OH:43][C:44]1([C:73]2[CH:74]=[N:75][CH:76]=[CH:77][CH:78]=2)[CH2:45][CH2:46][N:47]([C:50](=[O:72])[CH2:51][O:52][CH2:53][CH:54]2[CH2:58][CH2:57][CH2:56][N:55]2[S:59]([C:62]2[C:67]([CH3:68])=[CH:66][C:65]([O:69][CH3:70])=[CH:64][C:63]=2[CH3:71])(=[O:60])=[O:61])[CH2:48][CH2:49]1
Reactant: C[Si](C)(C)Cl
Agent: COc1cc(C)c(S(=O)(=O)N2CCCC2COCC(=O)N2CCC(O)(c3cccnc3)CC2)c(C)c1
Agent: COc1cc(C)c(S(=O)(=O)N2CCCC2COCC(=O)O)c(C)c1
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: CCC(C)=O
Solvent: ClCCl
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N,N′-Carbonyldiimidazole (71 mg, 0.441 mmol) was added to a solution of 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)acetic acid (acid unit S27) (150 mg, 0.420 mmol) in methylene chloride (7 ml) and the mixture was stirred for 1 h at room temperature. A solution of 4-(pyridin-3-yl)piperidin-4-ol (A2) (74 mg, 0.420 mmol) in methylene chloride (3 ml) was subsequently added and the reaction mixture was stirred for 15 h at room temperature. Thereafter, saturated sodium bicarbonate solution (10 ml) was added to the reaction mixture and the aqueous phase was subsequently extracted with methylene chloride (2×10 ml). The combined organic phases were extracted with saturated sodium chloride solution (10 ml), dried with sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography with ethyl acetate/methanol/hexane (10:1:1). 1-(4-Hydroxy-4-(pyridin-3-yl)piperidin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)ethanone (160 mg, 0.309 mmol) was dissolved in methyl ethyl ketone/diethyl ether (1:1; 5 ml), and chlorotrimethylsilane (59 μl, 0.464 mmol) was slowly added. Diethyl ether (10 ml) was subsequently added and the mixture was stirred for 1 h at 0° C. The precipitate formed was filtered off, dried with exclusion of air and washed with diethyl ether.