Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]([F:43])([F:42])[O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37]Br>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:37][C:36]3[CH:39]=[CH:40][CH:41]=[C:34]([O:33][C:32]([F:43])([F:42])[F:31])[CH:35]=3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Reactant: FC(F)(F)Oc1cccc(CBr)c1
Product: Cc1nc2c(ccn2Cc2cccc(OC(F)(F)F)c2)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 3-(trifluoromethoxy)benzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.52-7.42 (m, 1 H), 7.35 (t, J=8.2 Hz, 1 H), 7.26-7.12 (m, 4 H), 7.06 (t, J=3.2 Hz, 1 H), 6.97-6.91 (m, 1 H), 6.30 (dd, J=3.5, 11.3 Hz, 1 H), 5.63-5.46 (m, 3 H), 4.33-4.25 (m, 2 H), 2.97-2.79 (m, 2 H), 2.78-2.70 (m, 3 H), 2.15-2.03 (m, 2 H), 1.03-0.88 (s, 9 H); LC/MS (m/z) ES+=569.35 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=C(I)C4C(=O)NC(=O)C=4[C:5]=3[C:4]=2[CH:3]=1.[Br-].[N+:22]([C:25]1[CH:26]=[C:27]([CH:48]=[CH:49][CH:50]=1)[CH2:28][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O-:24])=[O:23].[Li+].[CH3:52]C([N-]C(C)C)C>>[CH3:52][O:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](/[CH:9]=[CH:28]/[C:27]1[CH:48]=[CH:49][CH:50]=[C:25]([N+:22]([O-:24])=[O:23])[CH:26]=1)=[CH:5]2
Reactant: O=[N+]([O-])c1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CC(C)[N-]C(C)C
Reactant: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Agent: [Br-]
Agent: [Li+]
Product: COc1ccc2[nH]c(/C=C/c3cccc([N+](=O)[O-])c3)cc2c1
Reaction time: 5 h

Procedure:
The 5-methoxy-1H-indole-2-carbaldehyde (1) was reacted with (3-nitrobenzyl)(triphenyl)phosphonium bromide using the procedure described in example 37, except that the LDA and aldehyde were sequentially added at 0° C., the ratio of LDA:aldehyde was 1.5:1 and the reaction time was 5 h, to give (after crystallisation from MeOH/CH2Cl2/hexane) the diene (551) as an orange-red solid (the pure E isomer) (51%), mp 178–182° C. 1H NMR [(CD3)2SO] δ 11.27 (br s, 1H), 8.34 (t, J=1.9 Hz, 1H), 8.09 (dd, J=8.1, 1.8 Hz, 1H), 7.99 (d, J=7.9 Hz, 1H), 7.67 (t, J=8.0 Hz, 1H), 7.47 (d, J=16.5 Hz, 1H), 7.26 (d, J=8.6 Hz, 1H), 7.25 (d, J=16.6 Hz, 1H), 7.03 (d, J=2.4 Hz, 1H), 6.77 (dd, J=8.8, 2.5 Hz, 1H), 6.61 (d, J=1.6 Hz, 1H), 3.76 (s, 3H). Found: C, 69.36; H, 4.77; N, 9.78. C17H14N2O3 requires C, 69.38; H, 4.79; N, 9.52.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)=[CH2:2].C(O)(=O)C.[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[C:17]1([N:23]2[CH2:28][CH2:27][N:26]([CH2:2][CH2:1][C:3]3[CH:12]=[CH:11][C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[N:4]=3)[CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: C=Cc1ccc2ccccc2n1
Solvent: CCO
Solvent: CC(=O)O
Product: c1ccc(N2CCN(CCc3ccc4ccccc4n3)CC2)cc1
Temperature: 100 °C

Procedure:
To a mixture of 2-vinylquinoline (0.1 mole, 15g.) and glacial acetic acid (0.1 mole, 6 g.) in ethanol (95%, 100 ml.) N-phenylpiperazine (0.1 mole) was added and the solution was refluxed for 15 hrs. The solvent was removed and the remaining oil was heated in vacuo (1 mm. Hg) to 100°C. The oil left in the flask crystallized out on cooling and was recrystallized from ether-petroleum ether to give the titular product m.p. 79°C.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]([CH2:19][CH:20]=O)[N:13]([CH3:18])[C:14](=[O:17])[C:15]=2[OH:16])=[O:9])=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[C:29]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([BH3-])#N.[Na+]>CO>[C:29]([N:37]1[CH2:42][CH2:41][N:40]([CH2:20][CH2:19][C:12]2[N:13]([CH3:18])[C:14](=[O:17])[C:15]([OH:16])=[C:10]([C:8]([NH:7][CH2:6][C:5]3[CH:22]=[CH:23][C:2]([F:1])=[CH:3][CH:4]=3)=[O:9])[N:11]=2)[CH2:39][CH2:38]1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cn1c(CC=O)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Reactant: O=C(c1ccccc1)N1CCNCC1
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cn1c(CCN2CCN(C(=O)c3ccccc3)CC2)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Step 2 was dissolved in MeOH and treated with sodium acetate (1.6 eq.), 1-benzoylpiperazine (2 eq.), and sodium cyanoborohydride (1.43 eq.). The mixture was left stirring at room temperature for 1 hour. The reaction mixture was concentrated and the title compound was obtained by RP-HPLC purification (C18, eluting with water and acetonitrile containing 0.1% TFA).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:8][C:4]1[N:3]=[C:2]([O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: Fc1cccc(F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1ccc(Oc2cccc(F)n2)cc1
Yield: 69 %

Procedure:
2,6-Difluoropyridine (1.0 g), methyl 4-hydroxybenzenecarboxylate (1.32 g) and potassium carbonate (3.60 g) were suspended in acetonitrile (10 mL), and heated under reflux for 21 hours. Water (100 mL) was added to the reaction liquid, extracted with ethyl acetate (100 mL), and the organic layer was washed with aqueous 2 N sodium hydroxide solution (100 mL), water (100 mL) and saturated saline water (100 mL) in that order, dried with magnesium sulfate, and evaporated under reduced pressure to obtain a colorless oil. The resulting oil was purified through silica gel column chromatography (hexane/ethyl acetate=10/0 to 7/3) to obtain the entitled compound (1.48 g) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:49]2[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=2)([OH:48])[CH2:9][NH:10][C:11]2[N:19]=[C:18]([N:20]3[CH2:24][CH2:23][C@@H:22]([NH:25]C(OC(C)(C)C)=O)[CH2:21]3)[N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3[C@@H:33]2[CH2:37][C@H:36]([NH:38][C:39]([CH2:41][O:42]C(=O)C)=[O:40])[C@@H:35]([OH:46])[C@H:34]2[OH:47])=[CH:4][CH:3]=1.Cl>CO.O1CCOCC1>[NH2:25][C@@H:22]1[CH2:23][CH2:24][N:20]([C:18]2[N:17]=[C:16]3[C:12]([N:13]=[CH:14][N:15]3[C@@H:33]3[CH2:37][C@H:36]([NH:38][C:39](=[O:40])[CH2:41][OH:42])[C@@H:35]([OH:46])[C@H:34]3[OH:47])=[C:11]([NH:10][CH2:9][C:8]([C:49]3[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=3)([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[OH:48])[N:19]=2)[CH2:21]1
Reactant: CC(=O)OCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(O)(c4ccc(Cl)cc4)c4ccc(Cl)cc4)nc(N4CC[C@@H](NC(=O)OC(C)(C)C)C4)nc32)[C@H](O)[C@@H]1O
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N[C@@H]1CCN(c2nc(NCC(O)(c3ccc(Cl)cc3)c3ccc(Cl)cc3)c3ncn([C@@H]4C[C@H](NC(=O)CO)[C@@H](O)[C@H]4O)c3n2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of acetic acid {(1S,2R,3S,4R)-4-[6-[2,2-bis-(4-chloro-phenyl)-2-hydroxy-ethylamino]-2-((R)-3-tert-butoxycarbonylamino-pyrrolidin-1-yl)-purin-9-yl]-2,3-dihydroxy-cyclopentylcarbamoyl}-methyl ester (Intermediate ZO1) in MeOH (˜0.5M) is treated with an equal volume of 4M HCl in dioxane and stirred at room temperature for 2 hours. The solvent is removed in vacuo and purification is carried out by column chromatography/crystallisation to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1Br.C([Li])CCC.[B:14](OC(C)C)([O:19]C(C)C)[O:15]C(C)C>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[B:14]([OH:19])[OH:15]
Reactant: Fc1ccccc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccccc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
A solution of 50 g (285.6 mmol) of 2-fluorobromobenzene in 400 mL of tetrahydrofuran was cooled to −78° C. and 200 mL (320.0 mmol) of 1.6M n-Butyllithium was added via a cannula. The mixture was stirred at −78° C. for 60 minutes, then 98.9 mL (428.4 mmol) of triisopropyl borate was added via a cannula and stirring was continued for 60 minutes. The cooling bath was removed and the mixture was stirred at ambient temperature for 1.5 hours, then 150 mL of 6N hydrochloric acid was added and stirring was continued for 1.5 hours. To the mixture was added 100 mL of brine, and then the organic layer was separated and the aqueous layer was extracted three times with 30 mL each of ether. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was recrystallized from water to afford 25.2 g (63%) of the title compound.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31]C(C)(C)C)=[O:30])[C:26]([C:36]3[CH:37]=[N:38][N:39]([CH2:42][C:43]4([O:49][CH2:50][CH:51]=O)[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]4)[C:40]=3[CH3:41])=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].[NH:53]1[CH2:58][CH2:57][S:56](=[O:60])(=[O:59])[CH2:55][CH2:54]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(OCC)(=O)C.C(O)(C(F)(F)F)=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([OH:31])=[O:30])[C:26]([C:36]3[CH:37]=[N:38][N:39]([CH2:42][C:43]4([O:49][CH2:50][CH2:51][N:53]5[CH2:58][CH2:57][S:56](=[O:60])(=[O:59])[CH2:55][CH2:54]5)[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]4)[C:40]=3[CH3:41])=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: O=S1(=O)CCNCC1
Reactant: Cc1c(-c2ccc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)OC(C)(C)C)cnn1CC1(OCC=O)CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cnn1CC1(OCCN2CCS(=O)(=O)CC2)CCCCC1
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 167F (72 mg) and thiomorpholine 1,1-dioxide (13.5 mg) in dichloromethane (3 mL) was added sodium triacetoxyborohydride (32 mg). The mixture was stirred overnight. The mixture was dissolved in ethyl acetate (200 mL) and washed with 2N aqueous NaOH and brine, and dried over Na2SO4. Filtration and evaporation of the solvent gave crude product which was dissolved in dichloromethane (2 mL) and TFA (2 mL). After stirring overnight, the solvent was evaporated. The residue was purified by reverse phase chromatography using a Gilson system, eluting with 20-80% acetonitrile in 0.1% TFA water solution to provide the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 12.86 (s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.42 (m, 5H), 6.97 (d, 1H), 4.96 (s, 2H), 4.10 (s, 3H), 3.53 (m, 8H), 3.02 (t, 2H), 2.13 (s, 3H), 1.43 (m, 10H).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.[Br:13]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(#N)C>[Br:13][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1
Reactant: CC(=O)Cc1ccc(CO)cc1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: CC(=O)Cc1ccc(CBr)cc1

Procedure:
A mixture of 1-(4-hydroxymethylphenyl)propan-2-one (3.15 g) and dibromotriphenylphosphorane (8.11 g) was refluxed in acetonitrile (50 ml) for 1 hour. The solvent was removed and the residue chromatographed on silica. Elution with ether gave 1-(4-bromomethylphenyl)propan-2-one, 3.4 g. τ(CDCl3) 7.92 (3H, s), 6.4 (2H, s), 5.6 (2H, s), 2.9 (2H, d, J=8 Hz), 2.65 (2H, d, J=8 Hz). This was ketalised in an analogous manner to that described in Description 2 to give the title compound, 3.73 g. τ(CDCl3) 8.7 (3H, s), 7.1 (2H, s), 5.9-6.3 (4H, m), 5.54 (2H, s), 2.75 (4H, s).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[C@@H:16]([CH3:17])[CH2:15][CH2:14][C@H:13]1[C:18]1[NH:22][C:21]2[C:23]3[C:28]([CH:29]=[CH:30][C:20]=2[N:19]=1)=[CH:27][C:26]1[C:31]2[C:36]([CH2:37][O:38][C:25]=1[CH:24]=3)=[CH:35][C:34]([C:39]1[NH:43][C:42]([C@@H:44]3[CH2:48][C@H:47]([CH3:49])[CH2:46][N:45]3C(OC(C)(C)C)=O)=[N:41][CH:40]=1)=[CH:33][CH:32]=2)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].[CH3:57][O:58][C:59]([NH:61][C@H:62]([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:63]([OH:65])=O)=[O:60].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>Cl.CCO>[CH3:57][O:58][C:59]([NH:61][C@H:62]([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:63]([N:45]1[CH2:46][C@@H:47]([CH3:49])[CH2:48][C@H:44]1[C:42]1[NH:43][C:39]([C:34]2[CH:35]=[C:36]3[CH2:37][O:38][C:25]4[CH:24]=[C:23]5[C:28]([CH:29]=[CH:30][C:20]6[N:19]=[C:18]([C@@H:13]7[CH2:14][CH2:15][C@H:16]([CH3:17])[N:12]7[C:10](=[O:11])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:7]([CH3:9])[CH3:8])[NH:22][C:21]=65)=[CH:27][C:26]=4[C:31]3=[CH:32][CH:33]=2)=[CH:40][N:41]=1)=[O:65])=[O:60]
Reactant: COC(=O)N[C@H](C(=O)N1[C@@H](C)CC[C@H]1c1nc2ccc3cc4c(cc3c2[nH]1)OCc1cc(-c2cnc([C@@H]3C[C@H](C)CN3C(=O)OC(C)(C)C)[nH]2)ccc1-4)C(C)C
Reactant: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1[C@@H](C)CC[C@H]1c1nc2ccc3cc4c(cc3c2[nH]1)OCc1cc(-c2cnc([C@@H]3C[C@H](C)CN3C(=O)[C@H](NC(=O)OC)c3ccccc3)[nH]2)ccc1-4)C(C)C

Procedure:
A solution of tert-butyl (2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-methylpyrrolidine-1-carboxylate (80 mg, 0.11 mmol) in 1.25 N HCl in EtOH (2 mL) was heated to 50° C. for 3h. The reaction was concentrated and the crude material dissolved in DMF (1.5 mL). To this solution was added a solution of (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (29 mg, 0.14 mmol) and COMU (52 mg, 0.12 mmol). To the resulting solution was added diisopropylethylamine (0.057 mL, 0.33 mmol). After stirring for 2h at room temperature, the reaction was quenched with 1N HCl (0.200 mL) and purified by HPLC. After lyophilization, the TFA salt was dissolved in EtOAc and washed with saturated NaHCO3. The organic phase was dried over Na2SO4 and concentrated. The free base was then dissolved in MeCN/H2O and lyophilized to afford methyl {(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate: (42 mg, 45%). LCMS-ESI+: calculated for C48H52N8O7: 852.4; observed [M+1]+: 854.2.
Reaction SMILES: Cl[CH:2]1[CH2:8][N:7]2[C:9](=[O:23])[C:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:6]2[C:5]2[S:24][CH:25]=[CH:26][C:4]=2[S:3]1.N12CCCC1=NCCC2>CS(C)=O>[O:23]=[C:9]1[N:7]2[CH:8]=[CH:2][S:3][C:4]3[CH:26]=[CH:25][S:24][C:5]=3[C:6]2=[C:12]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=[C:10]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1SC(Cl)C2
Agent: C1CN=C2CCCN2C1
Solvent: CS(C)=O
Product: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1SC=C2
Temperature: 25 °C

Procedure:
ba) 6.05 g of methyl 5-chloro-5,6-dihydro-8 -oxo-9-phenyl-8H-pyrido[1,2-d]thieno[2,3-f][1,4]thiazepin-11-carboxylate were suspended in 60 ml of dimethyl sulfoxide. 3.6 ml of 1,5-diazabicyclo[4.3.0]non-5-ene were added, whereupon the mixture was heated to 70°-75° in order to complete the reaction. The mixture was then cooled to room temperature, whereby crystals separated. The mixture was poured into 300 ml of water, and the crystals were removed by filtration and washed with water. The still moist crystals were dissolved in chloroform. The solution was dried over sodium sulfate, filtered and evaporated in vacuo. After chromatography on silica gel, there was obtained methyl 8-oxo-9-phenyl-8H-pyrido[1,2-d]thieno[2,3-f][1,4]thiazepin-11-carboxylate as yellow crystals which were recrystallized from toluene. The product then has a m.p. of 207°-210°.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21]O)=[CH:17][CH:16]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:24].CO>C(Cl)Cl>[C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][Br:24])=[CH:17][CH:16]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccc(OCCc2coc(-c3ccccc3)n2)cc1
Solvent: ClCCl
Solvent: CO
Product: BrCc1ccc(OCCc2coc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To a suspension of 2-phenyl-4-(4-hydroxymethylphenoxy)ethyloxazole (30 g, 102 mmol) in 300 mL of methylene chloride at 5° C. under a nitrogen atmosphere was added phosphorous tribromide (10.02 mL, 107 mmol) dropwise keeping the temperature of the reaction below 20° C. The resulting solution was allowed to stir for about 2 hours at room temperature. The reaction was cooled to about 10° C. and 20 mL of methanol was added. After about 5 minutes, the solvent was removed and the solid remaining was partitioned between 1.35 L of ethyl acetate and 1.05 L of cold 5% aqueous sodium bicarbonate. The organics were washed with another 1.05 L of 5% aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and removed to give 33.3 g of the title compound.
Reaction SMILES: [CH:1]1([CH2:6][N:7]2[C:11]3=[N:12][C:13]([C:16]4[CH:21]=[C:20]([CH:22]([CH3:24])[CH3:23])[CH:19]=[CH:18][C:17]=4[O:25][CH3:26])=[CH:14][N:15]=[C:10]3[NH:9][C:8]2=[O:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:28]1(CN)CCCC1>C(O)C>[CH:1]1([CH:6]([N:7]2[C:11]3=[N:12][C:13]([C:16]4[CH:21]=[C:20]([CH:22]([CH3:23])[CH3:24])[CH:19]=[CH:18][C:17]=4[O:25][CH3:26])=[CH:14][N:15]=[C:10]3[NH:9][C:8]2=[O:27])[CH3:28])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NCC1CCCC1
Reactant: COc1ccc(C(C)C)cc1-c1cnc2[nH]c(=O)n(CC3CCCC3)c2n1
Solvent: CCO
Product: COc1ccc(C(C)C)cc1-c1cnc2[nH]c(=O)n(C(C)C3CCCC3)c2n1
Yield: 75 %

Procedure:
1-Cyclopentylmethyl-6-(5-isopropyl-2-methoxy-phenyl)-1,3-dihydro-imidazo[4,5-b]pyrazin-2-one. N-Bis-Boc-3-bromo-5-(5-isopropyl-2-methoxy-phenyl)-pyrazin-2-ylamine (see Example 5.C) (150 mg, 0.29 mmol), cyclopentylmethylamine (0.287 mL, 2.9 mmol) and ethanol (4 mL) were heated according to General Procedure E. The product was purified using reverse-phase semi-preparatory HPLC (5-70% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). Product fractions were concentrated and then triturated with 50% methanol in H2O to give a white solid (77 mg, 75% yield). 1H NMR (300 MHz, DMSO-d6) δ 11.98 (s, 1H), 8.36 (s, 1H), 7.60 (d, J=2.5, 1H), 7.26 (dd, J=8.7, 2.6, 1H), 7.08 (d, J=8.5, 1H), 3.82 (s, 3H), 3.78 (d, J=7.4, 2H), 2.45 (d, J=7.1, 1H), 1.58-1.70 (m, 4H), 1.53 (d, J=9.3, 2H), 1.38 (d, J=4.4, 2H), 1.22 (d, J=6.9, 6H); MS (ESI) m/z 367.5 [M+1]+.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)([OH:3])=O.[I-].[Cl:14]C1C=CC=C[N+]=1C.[CH2:22]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(C(C)C)C(C)C)C>CN1CCCC1=O.CC(C)=O>[ClH:14].[NH:8]1[C:9]2[C:5](=[C:4]([C:1]([N:33]3[CH2:34][CH2:35][N:30]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:31][CH2:32]3)=[O:3])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7]1
Reactant: C[n+]1ccccc1Cl
Reactant: O=C(O)c1cccc2[nH]ccc12
Reactant: c1ccc(CCN2CCNCC2)cc1
Agent: [I-]
Solvent: CC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cl
Product: O=C(c1cccc2[nH]ccc12)N1CCN(CCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
A solution of 2.0 g of 4-carboxyindole and 8.1 g of 2-chloro-1-methylpyridinium iodide in 60 ml of N-methylpyrrolidone (NMP) is treated with a solution of 2.36 g of 4-phenethylpiperazine and 8.2 g of ethyldi-isopropylamine (EDIPA) in 20 ml of NMP and subsequently stirred at room temperature for 3 hours. The mixture is worked up in the customary manner and the crude product is obtained. This is dissolved in acetone and the hydrochloride is precipitated using aqueous hydrochloric acid. After drying, 4.59 g of (1H-indol-4-yl)-(4-phenethylpiperazin-1-yl)methanone, hydrochloride, m.p. 289.3°, is obtained.
Reaction SMILES: C(OC1C=CC(N2CCN(CCCC3CCCCC3)CC2)=CC=1[Cl:30])C1C=CC=CC=1.C([O:38][C:39]1[CH:44]=[CH:43][C:42]([N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)=[CH:41][C:40]=1[F:51])C1C=CC=CC=1>>[ClH:30].[F:51][C:40]1[CH:41]=[C:42]([N:45]2[CH2:46][CH2:47][NH:48][CH2:49][CH2:50]2)[CH:43]=[CH:44][C:39]=1[OH:38]
Reactant: Fc1cc(N2CCNCC2)ccc1OCc1ccccc1
Reactant: Clc1cc(N2CCN(CCCC3CCCCC3)CC2)ccc1OCc1ccccc1
Product: Cl
Product: Oc1ccc(N2CCNCC2)cc1F

Procedure:
Production Example 30 was repeated except that 1-(4-benzyloxy-3-chlorophenyl)-4-(3-cyclohexylpropyl)piperazine was replaced with 1-(4-benzyloxy-3-fluorophenyl)piperazine (300 mg), to provide 2-fluoro-4-(piperazin-1-yl)phenol hydrochloride (267 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:12]([OH:25])[CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O)[CH:6]=[C:5]2[CH3:32].[CH3:33][NH2:34]>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C@@H:11]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@H:12]([OH:25])[CH2:13][NH:34][CH3:33])[CH:6]=[C:5]2[CH3:32]
Reactant: Cc1ccc(S(=O)(=O)OCC(O)C(c2ccccc2)n2cc(C)c3cc(F)ccc32)cc1
Reactant: CN
Solvent: CO
Product: CNC[C@@H](O)[C@H](c1ccccc1)n1cc(C)c2cc(F)ccc21
Reaction time: 12 h

Procedure:
A solution of (2S,3S)-3-(5-fluoro-3-methyl-1H-indol-1-yl)-3-phenylpropane-1,2-diol (1.03 g, 3.4 mmol) and p-toluenesulfonyl chloride (0.78 g, 4.1 mmol) in anhydrous pyridine (11 ml) was stirred at room temperature under nitrogen for 12 hours. The reaction was poured into a 1N aqueous solution of hydrochloric acid (50 mL) and extracted with ethyl acetate (50 mL). The organics were dried over anhydrous sodium sulfate, filtered, and concentrated to give (2S,3S)-toluene-4-sulfonic acid 3-(5-fluoro-3-methyl-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester. The product was used in the next step without further purification. To a solution of toluene-4-sulfonic acid 3-(5-fluoro-3-methyl-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester (1.6 g, 3.4 mmol) in methanol (10 mL) was added a 2N solution of methylamine in methanol (8.6 mL, 17 mmol) and the reaction stirred for 12 hours. Upon completion, the reaction was partitioned between saturated sodium bicarbonate (50 mL) and ethyl acetate (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified via Biotage chromatography (FlasH40i, silica, 20% MeOH/dichloromethane) to give (1S,2R)-1-(5-fluoro-3-methyl-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol as a clear oil. The free base was dissolved in a minimum amount of ethanol and treated with a 2N ethereal solution of hydrochloric acid and stirred for 1 hour. The ethanol was removed in vacuo and the clear oil was triturated with ether/dichloromethane to give (1S,2R)-1-(5-fluoro-3-methyl-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol hydrochloride as a white solid. MS (ESI) m/z 313.