Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:10]1[CH:19]=[CH:18][C:13]2[C:14](=[O:17])[O:15][CH2:16][C:12]=2[C:11]=1[CH3:20])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[F:21][C:22]1[CH:29]=[C:28]([CH:30]2[CH2:32][O:31]2)[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]>>[F:21][C:22]1[CH:29]=[C:28]([CH:30]([OH:31])[CH2:32][N:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[C:10]3[CH:19]=[CH:18][C:13]4[C:14](=[O:17])[O:15][CH2:16][C:12]=4[C:11]=3[CH3:20])[CH2:5][CH2:6]2)[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]
Reactant: Cc1c(C(O)CN2CCNCC2)ccc2c1COC2=O
Reactant: N#Cc1ccc(C2CO2)cc1F
Product: Cc1c(C(O)CN2CCN(CC(O)c3ccc(C#N)c(F)c3)CC2)ccc2c1COC2=O

Procedure:
2-fluoro-4-(1-hydroxy-2-{4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile was prepared in a similar fashion to that described for the synthesis of EXAMPLES 2C and 28-29 starting from 5-(1-hydroxy-2-piperazin-1-ylethyl)-4-methyl-2-benzofuran-1(3H)-one and 2-fluoro-4-oxiran-2-ylbenzonitrile. 1H NMR (500 MHz, DMSO-d6), δ 7.98 (m, 1H), 7.74 (m, 1H), 7.71 (m, 1H), 7.60 (d, J=10.5 Hz, 1H), 7.52 (d, J=7.9 Hz, 1H), 5.56 (d, J=7.7 Hz, 1H), 5.42 (dd, J=8.3 Hz, 2H), 5.38 (bs, 1H), 3.95-3.42 (m, 6H), 3.40-3.18 (m, 6H), 2.36 (s, 3H); LC/MS (M+1)+=440.02.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:18]3=[N:19][CH:20]=[C:21]([NH:23][NH:24]C(OC(C)(C)C)=O)[N:22]=[C:17]3[CH:16]=[CH:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(C1C=CC(S(N2C3=NC=C(N(C(OC(C)(C)C)=O)N)N=C3C=C2)(=O)=O)=CC=1)(C)(C)C.Cl>O1CCOCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]2[C:18]3=[N:19][CH:20]=[C:21]([NH:23][NH2:24])[N:22]=[C:17]3[CH:16]=[CH:15]2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NNc1cnc2c(ccn2S(=O)(=O)c2ccc(C(C)(C)C)cc2)n1
Agent: CC(C)(C)OC(=O)N(N)c1cnc2c(ccn2S(=O)(=O)c2ccc(C(C)(C)C)cc2)n1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Temperature: 60 °C
Yield: 87 %

Procedure:
To a mixture of tert-butyl 2-(5-(4-tert-butylphenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate and tert-butyl 1-(5-(4-tert-butylphenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate (11.24 g, 25.2 mmol, Preparation #2) in 1,4-dioxane (125 mL) was added HCl (4 M in 1,4-dioxane, 125 mL, 500 mmol). The reaction mixture was heated at about 60° C. for about 1 h and then the reaction mixture was cooled to ambient temperature. The mixture was filtered, while washing with Et2O (150 mL), and the solid was partitioned between EtOAc (500 mL) and saturated aqueous NaHCO3 (500 mL). The layers were separated and the organic layer was washed with saturated aqueous NaHCO3 and brine (200 mL each), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and dried in a vacuum oven at about 70° C. to give 5-(4-tert-butylphenylsulfonyl)-2-hydrazinyl-5H-pyrrolo[2,3-b]pyrazine as a tan solid (7.54 g, 87%): LC/MS (Table 2, Method a) Rt=2.20 min; MS m/z: 346 (M+H)+.
Reaction SMILES: C([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)(=O)C.[CH:14]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:27]=[C:28]3[C:34]([NH2:35])=[CH:33][N:32]([C:36]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:29]3=[N:30][CH:31]=2)=[CH:22][CH:21]=1)(=[O:19])=[O:18])([CH3:16])[CH3:15].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>C(Cl)Cl>[OH:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH:35][C:34]1[C:28]2[C:29](=[N:30][CH:31]=[C:26]([C:23]3[CH:24]=[CH:25][C:20]([S:17]([CH:14]([CH3:16])[CH3:15])(=[O:19])=[O:18])=[CH:21][CH:22]=3)[N:27]=2)[N:32]([C:36]([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:33]=1)=[O:9]
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc3c(n2)c(N)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)Oc1ccccc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc3c(n2)c(NC(=O)c2ccccc2O)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 5 mL microwave vial was charged with 2-acetoxybenzoic acid (33.87 mg, 0.1880 mmol) To this was added a solution of 2-(4-isopropylsulfonylphenyl)-5-trityl-pyrrolo[2,3-b]pyrazin-7-amine (100 mg, 0.1790 mmol), TBTU in DCM (1 mL) followed by PS-NMM. The reaction was shaken for 3 hours at ambient temperature then filtered and the resin washed with DCM (1 mL). This crude mixture was taken onto the next step as is.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:26][C:27]([F:34])([F:33])[CH2:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C>CN(C=O)C>[C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][N:23]([S:29]([CH2:28][C:27]([F:34])([F:33])[F:26])(=[O:31])=[O:30])[CH2:22][CH2:21]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)n[nH]c12
Reactant: O=S(=O)(Cl)CC(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CC(F)(F)F)CC3)n[nH]c12
Yield: 20.5 %

Procedure:
This compound was prepared in a fashion analogous to the procedure described in Example 3. Thus, 5-phenyl-3-(4-piperidinyl)-1H-indazole-7-carboxamide hydrochloride (Example 2) (0.030 g, 0.07 mmol) was reacted with 2,2,2-trifluoroethanesulfonyl chloride (0.015 mL, 0.105 mmol) in the presence of triethylamine (0.04 mL, 0.28 mmol) in DMF (2 mL) to give 6.7 mg of white solid.
Reaction SMILES: [CH2:1]([N:8]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:9]1[CH:14]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)[CH:12]=[CH:11][C:10]=1[N+:29]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:1]([N:8]([C:9]1[CH:14]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:28])[CH2:17][CH2:16]2)[CH:12]=[CH:11][C:10]=1[NH2:29])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1CCN(c2ccc([N+](=O)[O-])c(N(Cc3ccccc3)c3ccccc3)c2)CC1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: CCO
Product: Nc1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1N(Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
A suspension of N-benzyl-5-(4-benzoylpiperazin-1-yl)-2-nitro-N-phenylbenzenamine (1.2 g, 2.4 mmol), 2 M copper sulfate solution (10 ml, 2.0 mmol), and sodium borohydride (0.46 g, 12.2 mmol) in 40 ml ethanol was stirred at room temperature overnight. The run was quenched with additional 20 ml water, and it was extracted with acetyl acetate (3×20 ml). (4-(3-(N-benzyl-N-phenylamino)-4-aminophenyl)piperazin-1-yl)(phenyl)methanone (0.8 g, 71%) was obtained by flash column chromatograph (50% ethyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) δ (ppm) 3.29 (d, br, 4H), 3.56 (s, br, 4H), 3.93 (s, 2H), 4.88 (s, 2H), 6.68 (d, J=7.9 Hz, 2H), 6.80 (m, 4H), 7.19 (dd, J=7.4, 8.7 Hz, 2H), 7.25-7.45 (m, 5H), 7.47 (s, 5H). 13C NMR (125 MHz, CDCl3): δ (ppm) 51.6, 51.8, 51.9, 56.1, 114.2, 117.8, 118.1, 118.4, 119.5, 127.4, 127.5, 127.6, 128.9, 129.0, 129.7, 130.0, 133.9, 136.2, 138.8, 139.5, 145.1, 148.2, 170.8.
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]([Cl:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]([C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)=[C:12]([C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH:1][C:26]2[N:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=2)=[O:11])[CH:17]=1
Reactant: Clc1cnc(Cl)nc1
Reactant: C[C@@H]1CCCN(C(=O)c2cc(Cl)ccc2-c2ncccn2)[C@@H]1CN
Product: C[C@@H]1CCCN(C(=O)c2cc(Cl)ccc2-c2ncccn2)[C@@H]1CNc1ncc(Cl)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A45 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-chloro-2-(pyrimidin-2-yl)phenyl)methanone and 2,5-dichloropyrimidine. MS (ESI) 457 (M+H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[N:13]=[C:14]([N:35]3[CH2:40][CH2:39][N:38]([C:41]4[C:46]([C:47]([F:50])([F:49])[F:48])=[CH:45][CH:44]=[CH:43][N:42]=4)[CH2:37][CH2:36]3)[N:15](COCC[Si](C)(C)C)[C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]>C(O)(C(F)(F)F)=O>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]([C:12]2[N:13]=[C:14]([N:35]3[CH2:36][CH2:37][N:38]([C:41]4[C:46]([C:47]([F:48])([F:50])[F:49])=[CH:45][CH:44]=[CH:43][N:42]=4)[CH2:39][CH2:40]3)[NH:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)=[O:11])[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(C(=O)c2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)n(COCC[Si](C)(C)C)c2-c2ccc(C(F)(F)F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N1CCN(C(=O)c2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2-c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (4-isopropylpiperazin-1-yl)(5-(4-(trifluoromethyl)phenyl)-2-(4-(3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methanone from step (f) above was dissolved in TFA (1 mL). The solution was stirred at RT for 1 h. The solvent was removed and the residue was purified on silica gel using ISCO Combiflash® system with DCM/2M methanolic ammonia gradient to give the title compound as a white solid. MS (ESI, positive ion) m/z: 596 (M+1).
Reaction SMILES: [CH2:1]([O:9][CH2:10][C@H:11]([CH2:13][OH:14])[OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:15]1([C:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)Cl)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1COCC1.C(#N)C>C(N(CC)CC)C>[CH2:1]([O:9][CH2:10][C@H:11]([CH2:13][O:14][C:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([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)[OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOC[C@@H](O)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCOC[C@@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 73 %

Procedure:
34 grams of (S)-1-octyl-glycerol and 61 grams of triphenylchloromethane were added to a mixture of 500 ml of dry THF and 130 ml of dry acetonitrile. 46 ml of dry triethylamine was added, and the reaction mixture was refluxed for 17 hours. The reaction mixture was then cooled to room temperature and poured on ice (1 kilogram). The mixture was transferred to a separatory funnel and extracted thrice with 200 ml diethyl ether. The organic phase was washed consecutively with 150 ml water, twice with 100 ml dilute (1.5%) H2SO4, 200 ml water, 200 ml concentrated aqueous sodium bicarbonate, and again with 200 ml water. The solution was then dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The obtained residue, 80 grams of a brown oil, was dissolved in 500 ml hot hexane and kept at a temperature of 4° C. overnight. The precipitate was filtered off and the solvent from the filtrate was removed under reduced pressure. The obtained residue was purified by chromatography on silica gel. The resulting pure (R)-1-octyl-3-trityl-glycerol was eluted by mixtures of chloroform with 10% hexane, chloroform with 5% hexane, followed by chloroform with ethyl acetate (5% and 10%). The yield was 73%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:11]=[CH:12][C:13]3[N:17]=[N:16][N:15]([CH3:18])[C:14]=3[CH:19]=2)O)=[CH:4][CH:3]=1.P(Cl)(Cl)[Cl:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:11]=[CH:12][C:13]3[N:17]=[N:16][N:15]([CH3:18])[C:14]=3[CH:19]=2)[Cl:21])=[CH:4][CH:3]=1
Reactant: ClP(Cl)Cl
Reactant: Cn1nnc2ccc(C(O)c3ccc(Cl)cc3)cc21
Product: Cn1nnc2ccc(C(Cl)c3ccc(Cl)cc3)cc21

Procedure:
The alcohol (d) is reacted with phosphorus trichloride, yielding the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[NH2:19])=[CH:12][CH:11]=2)=[CH:5][C:4]=1[O:23][CH3:24])#[N:2].C(N(CC)CC)C.Cl[C:33]([O:36]C(=O)OC(Cl)(Cl)Cl)(Cl)Cl>C(Cl)Cl>[CH3:21][C:18]1([CH3:20])[C:17](=[O:22])[N:16]([C:13]2[CH:12]=[CH:11][C:10]([O:9][C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([O:23][CH3:24])[CH:5]=3)=[CH:15][CH:14]=2)[C:33](=[O:36])[NH:19]1
Reactant: COc1cc(Oc2ccc(NC(=O)C(C)(C)N)cc2)ccc1C#N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(Oc2ccc(N3C(=O)NC(C)(C)C3=O)cc2)ccc1C#N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84.2 %

Procedure:
N1-(4-{[4-cyano-3-(methyloxy)phenyl]oxy}phenyl)-2-methylalaninamide (Intermediate 191, 77.0 mg) was dissolved in DCM (10 mL). Triethylamine (0.218 mL, 1.57 mmol) was added and the obtained mixture was cooled at 0° C. Bis(trichloromethyl)carbonate (68.1 mg, 0.22 mmol) was dissolved in 5 mL of DCM and the obtained solution was added dropwise to the reaction mixture. The reaction mixture was stirred at 0° C. After 15 min, the reaction mixture was evaporated in vacuo to obtain the crude product that was purified by silica gel chromatography (from 100:0 to 50:50 Cyclohexane/EtOAc in 10 CV; then 50:50 Cyclohexane/EtOAc for 10 CV) to obtain 65.1 mg of the title compound as a white solid
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7].C(=O)=O.CC(C)=O.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[CH2:15]([C:4]1[S:3][C:2]([CH3:1])=[C:6]([CH3:7])[CH:5]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1ccsc1C
Reactant: BrCc1ccccc1
Agent: O=C=O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(Cc2ccccc2)sc1C
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 77.1 %

Procedure:
At -78° C., to a stirred solution of 2,3-dimethylthiophene (5.00 g, 44.6 mmol) in THF (89.3 mL) was added dropwise 2.5M BuLi/hexanes (17.9 mL, 44.6 mmol). After the addition was complete, the dry ice/acetone bath was replaced with a water ice bath and the reaction was stirred for 0.75 h. At -78° C., to the reaction was added a solution of benzyl bromide (5.30 mL, 44.6 mmol) in THF (44.6 mL) that had been previously cooled to -78° C. After the addition was complete, the reaction was stirred for 18 h eventually warming to ambient temerature. The reaction was filtered through a silica gel pad eluting with 1% EtOAc/pet ether and the filtrate was concentrated. Purification on Biotage KP-Sil eluting with 1% EtOAc/pet ether gave 6.960 g (77%) of the title compound as an oil. 1H NMR (DMSO-d6) δ 2.01 (s, 3 H), 2.21 (s, 3 H), 3.98 (s, 2 H), 6.58 (s, 1 H), 7.18-7.37 (m, 5 H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:15]=4[CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>CN(C)P(=O)(N(C)C)N(C)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:20]=[CH:19][C:18]([NH:21][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:17][C:15]=4[CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc2oc(-c3ccc4ccc(Cl)cc4n3)cc2c1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)CCCNc1ccc2oc(-c3ccc4ccc(Cl)cc4n3)cc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.1 %

Procedure:
A mixture of 7-Chloro-2-(5-aminobenzofuran-2-yl)-quinoline (0.17 g), sodium bicarbonate (0.2 g), ethyl 4-bromobutyrate (0.12 g) in hexamethylphosphoric triamide ml) was stirred at ambient temperature for 1 day. The resulting mixture was poured into ice-water. The appeared precipitates were collected by filtration, washed with water, and recrystallized from ethanol to give 7-chloro-2-[5-(3-ethoxycarbonylpropylamino)benzofuran-2-yl]quinoline (0.13 g).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[CH2:17][CH2:16][CH:15]([O:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[C:11]=3[CH:12]=[N:13][CH:14]=2)=[CH:5][CH:4]=1.[ClH:29].O1CCOCC1>C(Cl)Cl>[ClH:29].[F:27][C:2]([F:1])([F:28])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:10]3[CH2:17][CH2:16][CH:15]([O:18][CH2:19][C:20]([OH:22])=[O:21])[C:11]=3[CH:12]=[N:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)COC1CCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(O)COC1CCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
To a cooled (0° C.) solution of (rac)-tert-butyl 2-(4-(4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yloxy)acetate (example 97) (235 mg, 0.597 mmol) in CH2Cl2 (2 mL) was added 4M HCl in dioxane (1.49 mL, 5.97 mmol) and the reaction mixture was stirred at room temperature for 16 h. The mixture was evaporated to dryness to give the title compound (221 mg, 99%) as a grey solid. MS: 338.5 (M+H+).
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[CH2:4][CH2:5][O:6][CH:7]1[C:12]([O:15][CH3:16])([O:13][CH3:14])[CH2:11][CH2:10][N:9](CC2C=CC=CC=2)[CH2:8]1)[CH3:2].[H][H]>[Pd].CO>[CH2:24]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][O:6][CH:7]1[C:12]([O:15][CH3:16])([O:13][CH3:14])[CH2:11][CH2:10][NH:9][CH2:8]1)[CH3:25]
Reactant: CCN(CC)CCOC1CN(Cc2ccccc2)CCC1(OC)OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCN(CC)CCOC1CNCCC1(OC)OC
Yield: 100 %

Procedure:
A mixture of 13.5 parts of N,N-diethyl-2-[[4,4-dimethoxy-1(phenylmethyl)-3-piperidinyl]oxy]ethanamine and 120 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 10.5 parts (100%) of N,N-diethyl-2-[(4,4-dimethoxy-3-piperidinyl)oxy]ethanamine as a residue (intermediate 109).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:3].[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Mg]Cl.C1COCC1.[Cl-].[NH4+]>C(OCC)C>[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([OH:4])[CH2:2][CH3:3]
Reactant: CCC(=O)c1ccccc1
Reactant: Cc1ccccc1[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(O)(c1ccccc1)c1ccccc1C
Yield: 92 %

Procedure:
Propiophenone (6.7 g, 50 mmol) was added dropwise to a solution of 2-methylphenylmagnesium chloride (30 ml of a 2.0 M solution in diethyl ether) and dry THF (50 ml) under a nitrogen atmosphere. When the addition was complete the reaction mixture was heated at reflux temperature for 5 h. Excess of a saturated ammonium chloride solution was added and the mixture was extracted with diethyl ether (2×100 ml). The combined organic extracts were dried over potassium carbonate and the solvent was evaporated in vacuo to give 10.4 g (92%) of 1-(2-methyl phenyl)-1-phenyl-1- propanol. TLC: rf=0.50 (SiO2 ; n-heptane/THF=7:3).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@@H:4]1[CH2:8][CH:7]([N:9]=[N+]=[N-])[CH2:6][N:5]1[C:12](=[O:30])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:16]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:31])[C@@H:4]1[CH2:8][CH:7]([NH2:9])[CH2:6][N:5]1[C:12](=[O:30])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH:16]=1
Reactant: COC(=O)[C@@H]1CC(N=[N+]=[N-])CN1C(=O)CCc1cccc(CNC(=O)OC(C)(C)C)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H]1CC(N)CN1C(=O)CCc1cccc(CNC(=O)OC(C)(C)C)c1
Yield: 86 %

Procedure:
4.7 g (10.9 mmol) of 4-azido-1-[3-(3-tert-butyloxycarbonylaminomethylphenyl)propionyl]proline methyl ester (starting compound A10) are dissolved in 70 ml of methanol and, after addition of 0.5 g of Pd/C (10%), hydrogenated. After the reaction is complete, the catalyst is filtered off with suction and the filtrate is concentrated in vacuo. Drying under high vacuum results in 3.8 g of the title compound as a colorless solidified foam. The mass spectrum shows the molecular peak MH+ at 406 Da.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([Cl:9])[N:3]=1>[Cu]>[Cl:1][C:2]1[CH:7]=[C:6]([C:6]2[CH:5]=[C:4]([Cl:9])[N:3]=[C:2]([Cl:1])[CH:7]=2)[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: Clc1cc(I)cc(Cl)n1
Agent: [Cu]
Product: Clc1cc(-c2cc(Cl)nc(Cl)c2)cc(Cl)n1

Procedure:
a process of carrying out synthesis by stirring 2,6-dichloro-4-iodopyridine, listed as a starring material in Process (1-B), in the presence of a base by she catalysis of a copper catalyst such as copper powder with heating at 150° C. to 250° C. to yield 2,6,2′,6′-tetrachloro-[4,4′]bipyridyl, and treating this compound by the procedure of Process (B).
Reaction SMILES: Br[C:2]1[C:3]([O:9][CH3:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[C:11]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)(=[O:13])[CH3:12].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[F:8][C:6]1[CH:7]=[C:2]([C:17]2[CH:18]=[CH:19][C:14]([C:11](=[O:13])[CH3:12])=[CH:15][CH:16]=2)[C:3]([O:9][CH3:10])=[N:4][CH:5]=1
Reactant: COc1ncc(F)cc1Br
Reactant: CC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ncc(F)cc1-c1ccc(C(C)=O)cc1
Temperature: 150 °C
Yield: 81.6 %

Procedure:
A mixture of 3-bromo-5-fluoro-2-methoxy-pyridine (1.0 g, 4.9 mmol), 4-acetylphenylboronic acid (1.59 g, 9.7 mmol), tetrakis(triphenylphosphine)palladium (0) (0.28 g, 0.24 mmol), 2M aqueous sodium carbonate solution (2.4 ml) and 1,2-dimethoxyethane (5 ml) was heated in a microwave oven at 150° C. for 20 min. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was washed with water, brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue chromatographed on silica gel eluting with 3:1 heptane/ethyl acetate to give 1-[4-(5-fluoro-2-methoxy-pyridin-3-yl)-phenyl]-ethanone (1.0 g, 4.0 mmol, 82%). 1-[4-(5-fluoro-2-methoxy-pyridin-3-yl)-phenyl]-ethanone (1.0 g, 4.1 mmol) was treated with sodium borohydride (4.0 eq) in tetrahydrofuran and dichloromethane at room temperature. The solvent was evaporated to give 1-[4-(5-fluoro-2-methoxy-pyridin-3-yl)-phenyl]-ethanol (0.51 g, 2.1 mmol, 51%). To a solution 1-[4-(5-fluoro-2-methoxy-pyridin-3-yl)-phenyl]-ethanol (0.5 g, 2.0 mmol) in tetrahydrofuran (5 ml) was added triphenylphosphine (0.63 g, 2.4 mmol) and pthalimide (0.35 g, 2.4 mmol). The reaction was cooled to below 5° C. before adding diethylazodicarboxylate (0.42 g, 2.4 mmol) in a dropwise manner maintaining the temperature below 5° C. The reaction mixture was stirred for 24 h at room temperature. The solvent was evaporated and the residue partitioned between ethyl acetate and water.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[SH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1>C1COCC1>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[O:7])[S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: Sc1ccccn1
Solvent: C1CCOC1
Product: O=C(Sc1ccccn1)c1ccc(I)cc1

Procedure:
Following the general procedure described above, reaction of 4-iodobenzoyl chloride (8.01 g, 30.0 mmol) with 2-mercaptopyridine (3.33 g, 30.0 mmol) in THF (60 mL) for 30 min at room temperature afforded pale yellow solid after precipitation (9.61 g, 94%): mp 127° C.; 1H NMR δ 7.30-7.38 (m, 1H), 7.70-7.76 (m, 3H), 7.77-7.83 (m, 1H), 7.84-7.89 (m, 2H), 8.64-8.71 (m, 1H); Anal. Calcd for C12H8INOS: C, 42.25; H, 2.36; N, 4.11. Found: C, 42.27; H, 2.38; N, 4.05.