Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:24])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH:16]=[C:15]([C:18]3[S:19][CH:20]=[C:21]([CH3:23])[N:22]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1>[Pd].C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:24])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[S:19][CH:20]=[C:21]([CH3:23])[N:22]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: Cc1csc(C2=CCN(CCCC(O)c3ccc(F)cc3)CC2)n1
Agent: [Pd]
Solvent: CCO
Product: Cc1csc(C2CCN(CCCC(O)c3ccc(F)cc3)CC2)n1
Reaction time: 26 h

Procedure:
A 0.35 g. portion of 3,6-dihydro-α-(p-fluorophenyl)-4-(4-methyl-2-thiazolyl)-1(2H)-pyridinebutanol, prepared as described in Example 12, is dissolved in 10 ml. of ethanol and 0.1 g. of palladium on carbon catalyst is added. The mixture is reduced to room temperature and pressure for about 26 hours. The mixture is filtered and the filtrate evaporated yielding a white solid which is recrystallized from acetonitrile giving a white crystalline solid, m.p. 98°-99°C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19](=[NH:23])[NH:20][O:21][CH3:22])[C:3]=1[S:24]([CH3:26])=[O:25].[CH3:27]C(C)([O-])C.[K+].IC>C1COCC1>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19](=[N:23][CH3:27])[NH:20][O:21][CH3:22])[C:3]=1[S:24]([CH3:26])=[O:25]
Reactant: CC(C)(C)[O-]
Reactant: CONC(=N)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CN=C(NOC)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O
Reaction time: 16 h
Yield: 25.2 %

Procedure:
A solution of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-N-methoxy-4-methylsulfinyl-1H-pyrazole-3-carboximidamide (0.5 g) in anhydrous THF was stirred at 0-5° C. and potassium tert-butoxide (0. 13 g) and iodomethane (0.081 ml) added. After three hours further potassium tert-butoxide (0.068 g) and iodomethane (0.08 ml) were added at 0-5° C. The mixture was stirred at this temperature for 16 hours, evaporated and the residue purified by chromatography on silica gel eluting with 3:1 dichloromethane/ethyl acetate to give 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-N-methoxy-N′-methyl-4-methylsulfinyl-1H-pyrazole-3-carboximidamide (0.13 g), m.p.139-142° C. Compound 50.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]#[C:21][CH3:22])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].I[CH2:25][CH3:26]>>[CH3:1][O:2][C:3](=[O:23])[CH:4]([N:8]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]#[C:21][CH3:22])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[CH2:25][CH3:26])[CH:5]([CH3:7])[CH3:6]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)OC)C(C)C)cc1
Reactant: CCI
Product: CC#CCOc1ccc(S(=O)(=O)N(CC)C(C(=O)OC)C(C)C)cc1
Yield: 88.1 %

Procedure:
According to the procedure of Example 5, 0.350 g (1.032 mmol) of 2-(4-but-2-ynyloxy-benzenesulfonylamino)-3-methyl-butyric acid methyl ester and 0.25 mL (3.097 mmol) of iodoethane provided 0.334 g of 2-[(4-but-2-ynyloxy-benzenesulfonyl)-ethyl-amino]-3-methyl-butyric acid methyl ester as a white solid. Electrospray Mass Spec 368.4 (M+H)+.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[NH2:9][C:10]1[CH:11]=[CH:12][C:13]2[N:33]([CH:34]=1)[C:16]1[N:17]([C:26]3[CH:27]=[N:28][C:29]([Cl:32])=[CH:30][CH:31]=3)[C:18](=[O:25])[C:19]3[C:24]([C:15]=1[N:14]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3>CN(C=O)C>[Cl:32][C:29]1[N:28]=[CH:27][C:26]([N:17]2[C:16]3[N:33]4[CH:34]=[C:10]([N:9]=[CH:3][N:4]([CH3:6])[CH3:5])[CH:11]=[CH:12][C:13]4=[N:14][C:15]=3[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:25])=[CH:31][CH:30]=1
Reactant: COC(OC)N(C)C
Reactant: Nc1ccc2nc3c4ccccc4c(=O)n(-c4ccc(Cl)nc4)c3n2c1
Solvent: CN(C)C=O
Product: CN(C)C=Nc1ccc2nc3c4ccccc4c(=O)n(-c4ccc(Cl)nc4)c3n2c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
N,N-Dimethylformamide dimethyl acetal (10.0 equiv., 1.935 mmol, 0.231 g) was added to a suspension of compound 53 (1.0 equiv., 0.193 mmol, 0.070 g) in DMF (3 ml). The reaction mixture was stirred overnight at 110° C. The solvent was evaporated under reduced pressure. Isopropyl ether was added and the mixture was brought on a filter and washed with isopropyl ether to give 6-(6-chloro-pyridin-3-yl)-9-[[(dimethylamino)-methylene]amino]-pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5(6H)-one (84) (0.050 g, yield=62%, purity (LC)=77%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[O:9]1[CH2:13][CH2:12][O:11][CH:10]1[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.C(N(CC)CC)C>[O:9]1[CH2:13][CH2:12][O:11][CH:10]1[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][Br:1]
Reactant: OCc1cccc(C2OCCO2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: BrCc1cccc(C2OCCO2)c1
Temperature: -5 °C
Reaction time: 2 h

Procedure:
Solid N-bromosuccinimide (10.4 g., 58 mmol) was added in small portions to a stirred solution of 3-(1,3-dioxolan-2-yl)benzyl alcohol (9.6 g., 53 mmol) and triphenylphosphine (16.7 g., 64 mmol) in dichloromethane (250 ml) at ca. -5° C. The yellow solution was stirred for a further 2 hours at -5° C. then added to a suspension of silica (50 g) in dichloromethane (250 ml) and triethylamine (2.5 ml). The mixture was evaporated and the residual silica was placed on the top of a silica column (250 g) and eluted with ethyl acetate-hexane (1:4) to give the product as a pale solid.
Reaction SMILES: OS(O)(=O)=O.CC([N:15]1[N:19]=[N:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:27]([NH:52][C:53](=[O:64])[C@H:54]([C@H:60]([CH2:62][CH3:63])[CH3:61])[NH:55][C:56]([O:58][CH3:59])=[O:57])[CH2:28][C@H:29]([OH:51])[C@@H:30]([NH:38][C:39](=[O:50])[C@H:40]([C:46]([CH3:49])([CH3:48])[CH3:47])[NH:41][C:42]([O:44][CH3:45])=[O:43])[CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:22][CH:21]=2)=[N:16]1)(C1C=CC=CC=1)C>>[NH:18]1[C:17]([C:20]2[CH:21]=[CH:22][C:23]([CH2:26][N:27]([NH:52][C:53](=[O:64])[C@H:54]([C@H:60]([CH2:62][CH3:63])[CH3:61])[NH:55][C:56]([O:58][CH3:59])=[O:57])[CH2:28][C@H:29]([OH:51])[C@@H:30]([NH:38][C:39](=[O:50])[C@H:40]([C:46]([CH3:48])([CH3:49])[CH3:47])[NH:41][C:42]([O:44][CH3:45])=[O:43])[CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:24][CH:25]=2)=[N:16][N:15]=[N:19]1
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)NN(Cc1ccc(-c2nnn(C(C)(C)c3ccccc3)n2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C
Agent: O=S(=O)(O)O
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)NN(Cc1ccc(-c2nnn[nH]2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C
Reaction time: 1.25 h

Procedure:
35 ml of an 80% aqueous H2SO4 solution are added to 354 mg (0.435 mmol) of 1-{4-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-phenyl}-4(S)-hydroxy-2-N-(N-methoxycarbonyl-(L)-iso-leucyl)amino-5(S)-N-(N-methoxycarbonyl-(L)-tert-leucyl)amino-6-phenyl-2-azahexane, with ice-cooling. After stirring for 75 min, the mixture is worked up analogously to Example 26 to yield the title compound: HPLC20-100 : tRet =12.6; FAB MS (M+H)+ =696.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)=[O:4].C(N(CC)CC)C.[CH:21]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22]1>C(#N)C>[CH:21]1([NH:26][C:8]2[CH:9]=[CH:10][C:5]([C:3](=[O:4])[C:2]([F:13])([F:12])[F:1])=[CH:6][CH:7]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(c1ccc(F)cc1)C(F)(F)F
Reactant: NC1CCCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(c1ccc(NC2CCCC2)cc1)C(F)(F)F
Temperature: 25 °C

Procedure:
To a mixture of 3.94 g of 2,2,2,4′-tetrafluoroacetophenone (20.5 mmol) and 3.35 ml triethylamine (24.0 mmol) in 40 ml of acetonitrile at 0° C. were added 5.9 ml of cyclopentylamine (59.8 mmol). The reaction was allowed to warm to room temperature and then heated to reflux for 14 h. After this time the reaction mixture was cooled to room temperature, concentrated and partitioned between water and EtOAc. The organic layer was dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography on silica (hexanes:EtOAc, 4:1) to give the title compound. 1H-NMR (CDCl3) δ 1.53-1.57 (m, 2H), 1.69-1.78 (m, 4H), 2.08-2.13 (m, 2H), 3.88-3.95 (m, 1H), 4.63 (brs, 1H), 6.60 (d, J=8.9 Hz, 2H), 7.92 (d, J=8.9 Hz, 2H). Mass Spectrum (CI+) m/e=258.1 (M+1).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([CH2:34][NH2:35])=[CH:33][C:28]=2[CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C.[Cl:45][C:46]1[CH:47]=[N:48][CH:49]=[C:50]([Cl:64])[C:51]=1[S:52][C:53]1[S:57][C:56]([C:58](O)=[O:59])=[CH:55][C:54]=1[N+:61]([O-:63])=[O:62]>ClCCl>[Cl:64][C:50]1[CH:49]=[N:48][CH:47]=[C:46]([Cl:45])[C:51]=1[S:52][C:53]1[S:57][C:56]([C:58]([NH:35][CH2:34][C:32]2[CH:31]=[CH:30][C:29]3[O:25][CH2:26][CH2:27][C:28]=3[CH:33]=2)=[O:59])=[CH:55][C:54]=1[N+:61]([O-:63])=[O:62]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: NCc1ccc2c(c1)CCO2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1ccc2c(c1)CCO2)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 5.3 %

Procedure:
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (76.4 mg, 0.51 mmol), 2,3-dihydrobenzofuran-5-ylmethanamine (165.5 mg, 1.28 mmol) and diisopropylethylamine (12 mg, 0.12 mmol) was added to a suspension of 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (150 mg, 0.43 mmol) in dichloromethane (3 mL) and the resulting mixture was stirred at ambient temperature for 6 hours. TLC analysis showed no acid remaining so the mixture was diluted with dichloromethane and washed with water and brine. The organic layer was dried (Na2SO4), filtered and the solvent was removed to afford a solid. The crude material was purified by silica gel chromatography using a 70:30 mixture of hexane and ethyl acetate as eluent to afford the title product as a brown solid (11 mg, 5% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.28 (1H, m), 8.99 (2H, m), 8.46 (1H, s), 7.14 (1H, m), 7.00 (1H, m), 6.69 (1H, m), 4.48 (2H, m), 4.30 (2H, m), 3.15 (2H, m). MS m/z: 480.11, 482.11 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:18][C:19]2[N:27]=[C:26](Cl)[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][N:23]3[C@@H:29]2[CH2:33][C@H:32]([NH:34][C:35](=[O:38])[CH2:36][CH3:37])[C@@H:31]([OH:39])[C@H:30]2[OH:40])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.O.[NH2:42][NH2:43].C(O)(C)C>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:18][C:19]2[N:27]=[C:26]([NH:42][NH2:43])[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][N:23]3[C@@H:29]2[CH2:33][C@H:32]([NH:34][C:35](=[O:38])[CH2:36][CH3:37])[C@@H:31]([OH:39])[C@H:30]2[OH:40])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: NN
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NC(c4ccc(OC)cc4)c4ccc(OC)cc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Solvent: O
Solvent: CC(C)O
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NC(c4ccc(OC)cc4)c4ccc(OC)cc4)nc(NN)nc32)[C@H](O)[C@@H]1O
Reaction time: 12 h

Procedure:
A mixture comprising N-[(1S,2R,3S,4R)-4-(6-{[Bis-(4-methoxy-phenyl)-methyl]-amino}-2-chloro-purin-9-yl)-2,3-dihydroxy-cyclopentyl]-propionamide (1.6 g, 2.82 mmol), and hydrazine monohydrate (14 ml) is stirred at room temperature for 72 h. Then isopropyl alcohol (10 ml) is added and the solvent was decanted off to afford a gummy mixture. It is dissolved in water (10 ml) and stirred for 12 h. The fine solid obtained is filtered, washed with water and dried in vacuo to afford the title product which is used in the next step without further purification. LC-MS (0.1% formic acid, acetonitrile): (MH+ 563).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[C:14]4[CH2:15][NH:16][CH2:17][CH2:18][C:13]=4[NH:12][C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1.Cl[CH2:20][CH2:21][CH2:22][C:23]1[C:27]2[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=2[O:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[C:14]4[CH2:15][NH:16][CH2:17][CH:18]([CH2:20][CH2:21][CH2:22][C:23]5[C:27]6[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=6[O:25][N:24]=5)[C:13]=4[NH:12][C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(c1)ncc1[nH]c3c(c12)CNCC3
Reactant: Fc1ccc2c(CCCCl)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc2c(CCCC3CNCc4c3[nH]c3cnc5cc(Cl)ccc5c43)noc2c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture prepared from 5.15 g of 3-chloro-7,8,9,10-tetrahydro-11H-pyrido[3',4':4,5]pyrrolo[2,3-c]quinoline, 7.0 g of 3-(3-chloropropyl)-6-fluorobenzisoxazole, 4.0 g of potassium carbonate (powdered) and 30 ml of N,N-dimethylformamide was stirred at 100° C. for 2 hours. The mixture was diluted with 150 ml of water and the oily precipitate was purified by high performance liquid chromatography (HPLC) using dichloromethane/methanol mixtures of 95:5 and 10:1 ratios. The clean fractions were combined and concentrated. The residue was stirred in isopropanol and filtered. The yield was 1.2 g, mp=221°-222° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13](CC3C=C(F)C=CC=3Br)[C:12](=[O:23])[N:11]([CH3:24])[C:10](=[O:25])[CH:9]=2)[CH2:3]1.[Cl:26][C:27]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:28]=1[CH2:29]Br>>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:29][C:28]3[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:27]=3[Cl:26])[C:12](=[O:23])[N:11]([CH3:24])[C:10](=[O:25])[CH:9]=2)[CH2:3]1
Reactant: Fc1ccc(CBr)c(Cl)c1
Reactant: Cn1c(=O)cc(N2CCC[C@@H](N)C2)n(Cc2cc(F)ccc2Br)c1=O
Product: Cn1c(=O)cc(N2CCC[C@@H](N)C2)n(Cc2ccc(F)cc2Cl)c1=O

Procedure:
The title compound was prepared from compound 1 using the same procedures as described the preparation of compound 10, except that 2-chloro-4-fluoro-benzyl bromide was used in the place of 2-bromo-5-fluoro-benzyl bromide. 1H-NMR (400 MHz, CDCl3—CD3OD 10:1) δ 7.15 (dd, J=8.211, 2.400 Hz, 1H), 6.95-7.06 (m, 2H), 5.40 (s, 1H), 5.09-5.18 (ABq, J=37.7, 15.9 Hz, 2H), 3.33-3.39 (m, 1H), 3.30 (s, 3H), 3.23-3.29 (m, 1H), 2.98 (bd, J=12.9 Hz, 1H), 2.79 (t, J=10.4 Hz, 1H), 2.55-2.66 (t, J=11.2 Hz, 1H), 2.13 (m, 1H), 1.78-1.88 (m, 1H), 1.55-1.65 (m, 2H). MS (ES) [m+H] calc'd for C17H21ClFN4O2, 367.1; found 367.1.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:22])=[C:17]([CH:21]=1)[C:18](O)=O>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:22])=[C:17]([CH2:18][C:9]2[S:8][C:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:11][CH:10]=2)[CH:21]=1
Reactant: Clc1ccc(-c2cccs2)s1
Reactant: Cc1ccc(Br)cc1C(=O)O
Product: Cc1ccc(Br)cc1Cc1ccc(-c2ccc(Cl)s2)s1

Procedure:
To a solution of 2-bromo-5-chlorothiophene (4.11 g), thiophene-2-boronic acid (4.00 g), tetrakis(triphenylphosphine)palladium (0) (1.20 g) and 2M aqueous sodium carbonate solution (31.3 ml) in dimethoxyethane (100 ml) was heated under reflux under argon atmosphere for 2.5 hours. The reaction mixture was cooled, and extracted with ethyl acetate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane) to give 2-(5-chloro-2-thienyl)thiophene (3.37 g) as pale yellow oil. (2) The above 2-(5-chloro-2-thienyl)thiophene and 5-bromo-2-methylbenzoic acid obtained in Reference Example 4-(1) were used and treated in a manner similar to Reference Example 5 to give 5-bromo-1-(5-(5-chloro-2-thienyl)-2-thienylmethyl)-2-methylbenzene as a colorless solid. APCI-Mass m/Z 383/385 (M+H).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]([C:13]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=3[O:21][CH3:22])=[CH:11][C:10]([C:23](O)=[O:24])=[C:9]2[CH3:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:27][CH2:28][CH2:29][CH2:30][OH:31]>>[OH:31][CH2:30][CH2:29][CH2:28][NH:27][C:23]([C:10]1[CH:11]=[C:12]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[O:21][CH3:22])[N:8]([CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:9]=1[CH3:26])=[O:24]
Reactant: COc1ccc(OC)c(-c2cc(C(=O)O)c(C)n2CC2CCCCC2)c1
Reactant: NCCCO
Product: COc1ccc(OC)c(-c2cc(C(=O)NCCCO)c(C)n2CC2CCCCC2)c1

Procedure:
The coupling reaction between 1-cyclohexylmethyl-5-(2,5-dimethoxy-phenyl)-2-methyl-1H-pyrrole-3-carboxylic acid and 3-amino-propan-1-ol was similar to the reaction exemplified in the synthesis of Example 49 to give 1-cyclohexylmethyl-5-(2,5-dimethoxy-phenyl)-2-methyl-1H-pyrrole-3-carboxylic acid (3-hydroxy-propyl)-amide; MS (ISP) 415.3 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([CH3:11])[C:8]([OH:10])=O)[CH2:2]1.Cl.CN(C)CCCN=C=NCC.[O:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[N:30]1[C:38]2[C:33](=[CH:34][C:35]([C:39]3[N:43]=[CH:42][N:41]([C:44]([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[N:40]=3)=[CH:36][CH:37]=2)[C:32]([C:63]2[CH:64]=[C:65]([NH2:69])[CH:66]=[CH:67][CH:68]=2)=[N:31]1.CN(C)C=O>ClCCl>[O:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[N:30]1[C:38]2[C:33](=[CH:34][C:35]([C:39]3[N:43]=[CH:42][N:41]([C:44]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)[C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[N:40]=3)=[CH:36][CH:37]=2)[C:32]([C:63]2[CH:64]=[C:65]([NH:69][C:8](=[O:10])[CH:7]([CH:3]3[CH2:4][CH2:5][CH2:6][NH:1][CH2:2]3)[CH3:11])[CH:66]=[CH:67][CH:68]=2)=[N:31]1
Reactant: CC(C(=O)O)C1CCCNC1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)C1CCCNC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-piperidyl propanoic acid (0.125 g, 0.796 mmol) in 7 mL of dichloromethane was added 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (0.190 g, 0.99 mmol). After 10 min at room temperature, 3-{1-perhydro-2H-pyran-2-yl -5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.200 g, 0.59 mmol) was then added as a solid followed by 2 mL of dimethyl formamide. The reaction mixture was stirred at room temperature overnight. The completion of the reaction mixture was achieved after reacting an additional equivalent of reagents and stirring at room temperature for 24 hours. The crude mixture was partitioned between water and dichloromethane. The crude was not purified (yield not calculated). ES-MS (m/z) 742 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:22]2[C:30]3[CH:29]=[C:28]4[C:31]5([CH2:37][O:38][C:27]4=[CH:26][C:25]=3[CH2:24][CH2:23]2)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]5)=[O:21])=[CH:16][CH:15]=1.[CH3:39][O:40][CH2:41][CH2:42]Br>>[CH3:39][O:40][CH2:41][CH2:42][N:34]1[CH2:33][CH2:32][C:31]2([C:28]3[C:27](=[CH:26][C:25]4[CH2:24][CH2:23][N:22]([C:20]([C:17]5[CH:16]=[CH:15][C:14]([C:3]6[CH:4]=[CH:5][C:6]([C:8]7[O:9][C:10]([CH3:13])=[N:11][N:12]=7)=[CH:7][C:2]=6[CH3:1])=[CH:19][CH:18]=5)=[O:21])[C:30]=4[CH:29]=3)[O:38][CH2:37]2)[CH2:36][CH2:35]1
Reactant: COCCBr
Reactant: Cc1nnc(-c2ccc(-c3ccc(C(=O)N4CCc5cc6c(cc54)C4(CCNCC4)CO6)cc3)c(C)c2)o1
Product: COCCN1CCC2(CC1)COc1cc3c(cc12)N(C(=O)c1ccc(-c2ccc(-c4nnc(C)o4)cc2C)cc1)CC3

Procedure:
The title compound was prepared from 5-(2'-methyl-4'-(5-methyl-1,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (E17 in WO 96/19477) and 2-bromoethyl methyl ether using a similar procedure to Example 2, with a reaction time of 31 hours heating under reflux (33%). Hydrochloride salt m.p. 238-240° C.
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[CH2:15]([CH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([C:32]2[N:33]=[CH:34][N:35](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:36]=2)(O)[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl>[CH2:15]([CH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([C:32]2[N:33]=[CH:34][NH:35][CH:36]=2)=[CH:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: OC1(c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)CC(Cc2ccccc2)c2ccccc21
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C1=C(c2c[nH]cn2)c2ccccc2C1Cc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Triethylsilane (1 ml, 0.728 g, 6.26 mmol) and trifluoroacetic acid (1.9 ml, 2.81 g, 24.7 mmol) were added to the solution of 3-benzyl-1-(1-trityl-1H-imidazol-4-yl)indan-1-ol (0.387 g, 0.73 mmol) in dichloromethane (13 ml). The reaction was stirred at room temperature for 20 hr. Then the reaction was quenched with water and made basic with the 2 M sodium hydroxide solution. The dichloromethane layer was washed with water and dried over sodium sulfate. The solvent was removed under reduced pressure. Flash chromatography using a dichloromethane-methanol gradient afforded 4-(3-benzyl-3H-inden-1-yl)-1H-imidazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:17][CH2:16]2)[C:10](O)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl:47][C:48]1[CH:56]=[CH:55][C:51]([CH2:52][NH:53][CH3:54])=[CH:50][CH:49]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:47][C:48]1[CH:56]=[CH:55][C:51]([CH2:52][N:53]([CH3:54])[C:10](=[O:11])[CH:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:17][CH2:16]2)=[CH:50][CH:49]=1
Reactant: CNCc1ccc(Cl)cc1
Reactant: CS(=O)(=O)N1CCN(CCC(C(=O)O)c2ccc(Cl)c(Cl)c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(Cc1ccc(Cl)cc1)C(=O)C(CCN1CCN(S(C)(=O)=O)CC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 61.4 %

Procedure:
A mixture of 25 mg 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1-yl)-butyric acid (intermediate 1), 24.1 mg (0.075 mmol) TBTU, 11.67 mg (0.075 mmol) (4-chloro-benzyl)-methyl-amine (commercially available) and 0.06 mL N,N-diisopropyl ethylamine in 0.75 mL DMF was shaken at room temperature and subsequently subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. The product containing fractions were evaporated to yield 20.7 mg (67%) of the title compound as yellow viscous oil. MS(m/e): 534.2 (MH+).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[CH3:13])[CH2:4]1.[CH:30](=O)[CH:31]([CH3:33])[CH3:32]>>[Cl:14][C:11]1[C:12]([CH3:13])=[C:7]([CH:5]2[CH2:4][N:3]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:6]2)[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]2[C:21]3=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]3[C:19]([CH3:27])=[N:18]2)[CH3:16])[CH:10]=1
Reactant: CC(C)C=O
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Agent: Cl
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(CC(C)C)C1

Procedure:
This compound was prepared using procedures analogous to those for Example 1, with racemic 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride from Example 2, Step 1 and isobutyraldehyde instead of acetone. The crude purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. The product was isolated as a racemic mixture. LCMS calculated for C23H32ClN6O (M+H)+: m/z=443.2; Found: 443.1.