Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:13][CH2:14][N:15]([CH2:17][CH2:18]Cl)[CH3:16].C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>COCCOCCOC>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:18][CH2:17][N:15]([CH3:16])[CH2:14][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1N
Reactant: CN(CCCl)CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: COCCOCCOC
Product: CN1CCN(c2ccccc2C(C)(C)C)CC1
Temperature: 170 °C

Procedure:
2-tert-Butyl-phenylamine and bis-(2-chloro-ethyl)-methylamine were mixed together with K2CO3 (25 g), NaI (10 g) and diglyme (250 mL) and heated at 170° C. for 8 h. Cooled and filtered solid and evaporated solvent. Diluted with EtOAc, washed with NaHCO3 solution, extracted twice more with EtOAc, washed with brine, dried over Na2SO4 and evaporated to give the compound as a dark solid.
Reaction SMILES: [NH:1]([C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O)[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]>P(Cl)(Cl)(Cl)=O>[C:4]([C:3]1[C:2]2[NH:1][C:11]3[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:13](=[O:15])[C:10]=2[CH:9]=[CH:8][CH:7]=1)([OH:6])=[O:5]
Reactant: O=C(O)c1ccccc1Nc1ccccc1C(=O)O
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(O)c1cccc2c(=O)c3ccccc3[nH]c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94 %

Procedure:
2,2′-Iminodibenzoic acid (5.27 g, 20.5 mmol) was mixed with phosphorus oxychloride (20 ml). The resulting pale yellow slurry was heated to boiling. The slurry turned initially bright yellow, then dissolved to give a deep red solution which was intensely yellow at the meniscus. After 2 hrs at reflux, excess solvent was evaporated under vacuum to give a dark oil. This was quenched with ice, then diluted with 2.0M aqueous HCl (25 ml) and the resulting dark solution re-heated to boiling. After 20 mins a solid precipitated and the mixture became very thick; another 20 mls of water was then added to allow effective stirring. After 1.5 hrs, the mixture was allowed to cool to ambient temperature. The yellow solid was collected by vacuum filtration, washed well with water, then acetone, and dried under vacuum to give 4-carboxyacridone (4.61 g, 94%). λmax (EtOH)=408, 390, 256 nm. δH (300 MHz, DMSO-d6) 7.24-7.33 (2H, m), 7.67-7.76 (2H, m), 8.17 (1H, d), 8.38 (1H, dd), 8.47 (1H, dd) and 11.9 (broad s, partially exch). Mass spectrum: (ES+) 240 (M+H), 262 (M+Na). Melting Point>300° C.
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]([CH2:35][CH2:36][OH:37])[CH2:20][C:21]([NH:23][CH2:24][C:25]2[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([O:33][CH3:34])[CH:26]=2)=[O:22])[CH:15]=[CH:16][C:17]=1[Cl:18].CCN(CC)CC>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]([CH2:35][CH:36]=[O:37])[CH2:20][C:21]([N:23]([CH3:1])[CH2:24][C:25]2[CH:26]=[C:27]([O:33][CH3:34])[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=2)=[O:22])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: COc1cc(CNC(=O)CC(CCO)c2ccc(Cl)c(Cl)c2)cc(OC)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1cc(CN(C)C(=O)CC(CC=O)c2ccc(Cl)c(Cl)c2)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 129.6 %

Procedure:
Oxalyl chloride (3.2 g) in CH2Cl2 (125 mL) was cooled to -78° C. and treated with a solution of DMSO (4.12 g) in CH2Cl2 (20 mL) over 15 minutes. This mixture was stirred for 15 minutes whereupon a CH2Cl2 (30 mL) solution of 3,4-Dichloro-beta-(2-hydroxyethyl)-N-[(3,5-dimethoxyphenyl)methyl]benzenepropanamide (9.0 g) was added dropwise. The mixture was stirred for 30 minutes and then treated with a solution of Et3N (6.4 g) in CH2Cl2 (25 mL) and stirred for an additional 30 minutes at -78° C., then allowed to warm to ambient temperature. The reaction mixture was washed with water (125 mL), the organic fraction separated, dried over MgSO4, filtered and concentrated under reduced pressure to yield an oil (12 g). Silica gel chromatography eluting with 10% EtOAc/CH2Cl2 gave the title compound (8.2 g).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([OH:7])=[O:6].[I:15]C(I)I.N(OCCCC)=O>C1COCC1>[I:15][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([OH:7])=[O:6]
Reactant: Nc1cc(C(=O)O)ccc1C(F)(F)F
Reactant: IC(I)I
Agent: CCCCON=O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C(F)(F)F)c(I)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
3-Amino-4-(trifluoromethyl)benzoic acid (commercially available) (6.5 g, 31.7 mmol) and triiodomethane (37.4 g, 95.1 mmol) were dissolved in THF (300 ml). The reaction mixture was heated to 80° C. and then butyl nitrite (5.56 ml, 47.6 mmol) was added slowly at this temperature. Heating was continued at this temperature for 4 hours and then the reaction was concentrated in vacuo to give the crude product. Purification by column chromatography (hexane to 30% EtOAc in hexane). This material was combined with another batch from a similar reaction performed on 2 g of 3-amino-4-(trifluoromethyl)benzoic acid. The combined material was purified by preparative HPLC to give the title compound (6.1 g). MS C8H4F3IO2 requires 316; found 315 (M−H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[NH2:1][C:2]1[CH:3]=[C:4]([C:5]([N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=4[CH2:25][C@H:14]23)=[O:7])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(C(=O)O)cc1N
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1ccc(C(=O)N2CCC[C@@H]3c4ccccc4C[C@@H]32)cc1N
Yield: 77 %

Procedure:
The title compound is prepared from 3-amino-4-methoxy-benzoic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 77% of theory; LC (method 4): tR=1.75 min; Mass spectrum (ESI+): m/z=323 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([NH2:10])[CH:3]=1.[O:11](C(OC(C)(C)C)=O)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:11])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:11])[CH:3]=1
Reactant: CCc1cc(Cl)cc(N)n1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCc1cc(Cl)cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Yield: 27 %

Procedure:
Method 24 was followed using 4-chloro-6-ethylpyridin-2-amine (1.0 equiv.), BOC2O (2.0 equiv.), and DMAP (cat.) in DCM to yield 4-chloro-6-ethyl-N,N-di-BOC-pyridin-2-amine (27% yield). LCMS (m/z): 357.1 (MH+); LC Rt=4.11 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:26][CH3:27])(=[O:25])=[O:24])=[CH:19][CH:18]=1.Cl[C:29]1[C:30]2[N:37]=[CH:36][N:35]([CH:38]([CH3:40])[CH3:39])[C:31]=2[N:32]=[N:33][CH:34]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CCOC(C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:29]2[C:30]3[N:37]=[CH:36][N:35]([CH:38]([CH3:40])[CH3:39])[C:31]=3[N:32]=[N:33][CH:34]=2)=[CH:4][C:3]=1[C:17]1[CH:18]=[CH:19][C:20]([S:23]([NH:26][CH3:27])(=[O:24])=[O:25])=[CH:21][CH:22]=1
Reactant: CC(C)n1cnc2c(Cl)cnnc21
Reactant: CNS(=O)(=O)c1ccc(-c2cc(B3OC(C)(C)C(C)(C)O3)ccc2F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CNS(=O)(=O)c1ccc(-c2cc(-c3cnnc4c3ncn4C(C)C)ccc2F)cc1
Temperature: 120 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
To a solution of 2′-fluoro-N-methyl-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-4-sulfonamide (Preparation 44, 112 mg, 0.29 mmol) and 4-chloro-7-isopropyl-7H-imidazo[4,5-c]pyridazine (Preparation 6, 54 mg, 0.27 mmol) in anhydrous dioxane (1.6 mL) was added aqueous Na2CO3 solution (2M, 0.41 mL, 0.81 mmol) and a stream of nitrogen gas was bubbled through the suspension for 5 minutes. Tetrakistriphenylphosphine palladium(0) (5.8 mg, 0.005 mmol) was added and the mixture was heated under microwave irradiation at 120° C. for 12 minutes. The reaction mixture was cooled and diluted with EtOAc (15 mL) and water (30 mL). The organic phase was extracted and the aqueous layer was back-extracted with EtOAc (2×15 mL). The organic layers were combined, washed with brine, dried over Na2SO4, filtered and the filtrate was evaporated in vacuo to leave a tan solid that was suspended in EtOAc (2.5 mL) and stirred at room temperature for 18 hours. The solid was filtered, rinsed with EtOAc (2×1 mL) and further dried to afford the title compound as an off-white solid in 82% yield, 120 mg.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:3]=1.[NH2:15][C:16]1[CH:24]=[CH:23][C:19]([CH2:20][CH2:21][OH:22])=[CH:18][CH:17]=1>>[CH:10]1([C:4]2[N:3]=[C:2]([NH:15][C:16]3[CH:24]=[CH:23][C:19]([CH2:20][CH2:21][OH:22])=[CH:18][CH:17]=3)[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCc1cc(Cl)nc(C2CCCC2)n1
Reactant: Nc1ccc(CCO)cc1
Product: CCc1cc(Nc2ccc(CCO)cc2)nc(C2CCCC2)n1
Yield: 62.9 %

Procedure:
Following General Procedure A2, 4-chloro-2-cyclopentyl-6-ethylpyrimidine (0.100 g, 0.47 mmol) was reacted with 4-aminophenethyl alcohol (0.078 g, 0.57 mmol) to afford the title compound (0.092 g, 92%) as an off-white solid. MW=311.42. 1H NMR (DMSO-d6, 500 MHz) δ 14.15 (s, 1H), 11.14 (s, 1H), 7.62 (s, 1H), 7.34-7.17 (m, 2H), 6.75 (s, 1H), 4.63 (s, 1H), 3.61 (t, J=6.9 Hz, 2H), 2.80-2.67 (m, 4H), 2.12-2.00 (m, 2H), 1.93-1.73 (m, 4H), 1.71-1.58 (m, 2H), 1.24 (s, 3H); APCI MS m/z 312 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20]([OH:22])=O.FC1C=CC(C2(C3C=CC(F)=CC=3)CCN(CC(O)=O)C2=O)=CC=1.O[NH:48]/[C:49](=[N:60]\[H])/[C:50]1[CH:55]=[C:54]([C:56]([F:59])([F:58])[F:57])[CH:53]=[N:52][CH:51]=1.ON/C(=N\[H])/C1C=CC(C(F)(F)F)=CC=1>>[C:7]1([C:6]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:5][CH2:4][N:3]([CH2:19][C:20]3[O:22][N:60]=[C:49]([C:50]4[CH:51]=[N:52][CH:53]=[C:54]([C:56]([F:59])([F:57])[F:58])[CH:55]=4)[N:48]=3)[C:2]2=[O:1])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: [H]/N=C(\NO)c1cncc(C(F)(F)F)c1
Agent: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: [H]/N=C(\NO)c1ccc(C(F)(F)F)cc1
Product: O=C1N(Cc2nc(-c3cncc(C(F)(F)F)c3)no2)CCC1(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared using the procedure described in Example 190 substituting 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid from Example 1C for 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid and (Z)—N-hydroxy-5-(trifluoromethyl)nicotinimidamide for (Z)—N-hydroxy-4-(trifluoromethyl)benzimidamide. 1H NMR (300 MHz, CDCl3) δ ppm 9.41 (d, J=1.7, 1H), 9.02 (d, J=1.2, 1H), 8.51 (s, 1H), 7.49-7.19 (m, 10H), 4.93 (s, 2H), 3.59 (t, J=6.5, 2H), 2.91 (t, J=6.5, 2H); MS (DCI) m/z 465.1 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]2[NH:7][C:8]3[S:9][C:10]([CH3:16])=[CH:11][C:12]=3[C:13]([NH2:15])=[N:14][C:5]=2[CH:4]=1.[OH:19][CH2:20][CH2:21][C@H:22]1[CH2:27]N[CH2:25][CH2:24][NH:23]1>>[Cl:2][C:3]1[CH:18]=[CH:17][C:6]2[NH:7][C:8]3[S:9][C:10]([CH3:16])=[CH:11][C:12]=3[C:13]([N:15]3[CH2:25][CH2:24][NH:23][C@@H:22]([CH2:21][CH2:20][OH:19])[CH2:27]3)=[N:14][C:5]=2[CH:4]=1
Reactant: OCC[C@H]1CNCCN1
Reactant: Cc1cc2c(s1)Nc1ccc(Cl)cc1N=C2N
Agent: Cl
Product: Cc1cc2c(s1)Nc1ccc(Cl)cc1N=C2N1CCN[C@@H](CCO)C1

Procedure:
By using a method similar to Example 258, using 7-chloro-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride and (S)-2-(2-hydroxy-ethyl)-piperazine gives the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][C:6]=1[CH3:7].[CH3:13][CH:14]1OC(C)OC(C)O1>>[CH3:1][C:2]1[NH:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH2:13][CH3:14])[C:6]=1[CH3:7]
Reactant: CC1OC(C)OC(C)O1
Reactant: CCOC(=O)c1cc(C)c(C)[nH]1
Product: CCOC(=O)c1[nH]c(C)c(C)c1CC

Procedure:
As in Example 32 but using 2,3-dimethyl-5-carbethoxy-pyrrole and paraldehyde. Colourless prisms (51%), m.p. 95°-97° (lit16) m.p. 97°). Anal. Calc. for C11H17NO2 : C, 67.66; H, 8.78; N, 7.17. Found: C, 67.59; H, 8.49; N, 7.23.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:26]=[CH:25][C:21]4[N:22]=[CH:23][NH:24][C:20]=4[CH:19]=3)[C:11]3[N:12]([CH:14]=[CH:15][N:16]=3)[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:34]([C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35]>C1COCC1>[N:22]1[C:21]2[CH:25]=[CH:26][C:18]([NH:17][C:10]3[C:11]4[N:12]([CH:14]=[CH:15][N:16]=4)[CH:13]=[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:42](=[O:43])[C:41]5[CH:45]=[CH:46][C:38]([C:34]([CH3:36])([CH3:35])[CH3:37])=[CH:39][CH:40]=5)[CH:7]=[CH:6][CH:5]=4)[N:9]=3)=[CH:19][C:20]=2[NH:24][CH:23]=1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: Nc1cccc(-c2cn3ccnc3c(Nc3ccc4nc[nH]c4c3)n2)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(C(=O)Nc2cccc(-c3cn4ccnc4c(Nc4ccc5nc[nH]c5c4)n3)c2)cc1
Temperature: 0 °C

Procedure:
After dissolving 0.34 g (1 mmole) [6-(3-amino-phenyl)-imidazo[1,2-a]pyrazin-8-yl]-(3H-benzoimidazol-5-yl)-amine in 20 mL anhydrous THF, 3 equivalents of triethylamine are added and the reaction solution is cooled to 0° C. A solution of 0.2 g of 4-tert-butyl-benzoyl chloride (1 mmole) in 5 mL THF is added dropwise to the 0° C. reaction solution under N2. The ice bath is removed and the reaction is allowed to warm slowly to rt for 1 hr. Diethyl ether is then added slowly to the reaction solution and the resulting solid filtered and washed with diethyl ether to provide pure N-{3-[8-(3H-benzoimidazol-5-ylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-4-tert-butyl-benzamide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[C:9]1([CH2:15][O:16][C:17]([NH:19][CH2:20][CH:21]=[CH2:22])=[O:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.B1C2CCCC1CCC2.[OH-].[Na+]>Cl[Pd]Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].OO>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:22][CH2:21][CH2:20][NH:19][C:17]([O:16][CH2:15][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:18])=[CH:3][CH:4]=1
Reactant: C=CCNC(=O)OCc1ccccc1
Reactant: Brc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: B1C2CCCC1CCC2
Product: O=C(NCCCc1ccc(Br)cc1)OCc1ccccc1
Yield: 54.1 %

Procedure:
Scheme IVc, step A: 1,4-Dibromobenzene (2 g, 8.5 mmol), (phenylmethoxy)-N-prop-2-enylcarboxamide (1.95 g, 10.1 mmol, prepared in example 8), 9-BBN-dimer (2.7 g, 11 mmol), [1,1′bis(diphenylphosphino)-ferrocene] dichloropalladium (II), PdCl2(dppf), (0.35 g, 0.42 mmol), 3N sodium hydroxide (3 mL), and pH=7 buffer hydrogen peroxide (2:1, 10 mL) were combined in a manner analogous to the procedure described in example 6 to provide the intermediate title compound, N-[3-(4-bromophenyl)propyl](phenylmethoxy)carboxamide, (1.6 g, 54%). Electron spray M.S. 348 (M*+2).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([B:8]([OH:10])[OH:9])[CH:5]=[CH:6][CH:7]=1.[C:11](Cl)(Cl)=[S:12]>CC(C)=O.C(Cl)(Cl)Cl>[N:1]([C:2]1[CH:3]=[C:4]([B:8]([OH:10])[OH:9])[CH:5]=[CH:6][CH:7]=1)=[C:11]=[S:12]
Reactant: S=C(Cl)Cl
Reactant: Nc1cccc(B(O)O)c1
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: OB(O)c1cccc(N=C=S)c1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a cooled (0° C.) solution of 3-aminophenylboronic acid (2.24 g, 0.013 mol) in acetone (5 ml) was added dropwise a solution of thiophosgene (1 ml, 0.013 mol) in chloroform (5 ml) over a period of 0.5 hour. The reaction mixture was stirred at 0° C. for 1 hour and at room temperature for 12 hours. The solvent was evaporated on a rotary evaporator and the residue was triturated with ether and filtered to remove the triethylamine hydrochloride. The ether solution was evaporated to a brown oil. This was chromatographed on silica gel (30 g) using acetone-chloroform (7:3) as eluent. Fractions containing the product were collected and evaporated to give a light brown solid. This solid was crystallized from ethyl acetate/hexane. M.P. 166°-67° C. Anal. Calcd. for C7H6NSBO2O: C, 46,00; H,3.59; N, 7.67; S, 17.54. Found: C, 46.17; H, 3.48; N, 7.59; S, 17.71.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10](I)=[N:9]2)=[CH:5][CH:4]=1.[NH2:29][C@@H:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][C@@H:31]1[F:43].N1CCC[C@H]1C(O)=O.C([O-])([O-])=O.[K+].[K+]>[Cu]I.CS(C)=O>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([NH:29][C@H:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:37])[CH2:32][C@H:31]3[F:43])=[N:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@@H](F)C1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: COc1ccc(Cn2nc(N[C@H]3CCN(C(=O)OC(C)(C)C)C[C@H]3F)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Temperature: 100 °C
Reaction time: 72 h

Procedure:
A mixture of 4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (0.123 g, 0.25 mmol, prepared according to Example 7, Step B), ±(3S*,4R*)-tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate (0.164 g, 0.750 mmol, prepared according to WO 2006/087543), copper(I)iodide (0.00952 g, 0.0500 mmol), (S)-pyrrolidine-2-carboxylic acid (0.0115 g, 0.100 mmol), K2CO3 (0.173 g, 1.25 mmol), and DMSO (1 mL) was stirred at 100° C. for 3 days. The reaction was partitioned between EtOAc and water. The phases were separated and the aqueous phase was re-extracted with EtOAc (5 mL). The combined organic phases were washed with water, dried (Na2SO4), filtered, and concentrated. The crude was purified by preparative TLC (1 mm thickness, Rf=0.56) eluting with 10% MeOH/CHCl3. LRMS (APCI+): m/z 581 (M+1) detected.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@@H:5]1[CH3:10])=[N+]=[N-].[C:11]1(=[O:15])[CH2:14][CH2:13][CH2:12]1>ClCCl.[Cl-].[Ti+4].[Cl-].[Cl-].[Cl-]>[CH3:10][C@H:5]1[CH2:6][CH2:7][CH2:8][CH2:9][C@H:4]1[N:1]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15]
Reactant: O=C1CCC1
Reactant: C[C@H]1CCCC[C@H]1N=[N+]=[N-]
Agent: [Ti+4]
Agent: [Cl-]
Solvent: ClCCl
Product: C[C@H]1CCCC[C@H]1N1CCCC1=O
Temperature: 0 °C
Yield: 36.3 %

Procedure:
Dissolve cis-1-azido-2-methyl-cyclohexane (Preparation 31) (3.68 g, 26.41 mmol) and cyclobutanone (1.85 g, 26.41 mmol) in dichloromethane (200 mL). Cool the solution to 0° C. and add titanium chloride (15.03 g, 79.23 mmol) under nitrogen. Stir the reaction for 24 hours at room temperature. Add water (200 mL), and extract the aqueous layer with dichloromethane (3×200 mL). Combine the organic layers and dry with Na2SO4, filter, concentrate and purify by flash column chromatography (silica gel, 20-50% of EtOAc/Hexane) to give 1.74 g (36%) of the title compound as a colorless oil.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:38](=[O:39])[C:37]3[CH:36]=[CH:35][C:34]([N:31]4[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33][CH2:32]4)=[CH:42][CH:41]=3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: CN1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: Cl
Product: CN1CCN(c2ccc(C(=O)N[C@H]3CC[C@H](CCN4CCCCC4c4coc5cccc-5c4)CC3)cc2)CC1

Procedure:
The title compound, off-white solid (56 mg, 42%), MS (ISP) m/z=529.4 [(M+H)+], mp 242° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-(4-methyl-piperazin-1-yl)-benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12](OC)=[O:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[S:19][CH2:18][CH2:17]2)[CH:3]=1.[NH3:27]>O1CCCC1.CO>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([NH2:27])=[O:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[S:19][CH2:18][CH2:17]2)[CH:3]=1
Reactant: COC(=O)c1ccc2nc(N3CCSc4ccccc4C3)cc(Cl)c2c1
Reactant: N
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)c1ccc2nc(N3CCSc4ccccc4C3)cc(Cl)c2c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
To a mixture of methyl 4-chloro-2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-6-carboxylate (400 mg, 1.04 mmol, prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-8-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine in Example 1-1) in tetrahydrofuran (5 mL) and a saturated solution of ammonia in methanol (30 mL) was heated with stirring for 16 hours at 120° C. in a sealed tube. The reaction mixture was concentrated in vacuo to afford 300 mg of the product (yield was 78%).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=[O:14])=[CH:8][CH:7]=1)[CH3:4]>C(O)C>[CH2:3]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH:12]([C:15]([F:16])([F:17])[F:18])[CH2:13][OH:14])=[CH:10][CH:11]=1)[CH3:4]
Reactant: CCOc1ccc(C(C=O)C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1ccc(C(CO)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.4 %

Procedure:
A hundred milligrams of sodium borohydride was added to a solution of 1.04 g of 2-(4ethoxyphenyl)-3,3,3-trifluoropropanal in 15 ml of ethanol with ice-cooling. The reaction solution was stirred at room temperature for 4hours. Thereafter, the reaction mixture was poured into ice water and extracted twice with ethyl acetate. The ethyl acetate layers were combined and washed with dilute HCl and saturated sodium chloride solution successively and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was subjected to column chromatography on silica gel [eluted with n-hexane/ethyl acetate (4:1) mixture] to obtain 0.77 g of the desired compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[CH:16]=[N:15][C:14]([C:18]3[O:22][N:21]=[C:20]([CH2:23][CH3:24])[N:19]=3)=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2.[C:25]1([C:31]2([OH:37])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[CH2:23]([C:20]1[N:19]=[C:18]([C:14]2[N:15]=[CH:16][C:17]3[N:5]([CH2:4][CH2:3][CH2:2][N:34]4[CH2:33][CH2:32][C:31]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)([OH:37])[CH2:36][CH2:35]4)[C:6]4[C:11]([C:12]=3[CH:13]=2)=[CH:10][CH:9]=[CH:8][CH:7]=4)[O:22][N:21]=1)[CH3:24]
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: CCc1noc(-c2cc3c4ccccc4n(CCCCl)c3cn2)n1
Solvent: CN(C)C=O
Product: CCc1noc(-c2cc3c4ccccc4n(CCCN4CCC(O)(c5ccccc5)CC4)c3cn2)n1
Temperature: 85 °C
Yield: 41.5 %

Procedure:
To a solution of Compound 3 (1.0 g, 3 mmol) in anhydrous DMF (50 mL), 4-phenylpiperidin-4-ol (0.63 g, 3.5 mmol) and TEA (1 mL) were added. The resulting mixture was heated at 85° C. for 76 h under a nitrogen atmosphere. The solvent was removed in vacuo, and the solid residue was submitted to column chromatography on silica gel with CH2Cl2 /methanol (9:1) as eluent. The purified compound was precipitated as the hydrochloride, giving the title compound (0.6 g, 36%) as an yellow solid. M.p. 169°-170° C.