Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:17]=2[CH:18]=[O:19])[C:5]([Cl:8])=[N:6][CH:7]=1.[BH4-].[Na+].O>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:17]=2[CH2:18][OH:19])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: O=Cc1c(-c2cc(Br)cnc2Cl)nc2ccccn12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1c(-c2cc(Br)cnc2Cl)nc2ccccn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.6 %

Procedure:
To a solution of 2-(5-bromo-2-chloropyridin-3-yl)imidazo[1,2-a]pyridine-3-carbaldehyde (100 mg, 0.29 mmol) in MeOH (5 mL), NaBH4 (20 mg, 0.53 mmol) was added at 0° C. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was added water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using PTLC (eluted with dichloromethane:MeOH=30:1) to provide (2-(5-bromo-2-chloropyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methanol (30 mg, yield: 29%). 1H-NMR (DMSO, 400 MHz) δ 8.66 (d, J=2.4 Hz, 1H), 8.49 (d, J=6.8 Hz, 1H), 8.25 (d, J=2.4 Hz, 1H), 7.64 (d, J=9.2 Hz, 1H), 7.35˜7.40 (m, 1H), 7.03˜7.07 (m, 1H), 5.33 (t, J=5.2 Hz, 1H), 4.75 (d, J=5.2 Hz, 2H). MS (M+H)+: 338/340.
Reaction SMILES: [CH:1]([O:3][C@@H:4]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[CH:6]([C@@H:7]([OH:24])[CH2:8][C@@H:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[OH:23])[CH2:5]1)=[O:2].C[N+]1([O-])CCOCC1>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH:1]([O:3][C@@H:4]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[CH:6]([C:7](=[O:24])[CH2:8][C@@H:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][C:13]2=[O:23])[CH2:5]1)=[O:2]
Reactant: C[C@]12CC[C@H]3[C@@H](C[C@H](O)C4C[C@H](OC=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: C[C@]12CC[C@@H](OC=O)CC1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a stirred solution of 3α-formyloxyandrostane-6α,17β-diol (2.50 g) in CH2Cl2 (100 mL), NMO (2.7 g) and molecular sieves (4 Å, 3.8 g) were added followed by the addition of TPAP (270 mg). After stirring for 2 h at room temperature, the solvent was removed and the mixture purified by flash chromatography (SiO2, n-hexane/EtOAc 65/35) to give 3α-formyloxyandrostane-6,17-dione in 90% yield as a white solid. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 8.15 (1H, s), 5.12 (1H, bs), 2.40-0.90 (20H, m), 0.77 (3H, s), 0.66 (3H, s).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([OH:19])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[C:20]1([CH2:26]Br)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CO[Na]>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([OH:19])[C:11]2[C:16]([C:17]=1[O:18][CH2:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(O)c2ccccc2c1O
Reactant: BrCc1ccccc1
Agent: CO[Na]
Product: CCCCOC(=O)c1nc(O)c2ccccc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 30.7 %

Procedure:
A mixture of 1,4-dihydroxy-isoquinoline-3-carboxylic acid butyl ester (26.13 g, 100 mmol; Example D-20 b), PhCH2Br (18.2 ml, 150 mmol), MeONa (0.5 M in MeOH, 200 ml, 100 mmol) was stirred at ambient temperature for 48 h. Then the solvent was evaporated and EtOAc (100 ml) was added to the residue. The mixture was stirred vigorously for 10 min before it was filtered. The filtrate was washed with aqueous 2.5N NaOH (2×100 ml) and aqueous 2N HCl (1×100 ml). The organic phase was dried over MgSO4 and evaporated in vacuo. The residue was recrystallized from MeOH (500 ml)/water (300 ml). The resulting yellow solid was further purified by flash column chromatography on silica gel using hexanes:EtOAc:NEt3=65:30:5 as the eluent to give 10.8 g of a yellow solid. 2 g of this material were further purified by flash column chromatography on silica gel using hexanes:EtOAc:NEt3=75:20:5 as the eluent to give 1.57 g of the title compound as a slightly yellowish solid; 1H NMR (CDCl3): δ=8.88 (bs, 1H), 8.46 (d, 1H), 8.42 (d, 1H), 7.26 to 7.96 (m, 7H), 5.06 (s, 2H), 4.38 (t, 2H), 1.69 (m, 2H), 1.37 (m, 2H), 0.91 (t, 3H).
Reaction SMILES: [CH3:1][NH2:2].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:15]([S:17]C)=S)[S:14][CH2:13][CH2:12][CH2:11][O:10]1.C>C(O)C>[CH3:1][NH:2][C:15]([C:9]1([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=2)[S:14][CH2:13][CH2:12][CH2:11][O:10]1)=[S:17]
Reactant: CN
Reactant: CSC(=S)C1(c2ccccn2)OCCCS1
Solvent: CCO
Product: CNC(=S)C1(c2ccccn2)OCCCS1
Temperature: 2 °C
Reaction time: 0.5 h

Procedure:
A 33% (weight/volume) solution of methylamine in ethanol (6.5 cc) is added dropwise, in the course of 10 minutes and at a temperature between 34° C. and 37° C., to a solution of methyl 2-(pyrid-2-yl)-1,3-oxathiane-2-carbodithioate (17.5 g) in ethanol (60 cc). The reaction mixture is then stirred for 30 minutes at 2° C. The resulting crystals are filtered off, washed twice with petroleum ether (40 cc in total) and dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. The product obtained (13.4 g) is dissolved in boiling ethanol (80 cc); decolourising charcoal (0.2 g) is added to the solution, which is filtered hot, and the filtrate is then cooled for 1 hour at a temperature of about 0° C. The resulting crystals are filtered off, washed twice with ethanol (20 cc in total) and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 50° C. N-Methyl-2-(pyrid-2-yl)-1,3-oxathiane-2-carbothioamide (12 g), melting at 157° C., is thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[C:11]2[C:18]([CH3:19])=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N+:21]=3CC3C=CC=CC=3)[NH:16][C:12]=2[N:13]=[CH:14][N:15]=1>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH:5][C:10]1[C:11]2[C:18]([CH3:19])=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[NH:16][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: Nc1cccc(Cl)c1
Reactant: Cc1c(-c2cccc[n+]2Cc2ccccc2)[nH]c2ncnc(Cl)c12
Solvent: CC(C)O
Product: Cc1c(-c2ccccn2)[nH]c2ncnc(Nc3cccc(Cl)c3)c12

Procedure:
With the exclusion of air, 529 μl (5.0 mmol) of 3-chloro-aniline are added to approximately 1.2 mmol of 4-chloro-5-methyl-6-(N-benzyl-pyridinium-2-yl)-7H-pyrrolo[2,3-d]-pyrimidine in 10 ml of isopropanol and the reaction mixture is boiled under reflux for 3 hours. The reaction mixture is concentrated by evaporation and the residue is chromatographed over silica gel. Elution with methylene chloride/ethanol (7:3) and methylene chloride/methanol (7:3) yields first 4-(3-chloro-anilino)-5-methyl-6-(pyrid-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (A) and then 4-(3-chloro-anilino)-5-methyl-6-(N-benzyl-pyridinium-2-yl)-7H-pyrrolo[2,3-d]pyrimidine bromide (B). A is also obtained by heating B. A: m.p. 251-252° C.; 1H-NMR (200 MHz, DMSO-d6): 12.75 and 9.25 (2sb), 8.75 (d, J=5, 1H), 8.35 (s, 1H), 8.05-7.85 (m, 3H), 7.66 (d, J=8, 1H), 7.45 (m, 2H), 7.29 (d, J=8, 1H), 2.84 (s, 3H); FAB-MS: (M+H)+ =336. B: m.p. 171-172° C. (intense foaming); 1H-NMR (200 MHz, DMSO-d6): 12.65 (sb), 9.48 (d, J=6, 1H), 8.80 (t, J=8, 1H), 8.59 (sb, 1H), 8.43 (s, 1H), 8.3 (m, 2H), 7.94 (m, 1H), 7.72 (d, J=8, 1H), 7.40 (t, J=8, 1H), 7.28 (m, 3H), 7.17 (d, J=8, 1H), 6.94 (m, 2H), 5.93 (s, 2H), 2.27 (s, 3H); FAB-MS: (M+H)+ =426.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH2:6][C:7]1[O:8][CH:9]=[CH:10][N:11]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Br:1][CH2:2][C:3]([NH:6][C:7]1[O:8][CH:9]=[CH:10][N:11]=1)=[O:4]
Reactant: O=C(Br)CBr
Reactant: Nc1ncco1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(CBr)Nc1ncco1
Reaction time: 16 h

Procedure:
A solution of bromoacetyl bromide (0.44 mL) in dry CHCl3 (5 mL) was added dropwise to a suspension of 2-amino-1,3-oxazole (0.39 g) and triethylamine (0.96 mL) in dry CHCI3 (92 mL) at room temperature. The brown mixture was allowed to stir for 16 h, then quenched with H2O (2 mL) and stirred for 20 mins before concentrating under reduced pressure to a light brown solid. The crude product was purified by silica gel chromatography eluting with 1-3% MeOH/dichloromethane to give the title compound (0.56 g) as an off-white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:37][C:38]1[C:39]([CH:47]2[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][CH3:55])[CH2:49][CH2:48]2)=[CH:40][C:41]([O:45][CH3:46])=[C:42]([CH:44]=1)[NH2:43].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:43][C:42]3[CH:44]=[C:38]([CH3:37])[C:39]([CH:47]4[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][CH3:55])[CH2:49][CH2:48]4)=[CH:40][C:41]=3[O:45][CH3:46])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: CCCN1CCC(c2cc(OC)c(N)cc2C)CC1
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: CCCN1CCC(c2cc(OC)c(Nc3nccc(-c4c(-c5ccc(OCC)c(C(=O)Nc6c(F)cccc6F)c5)nc5ccccn45)n3)cc2C)CC1
Temperature: 120 °C
Yield: 49.4 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (100 mg, 0.2 mmol), 5-methyl-2-(methyloxy)-4-(1-propyl-4-piperidinyl)aniline (Example 157, step D) (47 mg, 0.18 mmol), and p-toluenesulfonic acid (90 mg, 0.47 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 120° C. for 48 h. The mixture was transferred to a 50 mL round bottom and neutralized with 3 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (65 mg, 0.089 mmol, 50%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.73 (s, 1H), 9.38 (d, J=6.41 Hz, 1H), 8.46 (s, 1H), 8.24 (d, J=5.31 Hz, 1H), 8.03 (d, J=2.01 Hz, 1H), 7.66-7.76 (m, 2H), 7.53 (s, 1H), 7.41-7.46 (m, 1H), 7.32-7.41 (m, 1H), 7.25 (d, J=8.61 Hz, 1H), 7.17 (t, J=8.06 Hz, 2H), 6.95 (t, J=6.68 Hz, 1H), 6.89 (s, 1H), 6.57 (d, J=5.13 Hz, 1H), 4.25 (q, J=6.90 Hz, 2H), 3.80 (s, 3H), 2.90-3.02 (m, 2H), 2.57-2.68 (m, 1H), 2.21-2.32 (m, 2H), 2.17 (s, 3H), 1.91-2.02 (m, 2H), 1.62-1.74 (m, 4H), 1.38-1.49 (m, 5H), 0.85 (t, J=7.33 Hz, 3H). MS (ESI): 732 [M+H]+.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH:3]=[CH2:4].N1C=CN=C1.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].[NH4+].[Cl-]>CN(C=O)C>[CH2:1]([O:5][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=CCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of but-3-en-1-ol (2.39 mL, 27.73 mmol) in DMF was added imidazole (3.78 g, 55.46 mmol), and tert-butyldimethylsilyl chloride (6.3 g, 41.59 mmol). The mixture was stirred at room temperature overnight. Saturated NH4Cl was added and the mixture was extracted with ethyl acetate three times. Combined organic extracts were washed twice with water and brine then dried over Na2SO4. The solvent was evaporated in vacuo to give title compound.
Reaction SMILES: [CH:1]1([CH2:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].C[N+]1C=CN([C:25](=[O:34])[N:26]([CH3:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)C=1>>[CH:1]1([CH2:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:25](=[O:34])[N:26]([CH3:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:13][CH:12]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CC1CCCCC1)Nc1ccc(O)cc1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Product: CN(C(=O)Oc1ccc(NC(=O)CC2CCCCC2)cc1)c1ccccc1
Yield: 77.5 %

Procedure:
The title compound (284 mg, 77% yield, white crystals) was prepared from 2-cyclohexyl-N-(4-hydroxy-phenyl)-acetamide (233 mg, 1.00 mmol) and 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (343 mg, 1.00 mmol). HPLC-MS m/z=367 (M+1); Rt=4.51 min
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[NH:12])[NH:10]O)=[CH:4][CH:3]=1.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[C:14]#[CH:15].CCCC(C)C>CO.C1(OC2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[NH:12][C:14]([C:13]([O:17][CH2:18][CH3:19])=[O:16])=[CH:15][N:10]=2)=[CH:4][CH:3]=1
Reactant: C#CC(=O)OCC
Reactant: N=C(Cc1ccc(Cl)cc1)NO
Solvent: CO
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCC(C)C
Product: CCOC(=O)c1cnc(Cc2ccc(Cl)cc2)[nH]1
Temperature: 25 °C
Yield: 7 %

Procedure:
4-Chloro-N-hydroxy-benzeneethanimidamide (1.0 g) and ethyl propiolate (0.53 g) were dissolved in methanol (20 ml), heated under reflux for 20 hours and cooled to room temperature. The residue was dissolved in diphenylether, heated under reflux for 1 hour, cooled to room temperature and iso-hexane (300 ml) added. A solid was produced which was collected by filtration, triturated under ether and dried to give the product as a solid (0.1 g).
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][S:4][CH:3]1[C:7]([O:9][CH3:10])=[O:8].[CH3:11][CH:12]([C:31]1[CH:32]=C(O)[CH:34]=[C:35]([CH:37]=1)[OH:36])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[CH3:11][CH:12]([C:31]1[CH:37]=[C:35]([OH:36])[C:34]2[C:2]3[CH2:6][CH2:5][S:4][C:3]=3[C:7](=[O:8])[O:9][C:10]=2[CH:32]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCCCCCCCCCC(C)c1cc(O)cc(O)c1
Reactant: COC(=O)C1SCCC1=O
Product: CCCCCCCCCCCCCCCCCCC(C)c1cc(O)c2c3c(c(=O)oc2c1)SCC3

Procedure:
Following a procedure similar to that described in Example 1B hereinabove, methyl 3-oxo-2,3,4,5-tetrahydrothiophene-2-carboxylate is reacted with 5-(2-eicosyl)resorcinol to give 1,2-dihydro-7-(2-eicosyl)-9-hydroxy-4-oxo-4H-thieno [2,3-c] [1]benzopyran.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH3:12])[CH:3]=1.C([Li])CCC.CCCCCC.[F:24][C:25]1[CH:26]=[C:27]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[C:28](N(OC)C)=[O:29]>C1COCC1.O.C(O)(C)C>[CH2:11]([O:10][C:4]1[CH:3]=[C:2]([C:28]([C:27]2[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:25]([F:24])[CH:26]=2)=[O:29])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9])[CH3:12]
Reactant: CCOc1cc(Br)ccc1OC
Reactant: COc1ccc(C(=O)N(C)OC)cc1F
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CCOc1cc(C(=O)c2ccc(OC)c(F)c2)ccc1OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 44.2 %

Procedure:
To a solution of 4-bromo-2-ethoxy-1-methoxy-benzene (0.67 g, 2.9 mmol) in THF (10 mL) was added a solution of n-butyllitium in hexane (1.1 mL, 2.5 N, 2.8 mmol) at −78° C. and kept for 20 min. To the mixture was added a solution of 3-fluoro-4,N-dimethoxy-N-methyl-benzamide (0.56 g, 2.6 mmol) in THF (4 mL) at −78° C. After 2 h, isopropanol (1 mL) and water (30 mL) was added to the mixture, and the cold bath was removed. The mixture was stirred at room temperature for 20 min. The mixture was extracted with ethyl acetate (2×50 mL). The combined organic layers was washed with HCl (0.5 N, 50 mL), sodium hydrogen carbonate (50 mL, sat), brine (50 mL) and dried over magnesium sulfate. Removal of solvent and chromatography (Silica Gel) gave (3-ethoxy-4-methoxy-phenyl) -(3-fluoro-4-methoxy-phenyl)-methanone (350 mg, 44% yield): 1H NMR (DMSO-d6) δ 1.49 (t, J=7 Hz, 3H, 2CH3), 3.96 (s, 3H, CH3), 3.98 (s, 3H, CH3), 4.16 (q, J=7 Hz, 2H, CH2), 6.90 (d, J=8 Hz, 1H, Ar), 7.02 (t, J=9 Hz, 1H, Ar), 7.35 (dd, J=2, 8 Hz, 1H, Ar), 7.41 (d, J=2 Hz, 1H, Ar), 7.55-7.62 (m, 2H, Ar).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[N:20]5[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([O:27]CC)=[O:26])[C:19]5=[N:18][N:17]=4)=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.[Li+].[OH-]>C1COCC1>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]4[N:20]5[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:19]5=[N:18][N:17]=4)=[CH:14][CH:15]=3)[S:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1cccn2c(-c3ccc(Nc4nc5ccc(Cl)cc5s4)cc3)nnc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cccn2c(-c3ccc(Nc4nc5ccc(Cl)cc5s4)cc3)nnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a suspension of ethyl 3-(4-(6-chlorobenzo[d]thiazol-2-ylamino)phenyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (935 mg, 2.08 mmol) in THF (20 mL) was added 1 N aqueous LiOH solution (4 mL, 4 mmol). The mixture was stirred at room temperature overnight, concentrated to one third of the initial volume, and then acidified with 1 N aqueous HCl. To the resulting precipitate was added water (15 mL) and CH2Cl2 (5 mL). After stirring for 15 min, the precipitate was isolated by filtration, rinsed with water and CH2Cl2, and then air dried to yield the title compound as a brown solid (790 mg, 90%). HPLC/MS (Method C): retention time=1.92 min, [M+H]+=422.3.
Reaction SMILES: [ClH:1].C[O:3][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH3:26])[CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH:7]=[CH:8][CH:9]=1.[OH-].[NH4+]>O>[ClH:1].[NH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([CH2:14][CH2:13][N:12]([CH2:24][CH2:25][CH3:26])[CH2:11][CH2:10][C:6]2[CH:5]=[C:4]([OH:3])[CH:9]=[CH:8][CH:7]=2)=[CH:16]1
Reactant: CCCN(CCc1cccc(OC)c1)CCc1c[nH]c2ccccc12
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CCCN(CCc1cccc(O)c1)CCc1c[nH]c2ccccc12
Temperature: 220 °C
Reaction time: 8 h

Procedure:
The product of Step C was empasted with 50 ml of water and an excess of ammonium hydroxide was added thereto. The mixture was extracted with ethyl acetate and the organic phase was washed with water, dried and evaporated to dryness. The 11.55 g of orange oil residue were added to 45 g of pyridine and the mixture was refluxed at 220° C. under an inert atmosphere for 135 minutes. The mixture was cooled to 20° C. and was made alkaline with ammonium hydroxide. The mixture was then extracted with ethyl acetate and the organic phase was washed with water, dried and evaporated to dryness. The 12.8 g of reddish oil residue were dissolved in 60 ml of isopropanol and an excess of ethyl acetate saturated with hydrogen chloride was added thereto. The ethyl acetate was distilled and crystallization was induced after which the mixture was held overnight in a refrigerator. The mixture was vacuum filtered and the recovered product was washed with isopropanol and dried to obtain 9.3 g of 3-[2-({2-(1H-indol-3-yl)-ethyl}-propylamino)-ethyl]-phenol hydrochloride in the form of a clear beige solid melting at 192° C., then 197° C. Crystallization of the product from ethanol yielded a product melting at 198° C.
Reaction SMILES: Cl[CH:2]([C:9](=O)[CH2:10][CH2:11]C)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=1>C(O)CO.COC>[CH2:9]([C:2]1[N:14]=[C:15]2[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]2[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:10][CH3:11]
Reactant: CCCC(=O)C(Cl)CC(=O)OCC
Reactant: Cc1cccnc1N
Agent: COC
Solvent: OCCO
Product: CCCc1nc2c(C)cccn2c1C(=O)OCC

Procedure:
2.3 g (11.9 mMol) of ethyl 2-chloro-3-oxo-hexane carboxylate and 2.6 g (23.8 mMol) of 2-amino-3-picoline are dissolved in 10 ml of ethyleneglycol-dimethylether and refluxed for 3 days. Then the solvent is evaporated off in vacuo and the residue is taken up in water/ethyl acetate 1:1. After the extraction the organic phase is separated off, washed with saturated saline solution, dried over magnesium sulphate and evaporated down. The residue is purified over a silica gel column (particle size: 0.063 to 0.02 mm), using as eluant mixtures of petroleum ether/ethyl acetate of increasing polarity (85:15, 80:20 and 1:1). The uniform fractions are evaporated down in vacuo.
Reaction SMILES: C([O:3][C:4](=[O:46])[C:5]([CH3:45])([CH3:44])[CH2:6][C:7]1[N:8]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[N:40][CH:41]=3)=[CH:32][CH:31]=2)[C:9]2[C:14]([C:15]=1[S:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][C:12]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)=[CH:11][CH:10]=2)C.O[Li].O>C1COCC1.CO.O>[N:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][O:21][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]3[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[N:40][CH:41]=3)=[CH:34][CH:35]=1)[C:7]([CH2:6][C:5]([CH3:45])([CH3:44])[C:4]([OH:46])=[O:3])=[C:15]2[S:16][C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OCc3ccccn3)ccc2n1Cc1ccc(-c2ccc(OC)nc2)cc1
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(Cn3c(CC(C)(C)C(=O)O)c(SC(C)(C)C)c4cc(OCc5ccccn5)ccc43)cc2)cn1
Temperature: 55 °C
Yield: 94.1 %

Procedure:
3-[5-(Pyrid-2-ylmethoxy)-3-(2-methyl-2-propylthio)-1-[4-(2-methoxypyrid-5-yl)benzyl]indol-2-yl]-2,2-dimethylpropionic acid ethyl ester (693 g, 1.086 mol) was added to a reactor containing 6.91 L of THF/MeOH/water in a 2:1:1 ratio and stirred. LiOH.H2O (54.75 g, 1.3 mol) was added to the reactor and the mixture was heated to between 50 to 60° C. and stirred overnight (about 12 hours). TLC analysis (EtOAc/Petroleum ether, 1/5) showed the reaction had reached completion. The THF/MeOH/water solvent mixture was removed in vacuo and about 6 liters of water was added. The organic impurities were removed with extraction using EtOAc in 1.5 liter batches. The pH of the aqueous layer was adjusted to a pH of between 2 and 3 using 3N HCl. The compound was extracted twice with dichloromethane in 6 liter batches. Following a water wash and a brine wash, the organic layer was dried over Na2SO4. The solid was filtered and the organic layer was concentrated in vacuo to afford 623 g of desired product in 94% yield.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:4][CH2:3]1.F[C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]2[CH2:13][CH2:12][N:11]([C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)[CH2:6][CH2:7]1
Reactant: C[C@H]1CC[C@@H](N2CCNCC2)CC1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(N2CCN([C@H]3CC[C@@H](C)CC3)CC2)cc1
Temperature: 140 °C
Reaction time: 9 h

Procedure:
A mixture of cis-1-(4-methylcyclohexyl)piperazine (29.6 g), ethyl 4-fluorobenzoate (41.0 g) and potassium carbonate (67.3 g) in DMSO (300 ml) was stirred at 140° C. for 9 hours. The reaction mixture was poured into water (1.2 l) and extracted twice with ethyl acetate (400 ml). The extracts were collected, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (1 l) eluting with a mixture of n-hexane and ethyl acetate (2:1 v/v). The fractions containing the desired compound were collected and evaporated under reduced pressure to give ethyl 4-[cis-4-(4-methylcyclohexyl)-1-piperazinyl]benzoate (37.64 g).