Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:14]2[NH:13][CH:12]=[CH:11][C:10](=[O:15])[C:9]=2[C:8]2[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=2[CH:6]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[I:26]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C>[I:26][C:11]1[C:10](=[O:15])[C:9]2[C:8]3[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=3[CH:6]=[C:5]([O:4][CH2:1][CH2:2][CH3:3])[C:14]=2[NH:13][CH:12]=1
Reactant: II
Reactant: CCCOc1cc2ccccc2c2c(=O)cc[nH]c12
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOc1cc2ccccc2c2c(=O)c(I)c[nH]c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.4 %

Procedure:
5-Propoxy-4H-benzo[f]quinolin-1-one (2.66 g, 10.5 mmol) was suspended in DMF (20 ml). Potassium carbonate (1.63 g, 11.8 mmol) and iodine (2.95 g, 11.6 mmol) were added to the suspension, followed by stirring at room temperature for 3 hours. The reaction mixture was poured into an aqueous sodium thiosulfate solution (9.14 g, 100 ml), followed by stirring for 5 minutes. Ethyl acetate was added to the reaction mixture and stirred. Subsequently, insoluble matter was collected by filtration, and the filtrate was then separated. The thus-obtained organic layer was washed with an aqueous saturated sodium chloride solution, and then concentrated to dryness under reduced pressure. The residue was added to the collected insoluble matter, followed by purification using silica gel column chromatography (dichloromethane:methanol=50:1→20:1). The purified product was concentrated to dryness under reduced pressure, giving a pale brown powder of 2-iodo-5-propoxy-4H-benzo[f]quinolin-1-one (3.48 g, yield: 87%).
Reaction SMILES: [Si]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[C:12]([NH2:23])[N:13]=[C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]3=2)[N:10]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>O1CCCC1>[NH2:23][C:12]1[C:11]2[NH:10][C:9](=[O:8])[CH:18]=[CH:17][C:16]=2[C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[N:13]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(n1)c(N)nc1ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Nc1nc2ccccc2c2ccc(=O)[nH]c12
Reaction time: 0.25 h

Procedure:
To a solution of 3-(tert-butyldimethylsilyloxy)benzo[f][1,7]naphthyridin-5-amine (from step 4) (1.0 eq.) in tetrahydrofuran (0.05 M) was added tetra-n-butylammonium fluoride (TBAF) (1.0 eq.) and acetic acid (1.0 eq.). The reaction was stirred for 15 minutes, and then concentrated en vacuo. The crude residue was suspended in water and neutralized by addition of saturated aqueous NaHCO3 solution to pH 7. The solids were filtered, washed with acetone, and dried to give 5-aminobenzo[f][1,7]naphthyridin-3(4H)-one. 1H NMR (DMSO d-6): δ 8.59 (d, 1H), 8.20 (d, 1H), 7.49 (d, 1H), 7.37-7.41 (dd, 1H), 7.23-7.27 (dd, 1H), 6.88 (br, 2H), 6.79 (d, 1H). LRMS [M+H]=212.1
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH:18]=O)[CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][C:24]1=[O:29]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH2:18][N:26]4[CH2:27][CH2:28][N:23]([CH3:22])[C:24](=[O:29])[CH2:25]4)[CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1c(-c2cncc(C=O)c2)c(C#N)c2ccc(Cl)cc21
Reactant: CN1CCNCC1=O
Product: CN1CCN(Cc2cncc(-c3c(C#N)c4ccc(Cl)cc4n3C)c2)CC1=O

Procedure:
6-Chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile (Example 126) and 1-methyl-piperazin-2-one are processed according to the method described in Example 170 to give 6-chloro-1-methyl-2-[5-(4-methyl-3-oxo-piperazin-1-ylmethyl)-pyridin-3-yl]-1H-indole-3-carbonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.70 (br. s., 2H), 2.82 (s, 3H), 3.09 (s, 2H), 3.29 (dd, J=11.0, 5.4 Hz, 2H), 3.73 (s, 2H), 3.80 (s, 3H), 7.36 (dd, J=8.6, 1.8 Hz, 1H), 7.72 (d, J=8.3 Hz, 1H), 7.96 (d, J=1.5 Hz, 1H), 8.09 (s, 1H), 8.74 (d, J=2.0 Hz, 1H), 8.81 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 394.1437 [(M+H)+ Calcd for C21H21ClN5O: 394.1435].
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[CH2:2].Cl[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1.F[K].C(P)(C)(C)C>C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd].O1CCOCC1>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:17][CH:18]=2)=[CH:5][CH:4]=1)=[CH2:2]
Reactant: Clc1ccc(-c2cccnc2)cc1
Reactant: C=Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: CC(C)(C)P
Agent: F[K]
Solvent: C1COCCO1
Product: C=Cc1ccc(-c2ccc(-c3cccnc3)cc2)cc1
Temperature: 80 °C
Yield: 47 %

Procedure:
This Example was carried out in the same manner as Example 10, except that 23.42 g (0.158 mol) of 4-vinyl-phenyl boronic acid, 20.0 g (0.1055 mol) of 3-(4-chloro-phenyl)pyridine, 500□ of 1,4-dioxane, 27.54 g (0.474 mol, 3.3 equivalent) of fluoro-potassium, 1.69 g (0.0084 mol, 5.3 mol %) of t-butylphosphine [P( t-Bu)3)], and 2.6 g (0.0028 mol, 1.8 mol %) of palladium tris(dibenzylidene acetone) [Pd2(dba)3] were used. Finally, after the resulting solution was heated to reflux at 80° C. for 24 hours, the 3-(4′-vinyl-biphenyl-4-yl)pyridine was isolated. The yield was 47%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[N:11]=[C:10]2[S:12][C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])=[N:14][C:9]2=[CH:8][CH:7]=1.C(OC([NH:32][CH:33]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:34](O)=[O:35])=O)(C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>N1C=CC=CC=1.C(OCC)(=O)C>[NH2:32][CH:33]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:34]([NH:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[N:11]=[C:10]2[S:12][C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])=[N:14][C:9]2=[CH:8][CH:7]=1)=[O:35]
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: NC(C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F)c1ccccc1
Temperature: 60 °C
Reaction time: 7 h
Yield: 54.2 %

Procedure:
N-[5-(3-Amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.58 mmol) produced in Example 16(vi) was dissolved in pyridine (3.0 mL), [(tert-butoxycarbonyl)amino](phenyl)acetic acid (290 mg, 1.2 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (440 mg, 1.2 mmol) were added, and the mixture was stirred at 60° C. for 7 hr. [(tert-Butoxycarbonyl)amino](phenyl)acetic acid (145 mg, 0.58 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (220 mg, 0.58 mmol) were added to the reaction mixture, and the mixture was further stirred at 60° C. for 1 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), and washed successively with 5% aqueous ammonium chloride solution (10 ml), saturated aqueous sodium hydrogen carbonate solution (5 mL) and saturated brine (5 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in trifluoroacetic acid (4 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was diluted with ethyl acetate (20 mL), and washed successively with saturated aqueous sodium hydrogen carbonate solution (20 mL) and saturated brine (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=40/60→100/0), and the obtained oil residue was crystallized from ethyl acetate/heptane to give the title compound (150 mg, 53%) as a pale-yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28]C)=[C:24]([F:30])[CH:23]=2)=[O:21])=[CH:5][CH:4]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([F:30])[CH:23]=2)=[O:21])=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OC)c(F)c2)cc1
Solvent: CN(C)C=O
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(O)c(F)c2)cc1
Temperature: 80 °C

Procedure:
500 mg (1.2 mmol) of [2-(4-methoxyphenyl)-6-methoxybenzo[b]thien-3-yl][3-fluoro-4-methoxyphenyl]methanone was dissolved in 6 mL of DMF and 200 mg (2.4 mmol) of NaSEt was added. The reaction was heated to 80° C. for 1.5 hours under a nitrogen atmosphere. The reaction mixture quickly filtered over a silica gel column eluted with CHCl3 to remove the solids and exchange the solvent. The effluent from the column was evaporated to a solid and re-dissolved in EtOAc. The EtOAc solution was chromatographed on a silica gel column eluted with a linear gradient beginning with EtOAc-hexane (3:7) and finishing with EtOAc-hexane (1:1). The appropriate fractions were determined by tlc, combined, and evaporated to dryness. This yielded 200 mg of the title compound as a tan amorphous solid.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]([CH3:31])[CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])=[N:23][N:24]=2)[CH:21]=1.N>CN(C=O)C.CO.C(Cl)Cl>[NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([O:12][C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:22]([N:25]([CH3:31])[CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])=[N:23][N:24]=3)[CH:21]=2)[CH2:4][CH2:3]1
Reactant: CN(C)CCN(C)c1nnc2ccc(F)cn12
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)CCN(C)c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Temperature: 60 °C
Yield: 46 %

Procedure:
To a solution of Intermediate A (143 mg, 0.88 mmol) in DMF (3 mL) was added NaH (60% in oil, 96 mg, 2.4 mmol) and the mixture stirred at RT for 20 min, before Intermediate 43a (190 mg, 0.80 mmol) was added. This mixture was heated at 60° C. in the microwave for 1 h. The reaction mixture was applied to an SCX-2 cartridge and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-20% [2M NH3 in MeOH] in DCM, gave the title compound as a pale brown oil (140 mg, 46%). LCMS (Method 1): Rt 1.34 min, ink 381 [MH+].
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:13]=2[O:21][CH3:22])[CH2:6][CH2:7][CH3:8])[CH2:3][CH2:2]1.ClCCl.CO.N>>[CH:1]1([CH2:4][N:5]([CH2:6][CH2:7][CH3:8])[CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=2[O:21][CH3:22])[CH2:3][CH2:2]1
Reactant: CCCN(CCOc1ccc([N+](=O)[O-])cc1OC)CC1CC1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: CCCN(CCOc1ccc(N)cc1OC)CC1CC1

Procedure:
Prepared analogously to Example 3.1.b. from 950 mg (3.1 mmol) of cyclopropylmethyl-[2-(2-methoxy-4-nitrophenoxy)ethyl]propylamine. Yield: 0.74 g (86% of theory); C16H26N2O2 (M=278.39); calc.: molecular ion peak (M+H)+: 279; found: molecular ion peak (M+H)+: 279; Rf value: 0.4 (silica gel, dichloromethane/methanol/ammonia (9:1:0.1)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH3:31])=[C:11]([CH2:13][CH2:14][O:15][C:16]2[CH:30]=[CH:29][C:19]([CH:20]=[C:21]([C:27]#[N:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=2)[N:12]=1.O1CCOCC1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH3:31])=[C:11]([CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:20][CH:21]([C:27]#[N:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:29][CH:30]=2)[N:12]=1
Reactant: CCOC(=O)C(C#N)=Cc1ccc(OCCc2nc(-c3ccccc3Cl)oc2C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)C(C#N)Cc1ccc(OCCc2nc(-c3ccccc3Cl)oc2C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a mixture of ethyl 4-[2-[2-(2-chlorophenyl)-5-methyl-4-oxazolyl]ethoxy]-α-cyanocinnamate (2.25 g) and dioxane (30 ml)--ethanol (30 ml) was added sodium borohydride (0.06 g) under ice-cooling. The mixture was stirred for one hour at the same temperature. The reaction mixture was poured into ice-water, which was made acid and subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), then the solvent was distilled off under reduced pressure. The residue was subjected to a silica gel column chromatography. From the fractions eluted with chloroform-methanol (50:1, v/v), was obtained ethyl 3-[4-[2-[2-(2-chlorophenyl)-5-methyl-4-oxazolyl]ethoxy]phenyl]-2-cyanopropionate (2.25 g, quant.) as an oily product. NMR(δ ppm in CDCl3): 1.27(3H,t,J=7Hz), 2.39(3H,s), 3.00(2H,t,J=6.5Hz), 3.12(1H,dd,J=14&8Hz), 3.22(1H,dd,J=14&6Hz), 3.66(1H,dd,J=8&6Hz), 4.22(2H,q,J=7Hz), 4.24(2H,t,J=6.5Hz), 6.87(2H,d,J=9Hz), 7.17(2H,d,J=9Hz), 7.25-7.5(3H,m), 7.85-8.0(1H,m).
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17]C)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.[Cl-].[NH+]1C=CC=CC=1.C(=O)([O-])O.[Na+]>CN(C=O)C.C(#N)C>[CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([OH:17])[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(c1cc(OC)ncn1)C1CC1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCOC(=O)CC(c1cc(O)ncn1)C1CC1
Temperature: 130 °C
Reaction time: 0.33 h

Procedure:
Under a nitrogen atmosphere, to a solution of ethyl 3-cyclopropyl-3-(6-methoxypyrimidin-4-yl)propanoate (entire amount) in DMF (15 mL) was added pyridinium chloride (25.9 g), and the mixture was stirred at 130° C. for 20 min. The reaction mixture was cooled to 0° C. and diluted with acetonitrile (20 mL). Sodium hydrogen carbonate (17.0 g) was added to the reaction mixture, the insoluble material was filtered off, and the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was washed with diisopropyl ether to give the title compound (3.66 g) as a white solid.
Reaction SMILES: [CH:1]12[C:10](=O)[O:9][C:7](=O)[CH:2]1CC=C[CH2:6]2.[Pd:12]([Cl:14])[Cl:13].[C:15](#[N:17])[CH3:16]>CN(C)C=O>[Pd:12]([Cl:14])[Cl:13].[CH2:10]([O:9][CH:7]=[CH2:2])[CH:1]([CH3:6])[CH3:15].[Pd:12]([Cl:14])[Cl:13].[C:15](#[N:17])[CH3:16].[CH:7]([O:9][CH2:10][CH:1]([CH3:6])[CH3:15])=[CH2:2]
Reactant: O=C1OC(=O)C2CC=CCC12
Agent: Cl[Pd]Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: C=COCC(C)C

Procedure:
4-cyclohexene-1,2-dicarboxylic acid anhydride is dissolved in three times its quantity of dimethyl formamide. Its equimolar quantity of acetonitrile palladium dichloride is added at 40° C. in the course of 2 hours. Dimethyl formamide and acetonitrile are distilled off at 45° C./25 mbar. A brownish solid with a melting point of 53°-54° C. is obtained in a 90% yield. Isobutylvinyl ether palladium dichloride is obtained in analogous manner from acetonitrile palladium dichloride and isobutyl vinyl ether, melting point 57°-60° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6]([CH2:9][CH2:10][C:11]2=[O:13])=[CH:7][CH:8]=1
Reactant: COc1ccc(CCC(=O)O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2c(c1)C(=O)CC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
To a solution of 3-(4-methoxyphenyl)propionic acid (50.34 g, 0,279 mol) in 500 mL of methylene chloride cooled to 0° C. was added slowly at 0° C. 30.5 mL (0.418 mol) of thionyl chloride, the mixture was stirred 10 h at room temperature and the solvent was removed in vacuo. The residue was dissolved in 1000 mL of methylene chloride, cooled to 0° C., and 40.92 g (0.306 mol) of aluminum chloride was added in small portions and the resulting mixture was stirred at room temperature for 1 h. The above mixture was poured onto ice, the resulting mixture was filtered through celite, and the aqueous layer was extracted with methylene chloride (2×200 mL). The combined organic layer was dried over sodium sulfate, concentrated in vacuo, and the residue was extracted with hexane to afford 40 g (88%) of 6-methoxy-1-indanone.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=1)=[O:11].Br[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][N:31]=1>>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=2)=[O:11])=[N:31][CH:32]=1
Reactant: Clc1ccc(Br)nc1
Reactant: Cc1ccc(-c2ccc(C(F)(F)F)cn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-c2ccc(C(F)(F)F)cn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(Cl)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(5-(trifluoromethyl)pyridin-2-yl)phenyl)methanone and 2-bromo-5-chloropyridine. MS (ESI) 503 (M+H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=4)[N:13]([CH2:22][CH3:23])[CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(Br)[C:25]1[CH:30]=[CH:29]C=[CH:27][CH:26]=1>>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=4)[N:13]([CH2:22][C:23]4[CH:29]=[CH:30][CH:25]=[CH:26][CH:27]=4)[CH:12]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: BrCc1ccccc1
Reactant: CCn1cc(C2CCC3(CC2)OCCO3)c2cc(C#N)ccc21
Product: N#Cc1ccc2c(c1)c(C1CCC3(CC1)OCCO3)cn2Cc1ccccc1
Yield: 57 %

Procedure:
This compound was prepared in the manner described above for intermediate 5b by replacing ethylbromide with benzylbromide (14.3 g, 84 mmol) to afford 6.04 g (57%) of the title compound as a white solid: mp 129-130° C.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH2:14][NH:15]C2CC2)C=[C:7](/[CH:9]=[CH:10]/[CH2:11]OC)[CH:8]=1.[CH3:19]COC(C)=O>[Pd]>[CH3:19][CH2:11][CH2:10][CH2:9][CH2:7][CH2:8][CH2:3][CH2:4][CH2:5][CH2:14][NH2:15]
Reactant: COC/C=C/c1cc(CNC2CC2)cc(OC)c1
Reactant: CCOC(C)=O
Agent: [Pd]
Product: CCCCCCCCCCN
Reaction time: 1.5 h

Procedure:
To a solution of N-({3-(methyloxy)-5-[(1E)-3-(methyloxy)-1-propen-1-yl]phenyl}methyl)cyclopropanamine (1 eq.) from the previous step in EtOAc (0.04 M) was added palladium (10% w/w over activated carbon, 0.1 eq). The vessel was evacuated and back filled with hydrogen. The reaction suspension was then stirred under a balloon atmosphere of hydrogen for 1.5 h. The reaction was quenched with dichloromethane and filtered through a bed of celite. The insolubles were washed further with EtOAc and methanol. Concentration of the filtrate in vacuo afforded the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[OH:11].[C:12]([OH:21])(=[O:20])[C@@H:13]([C@H:15]([C:17]([OH:19])=[O:18])[OH:16])[OH:14].O>C(O)C.CO>[NH2:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[OH:11].[CH3:13][OH:14].[C:17]([C@@H:15]([C@H:13]([C:12]([OH:21])=[O:20])[OH:14])[OH:16])([OH:19])=[O:18]
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: O
Solvent: CCO
Solvent: CO
Product: N[C@H]1c2ccccc2C[C@H]1O
Temperature: 60 °C

Procedure:
Racemic cis-1-amino-2-indanol (25.1 g) was dissolved in 375 ml of ethanol. At room temperature a solution of (R,R)-tartaric acid (27.5 g) in 375 ml of methanol was added. The water content was less than 0.1 wt. % relative to methanol. Then the mixture was heated to 60° C. and then cooled down again to 20° C. The solid was recovered by filtration and washed with 100 ml of methanol. After drying, 23.7 g of (1S,2R)-1-amino-2-indanol-(R,R)-tartrate methanol solvate were obtained with an e.e. of 93.1%. D[v, 0.9]=92.7 μm (measured with a Malvern 2600 apparatus).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OCC)(=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([S:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)(=[O:21])=[O:20])[C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccc2cc(Br)cnc21
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a well stirred solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (10.0 g, 50.7 mmol) in dry THF (100 mL) was added NaH (60% oil suspension; 3.0 g, 75 mmol) at 0° C. and stirred for 30 min. Phenylsulfonyl chloride (10.7 g, 60 mmol) was added slowly and the mixture was stirred at ambient temperature for 16 h (TLC monitoring: 60% ethyl acetate in hexanes). Solvent was removed under reduced pressure, water (25 mL) was added to the residue, and the mixture was extracted with dichloromethane (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue thus obtained was crystallized from dichloromethane to yield the title compound (13.0 g, 76%). 1H NMR (CDCl3, 300 MHz): δ=6.55 (d, J=4.2 Hz, 1H), 7.46-7.62 (m, 3H), 7.74 (d, J=4.0 Hz, 1H), 7.97 (d, J=2.1 Hz, 1H), 8.15-8.18 (m, 2H), 8.44 (d, J=2.1 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C@@H:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:16][N:15]=2)[CH3:13])=[O:10])=[CH:4][CH:3]=1.Br[C:27]1[S:28][CH:29]=[CH:30][N:31]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(Cl)Cl.[Cu]>[S:28]1[CH:29]=[CH:30][N:31]=[C:27]1[O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:11][C@@H:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][CH2:21][C:22]([F:25])([F:23])[F:24])=[CH:16][N:15]=2)[CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: C[C@@H](NC(=O)Cc1ccc(O)cc1)c1ccc(NCC(F)(F)F)cn1
Reactant: Brc1nccs1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)Cc1ccc(Oc2nccs2)cc1)c1ccc(NCC(F)(F)F)cn1
Yield: 24.3 %

Procedure:
To a solution of the starting 2-(4-hydroxyphenyl)-N-((1R)-1-{5-[(2,2,2-trifluoroethyl)amino]pyridin-2-yl}ethyl)acetamide (60.0 mg, 0.17 mmol) in 1.0 ml of dry DMF was added the 2-bromo-1,3-thiazole (30.6 mg, 0.186 mmol), Cs2CO3 (166 mg, 0.508 mmol), and copper powder (1.1 mg, 0.017 mmol). The mixture was irradiated with microwave at 100° C. for 1 h. The mixture was cooled, diluted with CH2Cl2, and washed with saturated sodium bicarbonate solution and brine. The combined aqueous washes were extracted with CH2Cl2. The combined organic phase was dried over Na2SO4, filtered and concentrated in vacuo. Purification by reverse phase chromatography gave 2-[4-(1,3-thiazol-2-yloxy)phenyl]-N-((1R)-1-{5-[(2,2,2-trifluoroethyl)amino]pyridin-2-yl}ethyl)acetamide as a white solid (18 mg, 24%). 1H NMR (CDCl3, 400 MHz) δ 8.227 (d, J=2.75 Hz, 1H); 7.329 (m, 2H); 7.242 (m, 5H); 6.825 (d, J=2.85 Hz, 1H); 6.765 (d, J=7.14 Hz, 1H); 5.106 (quintet, J=6.84 Hz, 1H); 4.381 (dd, J=7.87, 15.93 Hz, 2H); 3.592 (s, 2H); 1.411 (d, J=6.78 Hz, 3H); MS (ES): m/z 438.1 (M+H). FLIPR alpha1I IP=46 nM.