Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH:6]=[C:7]([C@@H:25]([NH2:27])[CH3:26])[C:8]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[N:23][CH:22]=[CH:21][N:20]=4)[CH2:15][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.Cl[C:29]1[C:30]2[N:38]=[CH:37][CH:36]=[CH:35][C:31]=2[N:32]=[CH:33][N:34]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[F:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH:6]=[C:7]([C@@H:25]([NH:27][C:29]3[C:30]4[N:38]=[CH:37][CH:36]=[CH:35][C:31]=4[N:32]=[CH:33][N:34]=3)[CH3:26])[C:8]([N:13]3[CH2:14][CH2:15][N:16]([C:19]4[CH:24]=[N:23][CH:22]=[CH:21][N:20]=4)[CH2:17][CH2:18]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1c(F)ccc2cc([C@H](C)N)c(N3CCN(c4cnccn4)CC3)nc12
Reactant: Clc1ncnc2cccnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1c(F)ccc2cc([C@H](C)Nc3ncnc4cccnc34)c(N3CCN(c4cnccn4)CC3)nc12
Yield: 46.7 %

Procedure:
Following the procedure described for Intermediate 13, Intermediate 15 (470 mg, 1.1 mmol) and TFA (3 mL) in DCM (6 mL) afforded (S)-1-{7-fluoro-8-methyl-2-[4-(pyrazin-2-yl)piperazin-1-yl]quinolin-3-yl}ethanamine as a white foam, which was used in the next step without any further purification. Following the procedure described for Example 5, (S)-1-{7-fluoro-8-methyl-2-[4-(pyrazin-2-yl)piperazin-1-yl]quinolin-3-yl}-ethanamine (60 mg, 0.16 mmol), 4-chloropyrido[3,2-d]pyrimidine (33 mg, 0.19 mmol) and DIPEA (0.14 mL, 0.8 mmol) in NMP (1.2 mL) afforded the title compound (37 mg, 46%) as a brown solid. δH (DMSO-d6) 8.95-8.89 (2H, m), 8.55 (2H, d, J 14.1 Hz), 8.45 (1H, d, J 1.5 Hz), 8.19-8.14 (2H, m), 7.93-7.88 (2H, m), 7.74 (1H, dd, J 8.9, 6.3 Hz), 7.33 (1H, t, J 9.1 Hz), 5.98-5.90 (1H, m), 3.96-3.87 (2H, m), 3.87-3.75 (4H, m), 3.33-3.25 (2H, m), 2.58 (3H, d, J 2.3 Hz), 1.68 (3H, d, J 6.7 Hz). LCMS (ES+) 496 (M+H)+, RT 4.07 minutes (Method 4).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:30][CH2:31][C@H:32]2[CH2:36][CH2:35][CH2:34][N:33]2C(OC(C)(C)C)=O)=[CH:5][C:6]2[NH:12][C:11]3[CH:13]=[C:14]([C:17]4[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]([O:26][CH3:27])[CH:18]=4)[CH:15]=[CH:16][C:10]=3[C:9](=[O:28])[NH:8][C:7]=2[CH:29]=1.Cl.O1CCOCC1>CO>[CH3:1][O:2][C:3]1[C:4]([O:30][CH2:31][C@H:32]2[CH2:36][CH2:35][CH2:34][NH:33]2)=[CH:5][C:6]2[NH:12][C:11]3[CH:13]=[C:14]([C:17]4[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]([O:26][CH3:27])[CH:18]=4)[CH:15]=[CH:16][C:10]=3[C:9](=[O:28])[NH:8][C:7]=2[CH:29]=1
Reactant: COc1cc2c(cc1OC[C@H]1CCCN1C(=O)OC(C)(C)C)Nc1cc(-c3ccc([N+](=O)[O-])c(OC)c3)ccc1C(=O)N2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc2c(cc1OC[C@H]1CCCN1)Nc1cc(-c3ccc([N+](=O)[O-])c(OC)c3)ccc1C(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 9 %

Procedure:
A mixture of Example 489B in methanol (2 mL) was treated with 4.0N HCl/dioxane (0.15 mL, 0.6 mmol), stirred overnight at room temperature, concentrated under vacuum, and purified by preparative HPLC to give 3.9 mg (9%) of the desired product as the TFA salt. MS (ESI) m/e 491 (M+H)+; 1H NMR (300 MHz, DMSO-d6) □ 9.72 (s, 1H), 8.70 (s, 1H), 8.02 (d, J=8.1 Hz, 1H), 7.77-7.80 (m, 2H), 7.53 (d, J=1.4 Hz, 1H), 7.29-7.36 (m, 3H), 6.75 (s, 1H), 6.71 (s, 1H), 4.15 (m, 1H), 4.03 (s, 3H), 3.83-3.96 (m, 1H), 3.71 (s, 3H), 3.17-3.27 (m, 3H), 2.13 (m, 1H), 1.84-2.01 (m, 2H), 1.72 (m, 1H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[OH:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[OH:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[CH2:14][CH2:13]1
Reactant: OCC1CCNCC1
Reactant: O=Cc1ccccc1F
Product: O=Cc1ccccc1N1CCC(CO)CC1

Procedure:
Prepared from 2-fluorobenzaldehyde and 4-hydroxymethylpiperidine.
Reaction SMILES: CC(C1C=CC=C(C(C)C)C=1CC([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=O)C.C(C1C=CC=C(C(C)C)C=1CC(O)=O)(C)C.[CH3:49][CH:50]([C:52]1[CH:57]=[C:56]([CH:58]([CH3:60])[CH3:59])[CH:55]=[C:54]([CH:61]([CH3:63])[CH3:62])[C:53]=1[CH2:64][CH2:65][C:66](O)=[O:67])[CH3:51]>>[O:67]=[C:66]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:28])(=[O:29])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)[CH2:65][CH2:64][C:53]1[C:52]([CH:50]([CH3:49])[CH3:51])=[CH:57][C:56]([CH:58]([CH3:60])[CH3:59])=[CH:55][C:54]=1[CH:61]([CH3:63])[CH3:62]
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Reactant: CC(C)c1cc(C(C)C)c(CCC(=O)O)c(C(C)C)c1
Agent: CC(C)c1cccc(C(C)C)c1CC(=O)O
Product: CC(C)c1cc(C(C)C)c(CCC(=O)c2ccc(C(C)C)c(OS(N)(=O)=O)c2C(C)C)c(C(C)C)c1

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetic acid was replaced with 3-[2,4,6-tris(1-methylethyl)phenyl]propionic acid, mp 138°-141° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18]([F:21])([F:20])[F:19])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:24]=1[C:25](Cl)=[O:26]>>[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:24]=1[C:25]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([O:17][C:18]([F:21])([F:19])[F:20])=[CH:13][CH:12]=2)[C:8]([C:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=2)=[CH:9]1)=[O:26]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: CN1CC=C(c2c[nH]c3ccc(OC(F)(F)F)cc23)CC1
Product: CN1CC=C(c2cn(C(=O)c3c(Cl)cccc3Cl)c3ccc(OC(F)(F)F)cc23)CC1

Procedure:
(14.3 mg, 43%); from 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-5-trifluoromethoxy-1H-indole (Example 4h, 20 mg, 0.068 mmol) and 2,6-dichlorobenzoyl chloride (22.4 mg, 0.107 mmol), HRMS-FAB+ for C22H17N2O2ClF3, calculated MH+ : 469.06973; found: 469.07199.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.Cl[CH2:10][CH:11]=O>C(O)C>[I:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:10]=[CH:11][N:8]=[C:4]2[CH:3]=1
Reactant: O=CCCl
Reactant: Nc1cc(I)ccn1
Solvent: CCO
Product: Ic1ccn2ccnc2c1
Temperature: 83 °C
Reaction time: 15 h
Yield: 31.6 %

Procedure:
Combine 4-iodo-pyridin-2-ylamine (4.00 g, 18.18 mmol) and chloroacetaldehyde (2.77 mL, 21.82 mmol) in ethanol (40 mL). Attach a reflux condenser, and heat the mixture to 83° C., stir overnight (15 hours), and cool to room temperature. Filter the resulting solution to yield the product as a tan solid (1.40 g, 32%). MS(ES), m/z 245 (M+1)
Reaction SMILES: C[O:2][C:3]1[C:4]([CH:12]=[O:13])=[CH:5][C:6]2[O:10][CH2:9][CH2:8][C:7]=2[CH:11]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[C:4]([CH:12]=[O:13])=[CH:5][C:6]2[O:10][CH2:9][CH2:8][C:7]=2[CH:11]=1
Reactant: COc1cc2c(cc1C=O)OCC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1cc2c(cc1O)CCO2
Reaction time: 2.5 h
Yield: 75.9 %

Procedure:
A solution of 5-methoxy-2,3-dihydrobenzofuran-6-carboxaldehyde (24.00 g, 135 mmol) in dry methylene chloride (800 mL) under nitrogen was cooled to an internal temperature of -67°. A solution of boron tribromide (1M in methylene chloride, 63.0 mL 63.0 mmol) was added dropwise. The cooling bath was removed and the mixture allowed to stir for 2.5 hours. The reaction was then quenched by the dropwise addition of methanol (25 mL) and the resulting mixture poured into 10% aqueous sodium chloride (100 mL). The layers were separated and the aqueous layer washed with methylene chloride (2×250 mL), and the combined organic extracts washed with 10% sodium chloride (2×500 mL), dried (Na2SO4), and concentrated. Purification by preparative HPLC (Waters Prep 500, 9:1 hexane:ethyl acetate as eluant) afforded 5-hydroxy-2,3-dihydrobenzofuran-6-carboxaldehyde (16.82 g, 76.1%), m.p. 102-104° C.
Reaction SMILES: C([SiH](CC)CC)C.[CH3:8][O:9][C:10](=[O:32])[C@@H:11]([O:29][CH2:30][CH3:31])[C@@H:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:16][C:15]=1[CH3:28])O>FC(F)(F)C(O)=O>[CH3:8][O:9][C:10](=[O:32])[C@@H:11]([O:29][CH2:30][CH3:31])[CH2:12][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:16][C:15]=1[CH3:28]
Reactant: CCO[C@H](C(=O)OC)[C@H](O)c1ccc(OCc2ccccc2)cc1C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCO[C@@H](Cc1ccc(OCc2ccccc2)cc1C)C(=O)OC
Yield: 44.8 %

Procedure:
Triethylsilane (23 ml, 145 mmol) was added to a vigorously stirred, ice-cooled solution of (2S,3R)-3-(4-benzyloxy-2-methyl-phenyl)-2-ethoxy-3-hydroxy-propionic acid methyl ester (5 g, 14.5 mmol) in trifluoroacetic acid (84 ml) under an argon atmosphere. The mixture was stirred at 0° C. for 30 min and for additional 2 h at ambient temperature. The solution was poured onto crashed ice and extracted with ethyl acetate. The organic layer was washed two times with water and neutralized with saturated aqueous sodium bicarbonate solution. The ethyl acetate layer was washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure to give a colorless oil which was purified by column chromatography (silica gel, cyclohexane/AcOEt) to yield 2.15 g (6.5 mmol, 45%) of the title compound as colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:2]=1.[CH:12]([O:15][C:16](C)=[O:17])(C)[CH3:13]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]=1[C:16]([O:15][CH2:12][CH3:13])=[O:17]
Reactant: CC(=O)OC(C)C
Reactant: CCOC(=O)c1cccnc1
Product: CCOC(=O)c1cccnc1C(=O)OCC

Procedure:
To a suspension of 2,3-pyridinedicarboxylic acid (200 g, 1.2 mol) in ethanol (800 ml) was added conc H2SO4 (100 ml) and this mixture was heated to reflux for 3 days (mechanical stirring). It was then cooled down to r.t. and added to crushed ice. Conc NH4OH (405 ml) was then added slowly and the pH was adjusted to 9 by addition of some aq. NH4Cl. The products were extracted into i-PrOAc, dried over Na2SO4 and concentrated to yield 182.48 g of an orange oil containing 88% of the diester (60% yield), 8.1% of ethyl 3-pyridinecarboxylate and 3.5% i-PrOAc. This mixture was used as such in the next step.
Reaction SMILES: [I:1][C:2]1[C:7]([CH2:8][CH:9]=[CH:10][OH:11])=[C:6]([I:12])[C:5]([CH2:13][CH:14]=[CH:15][OH:16])=[C:4]([I:17])[C:3]=1[CH2:18][CH:19]=[CH:20][OH:21]>N1C=CC=CC=1.C(OC(=O)C)(=O)C>[I:1][C:2]1[C:3]([CH2:18][CH:19]=[CH:20][O:21][C:10](=[O:11])[CH3:9])=[C:4]([I:17])[C:5]([CH2:13][CH:14]=[CH:15][O:16][C:15](=[O:16])[CH3:14])=[C:6]([I:12])[C:7]=1[CH2:8][CH:9]=[CH:10][O:11][C:20](=[O:21])[CH3:19]
Reactant: OC=CCc1c(I)c(CC=CO)c(I)c(CC=CO)c1I
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC=CCc1c(I)c(CC=COC(C)=O)c(I)c(CC=COC(C)=O)c1I
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1,3,5-Triiodo-2,4,6-tris(1-hydroxyprop-en-3-yl)benzene (560 mg, 0.90 mmol) was dissolved in a mixture of pyridine (8 ml) and acetic anhydride (8 ml). After stirring at ambient temperature for 16 hours, the solvent was evaporated and the residue was purified by preparative HPLC (RP-18, CH3CN: H2O 80:20). Yield 310 mg (46%).
Reaction SMILES: [K].Br[CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)([OH:20])[C:14]2[N:18]([CH3:19])[CH:17]=[N:16][CH:15]=2)=[CH:9][C:8]=1[CH:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=1)[OH:29])=[O:5]>CC(O)C>[Cl:36][C:32]1[CH:31]=[C:30]([CH:28]2[C:8]3[CH:9]=[C:10]([C:13]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=4)([OH:20])[C:14]4[N:18]([CH3:19])[CH:17]=[N:16][CH:15]=4)[CH:11]=[CH:12][C:7]=3[NH:6][C:4](=[O:5])[CH2:3][O:29]2)[CH:35]=[CH:34][CH:33]=1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc(NC(=O)CBr)c(C(O)c2cccc(Cl)c2)c1
Agent: [K]
Solvent: CC(C)O
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)OCC(=O)N2
Reaction time: 48 h
Yield: 10.7 %

Procedure:
2-methyl, 2-propanol, potassium salt (0.044 mol) was added to a mixture of intermediate (2) (0.011 mol) in 2-propanol (160 ml). The mixture was stirred for 48 hours, hydrolized and extracted with DCM and methanol. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue (4.1 g) was purified by column chromatography over silica gel (eluent: toluene/2-propanol/NH4OH 90/10/1 and 85/15/1; 15–40 μm). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-propanone and diethyl ether. The precipitate was filtered off and dried, yielding 0.58 g (11%) of 5-(3-chlorophenyl)-7-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1,5-dihydro-4,1-benzoxazepin-2(3H)-one, mp. 260° C.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][CH:16]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][C:5]=1[F:27].O.[OH-].[Li+]>O1CCCC1>[C:23]([O:22][C:20]([NH:19][CH:16]1[CH2:15][CH2:14][N:13]([S:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:28])=[O:2])=[C:5]([F:27])[CH:6]=2)(=[O:12])=[O:11])[CH2:18][CH2:17]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: COC(=O)c1ccc(S(=O)(=O)N2CCC(NC(=O)OC(C)(C)C)CC2)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(C(=O)O)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.9 %

Procedure:
4-(4-Tert-Butoxycarbonylamino-piperidine-1-sulfonyl)-2-fluoro-benzoic acid methyl ester (0.8 g, 2.0 mmol) was added to a 1:1 mixture of water and tetrahydrofuran (20 ml) containing lithium hydroxide (0.8 g, 20.4 mmol) and the mixture was stirred at room temperature for 2 hours. After this time the mixture was concentrated to half the original volume and the remaining solution was acidified to pH 1 with 1M HCl. The resulting precipitate was collected by filtration, washed with water (10 ml) and dried under vacuum to give the title compound (0.82 g, 99% yield) as a white solid. Tr=1.80 min m/z (ES+) (M+Na+) 425.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[NH2:10][C:11]([C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1)=[O:12].C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].N#N>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].COCCOC>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([C:11]([NH2:10])=[O:12])[CH:18]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(Br)cc1
Reactant: NC(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: COCCOC
Solvent: ClCCl
Product: NC(=O)c1cccc(-c2ccc(C=O)cc2)c1

Procedure:
A mixture of 4-bromobenzaldehyde (2.78 g; 15.0 mmol), [3-(aminocarbonyl)-phenyl]boronic acid (2.72 g; 16.5 mmol), PdCl2(dppf).CH2Cl2 (0.306 g; 0.38 mmol), DME (25 mL) and Na2CO3 (25 mL of a 2M solution) was sparged 20 min with N2 and heated under reflux for 90 min (consumption of aryl bromide observed by LC/MS). Upon cooling, the mixture was partitioned between EtOAc/H2O, layers were separated, and the aqueous layer was extracted with EtOAc (×2). Combined organics were washed (H2O, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording the title compound as a tan solid. LC/MS (method A) 1.91 min, m/z 226 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[C:14]([O:16][CH2:17][CH2:18][Cl:19])[C:13]([O:20][CH3:21])=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:22]#[N:23].ClC1C2C(=CC3C=C(OC)C(OCCCl)=CC=3C=2)N=CC=1C#N.Cl.N1C=CC=CC=1.[Cl:54][C:55]1[C:61]([O:62][CH3:63])=[CH:60][C:58]([NH2:59])=[C:57]([CH3:64])[CH:56]=1.C(OCCO)C>>[Cl:54][C:55]1[C:61]([O:62][CH3:63])=[CH:60][C:58]([NH:59][C:2]2[C:11]3[C:6](=[CH:7][C:8]4[CH:15]=[C:14]([O:16][CH2:17][CH2:18][Cl:19])[C:13]([O:20][CH3:21])=[CH:12][C:9]=4[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:22]#[N:23])=[C:57]([CH3:64])[CH:56]=1
Reactant: COc1cc2cc3c(Cl)c(C#N)cnc3cc2cc1OCCCl
Reactant: COc1cc(N)c(C)cc1Cl
Agent: COc1cc2cc3ncc(C#N)c(Cl)c3cc2cc1OCCCl
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc(Nc2c(C#N)cnc3cc4cc(OCCCl)c(OC)cc4cc23)c(C)cc1Cl
Temperature: 135 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
A mixture of 248 mg (0.714 mmol) of 4-chloro-7-methoxy-8-(2-chloroethoxy)benzo[g]quinoline-3-carbonitrile and 4-chloro-8-methoxy-7-(2-chloroethoxy)benzo[g]quinoline-3-carbonitrile (1:1 mixture), 10 mg of pyridine hydrochloride, 150 mg (0.874 mmol) of 4-chloro-5-methoxy-2-methylaniline and 5 mL of 2-ethoxyethanol is stirred and heated to 135° C. After 1 hour, the reaction is cooled to room temperature, quenched with 0.2 mL of triethylamine and concentrated in vacuo. The residue is dissolved in 1:1 hexane/ethyl acetate with a little dichloromethane and chromatographed on silica gel eluting with 1:1 hexane/ethyl acetate, then ethyl acetate to provide 0.282 g of 4-(4-chloro-5-methoxy-2-methylanilino)-7-methoxy-8-(chloroethoxy)benzo[g]quinoline-3-carbonitrile and 4-(4-chloro-5-methoxy-2-methylanilino)-8-methoxy-7-(chloroethoxy)benzo[g]quinoline-3-carbonitrile (1:1 mixture) as a dull yellow solid (81%), m.p. 132–68° C. dec.
Reaction SMILES: [C:1]([CH:8]([CH2:12][CH2:13][NH2:14])[C:9]([OH:11])=[O:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:15]I.[H-].[Na+]>C1COCC1>[C:1]([CH:8]([CH2:12][CH2:13][NH:14][CH3:15])[C:9]([OH:11])=[O:10])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CI
Reactant: CC(C)(C)OC(=O)C(CCN)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CNCCC(C(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.6 %

Procedure:
To a 0° C. solution of 5.00 g (24.6 mmol) of BOC-4-aminobutyric acid in 75 mL of dry THF, was added 12.2 mL (197 mmol) of methyl iodide followed by 2.95 g (73.8 mmol, 60% dispersion in mineral oil) of sodium hydride, portionwise. The reaction was rapidly stirred at room temperature for 12 h and quenched by the careful addition of water. The mixture was partitioned between ether and water, and the organic phase extracted with 1 N aq sodium bicarbonate. The combined aqueous phases were chilled and acidified to pH 3 with 1 N sodium hydrogen sulfate, then extracted with two portions of ethyl acetate. The combined organics were washed successively with water, 5% aq sodium thiosulfate, water, brine, and then dried over anhydrous magnesium sulfate. Concentration in vacuo afforded 5.00 g (94%) of BOC-4-(N-methylamino)butyric acid. 1H NMR: (300 MHz, CDCl3) δ 3.28 (2H, bt, J=7 Hz), 2.84 (3H,s), 2.36 (2H,t,J=7.5 Hz), 1.85 (2H, m), 1.45 (9H, s).
Reaction SMILES: Cl.[CH2:2]([S:9]([NH:12][C:13]1[C:14](=[O:28])[N:15]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[C:16]([CH3:19])=[CH:17][CH:18]=1)(=[O:11])=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(OCC)(=O)C>[CH2:2]([S:9]([NH:12][C:13]1[C:14](=[O:28])[N:15]([CH2:20][C:21]([OH:23])=[O:22])[C:16]([CH3:19])=[CH:17][CH:18]=1)(=[O:11])=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)O
Reaction time: 2 h

Procedure:
HCl gas was bubbled through a stirred suspension of 3-benzylsulfonylamino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone (1.4 g, 3.57 mmol), as prepared in the preceding step, in ethyl acetate (15 mL) at 0° C. until a solution was formed. After 2 h at room temperature, a thick suspension was formed. The mixture was degassed with nitrogen and filtered to give the title compound a white solid (1.1 g, 92%). 1H-NMR (300 MHz, CDCl3) δ8.67 (s, 1H), 7.34 (m, 5H), 7.12 (d, J=7.5 Hz, 1H), 6.10 (d, J=7.6 Hz, 1H), 4.78 (s, 2H), 4.51 (s, 2H), 2.26 (s, 3H).
Reaction SMILES: [OH:1][C:2]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:7][CH2:6][N:5]([C:8]([C@H:10]([NH:15][C:16]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[C:24]([CH:27]4[CH2:29][CH2:28]4)[N:25]=3)[N:20](COCC[Si](C)(C)C)[CH:19]=2)=[O:17])[C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C1OCCOCCOCCOCCOCCOC1.[F-].[Cs+]>C(#N)C>[OH:1][C:2]1([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:3][CH2:4][N:5]([C:8]([C@H:10]([NH:15][C:16]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[C:24]([CH:27]4[CH2:28][CH2:29]4)[N:25]=3)[NH:20][CH:19]=2)=[O:17])[C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CC(C)(C)[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(C3CC3)nc12)C(=O)N1CCC(O)(c2ccccc2)CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: CC(C)(C)[C@@H](NC(=O)c1c[nH]c2ncc(C3CC3)nc12)C(=O)N1CCC(O)(c2ccccc2)CC1
Temperature: 85 °C
Reaction time: 8 h
Yield: 28.7 %

Procedure:
In a round-bottomed flask, 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-hydroxy-4-phenyl-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amide (0.21 g, 0.33 mmol) was dissolved in acetonitrile (4.2 mL). 18-Crown-6 (89 mg, 0.33 mmol) and cesium fluoride (507 mg, 3.34 mmol) were added. The reaction mixture was stirred at 85° C. overnight and then at room temperature for 24 h. Silica Gel (˜1 g) was added to the reaction mixture and the suspension was concentrated and purified by chromatography over 12 g SiO2 with 0-100% EtOAc/heptane to 0-10% MeOH/EtOAc to afford an oil. Trituration with dichloromethane/hexanes afforded 45 mg (26%) of 2-cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-hydroxy-4-phenyl-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amide as a yellow powder. MS: (M+H)+=476.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:10][CH:9]2[CH2:11][CH:5]([CH2:6][CH:7]([OH:12])[CH2:8]2)[O:4]1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>N1C=CC=CC=1>[CH3:13][S:14]([O:12][CH:7]1[CH2:8][CH:9]2[CH2:11][CH:5]([O:4][CH:3]([CH2:2][O:1][S:14]([CH3:13])(=[O:16])=[O:15])[O:10]2)[CH2:6]1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1OC2CC(O)CC(C2)O1
Solvent: c1ccncc1
Product: CS(=O)(=O)OCC1OC2CC(CC(OS(C)(=O)=O)C2)O1

Procedure:
A solution of 0.87 g (5 mmols) of 3-hydroxymethyl-2,4-dioxabicyclo[3,3,1]nonan-7-ol of the formula IIa in 5 ml of anhydrous pyridine is cooled to -20°C and, while stirring, treated with 1,1 ml (14,2 mmols) of methanesulphonyl chloride. The cooling bath is removed and the reaction mixture is added after 11/4 hours to 40 ml of a normal sodium bicarbonate solution. The resulting mixture is extracted successively with 40 ml of ethyl acetate and 40 ml of methylene chloride. The combined organic solutions are washed with 10 ml of sodium bicarbonate solution, dried over magnesium sulphate and concentrated in a water jet vacuum. The crude product is recrystallised from acetone/heptane and gives 7-methylsulphonyloxy-3-methylsulphonyloxymethyl-2,4-dioxabicyclo[3,3,1]nonane of the formula IIb ##SPC10##
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:34]([OH:37])(=[S:36])[CH3:35].[CH2:38]([N:45]1[CH2:48][CH:47](O)[CH2:46]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>O1CCCC1>[CH2:38]([N:45]1[CH2:48][CH:47]([S:36][C:34](=[O:37])[CH3:35])[CH2:46]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(O)=S
Reactant: OC1CN(Cc2ccccc2)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)SC1CN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
Triphenylphosphine (3.08 g, 11.76 mmol) was dissolved in anhydrous tetrahydrofuran (THF) (30 ml). Oxygen was completely removed by passing nitrogen through the mixture, and the mixture was cooled to 0° C. Diisopropylazodicarboxylate (2.3 ml, 11.76 mmol) was added thereto, and stirred at 0° C. for 1 hour. Added slowly to the mixture in succession were thioacetic acid (840 μl, 11.76 mmol) and 1-benzyl-azetidine-3-ol (960 mg, 5.88 mmol) prepared in Preparation Example 37 and dissolved in tetrahydrofuran (20 ml). The resulting solution was heated to room temperature, stirred for 2 hours and concentrated under a reduced pressure to remove the solvent. The concentrate was dissolved in ethyl acetate, washed with water, dried over anhydrous magnesium sulfate and concentrated under a reduced pressure. The resulting residue was purified by column chromatography (eluent−ethyl acetate/normal hexane=1/1) to obtain 1.1 g (yield: 83%) of the title compound.