Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C@@:10]([CH3:25])([S:21]([CH3:24])(=[O:23])=[O:22])[C:11]([NH:13][O:14][C@@H]2CCCCO2)=[O:12])[C:4](=[O:26])[CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:55]=[CH:54][C:38]([O:39][CH2:40][C@H:41]3[CH2:46][CH2:45][C@H:44]([O:47]C4CCCCO4)[CH2:43][CH2:42]3)=[CH:37][CH:36]=2)O1.C(N)(=O)CCC>>[OH:14][NH:13][C:11](=[O:12])[C@:10]([CH3:25])([S:21]([CH3:24])(=[O:22])=[O:23])[CH2:9][CH2:8][N:5]1[CH:6]=[CH:7][C:2]([C:35]2[CH:36]=[CH:37][C:38]([O:39][CH2:40][C@H:41]3[CH2:46][CH2:45][C@H:44]([OH:47])[CH2:43][CH2:42]3)=[CH:54][CH:55]=2)=[CH:3][C:4]1=[O:26]
Reactant: CC1(C)OB(c2ccc(OC[C@H]3CC[C@H](OC4CCCCO4)CC3)cc2)OC1(C)C
Reactant: C[C@@](CCn1ccc(I)cc1=O)(C(=O)NO[C@@H]1CCCCO1)S(C)(=O)=O
Agent: CCCC(N)=O
Product: C[C@@](CCn1ccc(-c2ccc(OC[C@H]3CC[C@H](O)CC3)cc2)cc1=O)(C(=O)NO)S(C)(=O)=O

Procedure:
The title compound (489 mg, 49.7%) was prepared from (2R)-4-(4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-[(2R)-tetrahydro-2H-pyran-2-yloxy]butanamide (742 mg, 1.49 mmol) and 2-[(trans-4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}cyclohexyl)oxy]tetrahydro-2H-pyran (620 mg, 1.49 mmol) by a procedure analogous to that described for (2R)-2-methyl-2-(methylsulfonyl)-4-[2-oxo-4-(4-{[cis-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]methoxy}phenyl)pyridin-1(2H)-yl]-Netrahydro-2H-pyran-2-yloxy)butanamide, Example 8, Step E. LCMS m/z 659.8 (M−1).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[C:17]([F:30])[CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:32]1[N:37]=[N:36][C:35]([NH2:38])=[CH:34][CH:33]=1>>[NH2:38][C:35]1[N:36]=[N:37][C:32]([C:18]2[CH:19]=[CH:20][C:15]([C:10]3[C:9]([S:6]([NH:5][C:1]([CH3:2])([CH3:3])[CH3:4])(=[O:8])=[O:7])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:16][C:17]=2[F:30])=[CH:33][CH:34]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Reactant: Nc1ccc(Cl)nn1
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2ccc(N)nn2)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 444 using N-(tert-butyl)-3′-fluoro-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-sulfonamide and 6-chloropyridazin-3-amine. MS (ESI): mass calcd. for C20H21FN4O2S, 400.14; m/z found, 401.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.26-8.22 (m, 1H), 8.16-8.13 (m, 1H), 7.91-7.85 (m, 1H), 7.69-7.64 (m, 1H), 7.63-7.56 (m, 2H), 7.44-7.37 (m, 3H), 1.09 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=O)[CH2:6][CH2:5]2.[C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:15].CC(O)=O.C([O-])(=O)C.[NH4+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])/[C:7](=[C:16](\[C:14]#[N:15])/[C:17]([O:19][CH2:20][CH3:21])=[O:18])/[CH2:6][CH2:5]2
Reactant: CCOC(=O)CC#N
Reactant: COc1cc2c(cc1Cl)CCC2=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)/C(C#N)=C1\CCc2cc(Cl)c(OC)cc21
Temperature: 120 °C
Reaction time: 12 h
Yield: 61.6 %

Procedure:
To the solution of 5-chloro-6-methoxy-2,3-dihydro-1H-inden-1-one (Prep15, 12 g, 61.2 mmol) in toluene (240 ml) was added ethyl cyanoacetate (8.3 g, 73.46 mmol), AcOH (48 ml, 0.8 mol) and ammonium acetate (12 g, 0.16 mol). The mixture was stirred for 12 hours at 120° C., checked by TLC, concentrated, filtered and washed with water and ethanol twice and purified by FC to afford 11 g of title compound (y=62%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23]([OH:25])=O)=[CH:13][C:12]=2[N:11]=1.S(Cl)(Cl)=O.[Br:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1.[H-].[Na+]>C1COCC1.C1C=CC=CC=1>[Br:30][C:31]1[CH:37]=[CH:36][C:34]([NH:35][C:23]([C:14]2[C:15]3[O:19][C:18]([CH3:20])=[N:17][C:16]=3[C:21]3[NH:22][C:10]([NH:9][C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])=[N:11][C:12]=3[CH:13]=2)=[O:25])=[CH:33][CH:32]=1
Reactant: Nc1ccc(Br)cc1
Reactant: Cc1nc2c(o1)c(C(=O)O)cc1nc(Nc3c(Cl)cccc3Cl)[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1nc2c(o1)c(C(=O)Nc1ccc(Br)cc1)cc1nc(Nc3c(Cl)cccc3Cl)[nH]c12
Yield: 15 %

Procedure:
The title compound was prepared following the procedure as described for Example-177 using 7-[(2,6-dichlorophenyl)amino]-2-methyl-8H-imidazo[4,5-e][1,3]benzoxazole-4-carboxylic acid (Intermediate-55, 0.100 g, 0.276 mmol), benzene (4 mL), thionyl chloride (5.0 mL), 4-bromo aniline (0.142 g, 0.828 mmol), THF (5.0 mL) and 60% NaH (0.033 g, 0.825 mmol). The obtained product was further purified by column chromatography on neutral alumina eluting with 1.5-2.0% MeOH:DCM to afford 0.022 g of the desired product. 1HNMR (DMSO-d6): δ 2.70 (s, 3H), 6.54 (s, 1H), 6.67 (d, J=8.4 Hz, 1H), 6.83 (s, 1H), 6.98 (d, J=8.1 Hz, 1H), 7.12-7.26 (m, 2H), 7.33-7.38 (m, 2H), 8.61 (s, 1H), 9.04 (s, 1H); MS [M+H]+: 532.47.
Reaction SMILES: C([Li])CCC.[CH2:6]1[CH2:10][O:9][CH2:8][CH2:7]1.[CH2:11]([C:17]1[S:18]C=CC=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].CN(C=O)C>[Cl-].[NH4+]>[CH2:11]([C:17]1[S:18][C:6]([CH:10]=[O:9])=[CH:7][CH:8]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C1CCOC1
Reactant: CCCCCCc1cccs1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCCCCCc1ccc(C=O)s1
Reaction time: 0.25 h

Procedure:
Under a nitrogen atmosphere at 0° C., 24 ml of n-butyllithium (1.6M in hexane) were added by dripping to a THF solution containing 2-hexylthiophene (5 g). The solution was then stirred for another 15 minutes and, after adding DMF (5 ml), set to room temperature. The resulting solution was then poured into a IN ammonium chloride solution and extracted with methylene chloride. An organic layer was washed with water and dried with anhydrous magnesium sulfate. A crude product was collected by removing the solvent and then purified by a column chromatograph (carrier: silicon dioxide; eluate: hexane/methylene chloride-4/1 (volume ratio)) to obtain 4.6 g of a product.
Reaction SMILES: CC1(C)OCC2(CCC(CCN[C@H](C3C=CC=CC=3)CC)(O)CC2)C[O:3]1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.CC1(C)OC[C:43]2([CH2:63][CH2:62][C:46]3([O:51][C:50](=[O:52])[N:49]([C@H:53]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)[CH2:54][CH3:55])[CH2:48][CH2:47]3)[CH2:45][CH2:44]2)CO1>>[C:56]1([C@@H:53]([N:49]2[CH2:48][CH2:47][C:46]3([CH2:45][CH2:44][C:43](=[O:3])[CH2:63][CH2:62]3)[O:51][C:50]2=[O:52])[CH2:54][CH3:55])[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1
Reactant: CC[C@H](NCCC1(O)CCC2(CC1)COC(C)(C)OC2)c1ccccc1
Reactant: CC[C@@H](c1ccccc1)N1CCC2(CCC3(CC2)COC(C)(C)OC3)OC1=O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: CC[C@@H](c1ccccc1)N1CCC2(CCC(=O)CC2)OC1=O

Procedure:
The title compound is prepared from 3,3-dimethyl-9-{2-[(S)-1-phenyl-propylamino]-ethyl}-2,4-dioxa-spiro[5.5]undecan-9-ol and triphosgene following a procedure analogous to that described in Step 4 of Intermediate 2; the crude product, a mixture of the title compound and 12,12-dimethyl-3-[(S)-1-phenyl-propyl]-1,11,13-trioxa-3-aza-dispiro[5.2.5.2]hexadecan-2-one, obtained thereafter is treated as described in Step 10 of Intermediate 2 to convert the intermediate to the title compound as well. Yield: 56% of theory; LC (method 8): tR=1.20 min; Mass spectrum (ESI+): m/z=302 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](Br)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[B:11](OC(C)C)([O:16]C(C)C)[O:12]C(C)C.[Li]CCCC.C(Cl)Cl>C1COCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:9]=[C:8]([B:11]([OH:16])[OH:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(Br)cc1F
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: N#Cc1ccc(B(O)O)cc1F
Temperature: -75 °C
Reaction time: 0.25 h
Yield: 68.6 %

Procedure:
Dissolve 2-Fluoro-4-bromobenzonitrile (200 g, 990 mmol, 1.00 eq.) and triisopropyl borate (228 g, 1188 mmol, 1.2 eq.) in 700 mL of THF and 1400 mL of toluene. Cool the mixture with a dry ice/acetone bath to an internal temperature of −75° C. Slowly add n-BuLi (396 mL of a 2.5 M solution in hexanes) over a period of 2 hours. After addition is complete, a light-red, thin slurry occurs. Let the solution stir at −74° C. for 15 minutes, allow the solution to warm to −20° C. and then quench with 1500 mL of 2.5 M HCl. Let the solution warm to RT. Separate layers, extract the aqueous layer with EtOAc, dry the combined organic phases with Na2SO4, filter and concentrate in vacuo to yield a light-brown solid. Triturate the solid with hexane and transfer to a scintered glass funnel. Rinse with hexane one more time to obtain a pale-yellow filtrate. Stir the light-brown solid with cold CH2Cl2 and filter. Rinse with a small volume of CH2Cl2 to yield an off-white solid and a brown filtrate. Dry the solid in a vacuum oven at 40° C. and dried to yield 112 g (679 mmol, 69%) of 3-fluoro-4-cyanophenylboronic acid as an off-white solid.
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5]([CH3:32])([CH3:31])[CH2:6][NH:7][C:8]([C:10]1[N:11]=[C:12]([C:29]#[N:30])[C:13]2[C:18]([C:19]=1[OH:20])=[CH:17][CH:16]=[C:15]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)[CH:14]=2)=[O:9])C.O.CCOC(C)=O.Cl>CO.[OH-].[Na+]>[Cl:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[O:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19]([OH:20])=[C:10]([C:8]([NH:7][CH2:6][C:5]([CH3:32])([CH3:31])[C:4]([OH:33])=[O:3])=[O:9])[N:11]=[C:12]2[C:29]#[N:30])=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3cccc(Cl)c3)ccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CC(C)(CNC(=O)c1nc(C#N)c2cc(Oc3cccc(Cl)c3)ccc2c1O)C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3-{[7-(3-Chloro-phenoxy)-1-cyano-4-hydroxy-isoquinoline-3-carbonyl]-amino}-2,2-dimethyl-propionic acid ethyl ester (26 mg, 0.06 mmol) was dissolved in MeOH (4 mL) and 2 N NaOH (4 mL). After stirring for 5 hours at room temperature, H2O (15 mL) and EtOAc (15 mL) were added. To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-30% MeOH/CH2Cl2) to give the title compound in 18 mg. MS: (−) m/z 437.93 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12][CH2:11]1.[I:22]I>CO.S([O-])([O-])(=O)=O.[Ag+2]>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([I:22])=[CH:4][C:3]=1[CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12][CH2:11]1
Reactant: II
Reactant: CCOC(=O)CN1CCC(c2ccc(OC)cc2F)CC1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: CCOC(=O)CN1CCC(c2cc(I)c(OC)cc2F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl [4-(2-fluoro-4-methoxyphenyl)piperidin-1-yl]acetate (Step A; 21.6 mg; 0.073 mmol), iodine (45.6 mg; 0.146 mmol) and silver sulfate (37 mg; 0.146 mmol) in MeOH (1.5 mL) was stirred at room temperature for 2 h. The reaction was filtered through Celite and the filtrate was concentrated in vacuo. The residue was redissolved in ether (25 mL) and washed with H2O (25 mL). The aqueous layer was extracted with ether (3×25 mL) and the combined extracts were washed with brine (25 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-10% EtOAc/hexanes gradient) to afford ethyl [4-(2-fluoro-5-iodo-4-methoxyphenyl)piperidin-1-yl]acetate as a yellow oil. LCMS=421.8 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.61 (d, J=8.3 Hz, 1 H), 6.45 (d, J=11.9 Hz, 1 H), 4.21 (q, J=7.1 Hz, 2 H), 3.84 (s, 3 H), 3.26 (s, 2 H), 3.05 (d, J=11.2 Hz, 2 H), 2.80 (tt, J=12.0, 3.9 Hz, 1 H), 2.33 (t, J=10.6 Hz, 2 H), 1.87 (qd, J=12.3, 3.2 Hz, 2 H), 1.78 (d, J=12.1 Hz, 2 H), 1.29 (t, J=7.1 Hz, 3 H).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([C:27]2[NH:28][CH2:29][CH2:30][N:31]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[N+:34]([C:37]1[CH:47]=[CH:46][C:40]([CH2:41][O:42][C:43](Cl)=[O:44])=[CH:39][CH:38]=1)([O-:36])=[O:35].C(O)(=O)C>O1CCCC1.ClCCl>[Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([C:27]2[N:28]([C:43]([O:42][CH2:41][C:40]3[CH:39]=[CH:38][C:37]([N+:34]([O-:36])=[O:35])=[CH:47][CH:46]=3)=[O:44])[CH2:29][CH2:30][N:31]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](C2=NCCN2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](C2=NCCN2C(=O)OCc2ccc([N+](=O)[O-])cc2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 107.6 %

Procedure:
To a solution of (2S,4R)-4-t-butyldimethylsilyloxy-2-(2-imidazolin-2-yl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (930 mg) in tetrahydrofuran (20 ml) was added sodium hydride (62.8% suspension in oil, 103 mg), and to this mixture was dropwise added a solution of 4-nitrobenzyloxycarbonyl chloride (531 mg) in dichloromethane (15 ml) at 0° C. After stirring at 0° C. for 1.5 hours, acetic acid (0.18 ml) was added thereto. The mixture was evaporated, extracted with ethyl acetate, and washed with saturated sodium bicarbonate and brine successively. The dried organic layer was evaporated, the obtained oil was subjected to a column chromatography on silica gel and eluted with a mixture of dichloromethane and acetone (9:1, V/V) to give (2S,4R)-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)-2-[1-(4-nitrobenzyloxycarbonyl)-2-imidazolin-2-yl]pyrrolidine (1.4 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:15]([CH:17]1[O:19][CH2:18]1)Cl.N1CCCCC1.[OH-].[Na+]>ClCCl>[O:19]1[CH2:18][CH:17]1[CH2:15][O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(c2cccc(O)c2)=NN1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCNCC1
Solvent: ClCCl
Product: O=C1CCC(c2cccc(OCC3CO3)c2)=NN1
Yield: 60.9 %

Procedure:
A mixture of finely powdered 6-(3-hydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone (21.6 g, 0.11 mole), epichlorohydrin (90 ml, 1.1 mole), and piperidine (1 ml) was heated on a steam bath for 90 minutes. Evaporation of the solution under reduced pressure gave an oil which was dissolved in dichloromethane and stirred with dilute sodium hydroxide solution (60 ml). The organic phase was washed with water, dried, and evaporated under reduced pressure to a viscous oil (27 g, 96%). Purification on a silica column by eultion with chloroform gave 6-[3-(2,3-epoxypropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone (16.5 g, 59%) as an oil which, when treated with ether, gave a white solid (13.7 g, 49%, m.p. 108°-112° C). The pure epoxide, recrystallised from methanol-petroleum ether (b.p. 60°-80° C), had m.p. 110°-112° C. (Found: C, 63.96; H, 5.70; N, 11.43; M+ , 246. C13H14N2O3 requires: C, 63.39; H, 5.73; N, 11.38%; M, 246).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1[CH:10]1[C:22]2[NH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH2:13][CH2:12][NH:11]1.Cl[C:24]1[N:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[CH:26][N:25]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1[CH:10]1[C:22]2[NH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH2:13][CH2:12][N:11]1[C:24]1[N:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[CH:26][N:25]=1
Reactant: Clc1ncc(-c2ccccn2)cn1
Reactant: c1ccc2c(c1)CC(C1NCCc3c1[nH]c1ccccc31)O2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(-c2cnc(N3CCc4c([nH]c5ccccc45)C3C3Cc4ccccc4O3)nc2)nc1

Procedure:
1-(2,3-dihydrobenzofuranyl)-2,3,4,9-tetrahydro-1H-β-carboline (prepared according to the process as disclosed in WO97/43287, Intermediate 10, page 25) (1.35 g, 4.66 mmol), 2-chloro-5-(2-pyridinyl)-pyrimidine (893 mg, 4.66 mmol) and N,N-diisopropylethylamine (1.4 mL) were stirred in DMF (10 mL, anhydrous) at 120° C. for 16 h. The resulting mixture was quenched with 10% NaCl and extracted with ethyl acetate. The extracted organic layer was washed with 10% NaCl, brine and then dried with MgSO4. The reaction mixture solvent was evaporated and the residue purified by column chromatography (silica gel, ethyl acetate:hexanes=4:6) to yield the product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13](=O)[CH3:14])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]([NH:22][S@@:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])[CH3:14])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cnc(OCC2CC2)c(Cl)c1
Product: CC(N[S@](=O)C(C)(C)C)c1cnc(OCC2CC2)c(Cl)c1
Yield: 90 %

Procedure:
The title compound is prepared in 90% yield (1.22 g, colorless oil) from 1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethanone (923 mg, 4.09 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide (744 mg, 6.14 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: N#N.[CH3:3][C:4]1[O:5][C:6]([C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)=[C:7]([C:9]([OH:11])=O)[N:8]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[C:33]([Si:37]([CH3:54])([CH3:53])[O:38][CH:39]([C:41]1[O:42][C:43]([CH2:46][N:47]2[N:51]=[C:50]([NH2:52])[CH:49]=[N:48]2)=[CH:44][N:45]=1)[CH3:40])([CH3:36])([CH3:35])[CH3:34]>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[C:33]([Si:37]([CH3:54])([CH3:53])[O:38][CH:39]([C:41]1[O:42][C:43]([CH2:46][N:47]2[N:51]=[C:50]([NH:52][C:9]([C:7]3[N:8]=[C:4]([CH3:3])[O:5][C:6]=3[C:12]3[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=3)=[O:11])[CH:49]=[N:48]2)=[CH:44][N:45]=1)[CH3:40])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1ncc(Cn2ncc(N)n2)o1
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Agent: CN(C)c1ccncc1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1cccc(-c2oc(C)nc2C(=O)Nc2cnn(Cc3cnc(C(C)O[Si](C)(C)C(C)(C)C)o3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-methyl-5-m-tolyl-oxazole-4-carboxylic acid (34 mg, 0.16 mmol) in CH2Cl2 (1.0 mL) was treated at rt with HOBt (25 mg, 0.19 mmol), EDC (74 mg, 0.38 mmol), DMAP (5 mg, 0.04 mmol) and the resulting mixture was stirred at rt for 30 min. 2-{2-[1-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-oxazol-5-ylmethyl}-2H-[1,2,3]triazol-4-ylamine (50 mg, 0.16 mmol) in CH2Cl2 (0.6 mL) was then added and the resulting mixture was stirred at rt for 16 h. CH2Cl2 (20 mL) followed by water (15 mL) were added and the aqueous phase was extracted with CH2Cl2. The combined organic phases were washed with water, brine, dried over MgSO4, filtered, and the solvent removed under reduced pressure to give the title compound as a brown oil. LC-MS-conditions 02: tR=1.23 min, [M+H]+=523.56.
Reaction SMILES: [Mg].[C:2]1([CH2:8][CH2:9][CH2:10][CH2:11]Br)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13]([N:20]1[C:24]([CH:25]=[O:26])=[CH:23][N:22]=[CH:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>O1CCCC1>[CH2:13]([N:20]1[C:24]([CH:25]([OH:26])[CH2:11][CH2:10][CH2:9][CH2:8][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:23][N:22]=[CH:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=Cc1cncn1Cc1ccccc1
Reactant: BrCCCCc1ccccc1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: OC(CCCCc1ccccc1)c1cncn1Cc1ccccc1
Temperature: 25 °C

Procedure:
2,1 g of magnesium turnings are covered with 60 ml of dry tetrahydrofuran. A solution of 4-phenylbutylbromide (18,8 g) in 20 ml of dry tetrahydrofuran is then added dropwise to the mixture at such a rate that a smooth reaction is maintained. After the addition is complete, the reaction mixture is refluxed for one additional hour and cooled to room temperature. The reaction mixture is then added dropwise to a solution of 1-benzyl-5-imidazolecarbaldehyde (6,5 g) in 80 ml of tetrahydrofuran at 60° C. After the addition is complete, the reaction mixture is refluxed for 2 hours, cooled and poured into cold water. Tetrahydrofuran is evaporated and conc. hydrochloric acid is added to the solution. The product which is separated as an oil, is extracted with methylene chloride and evaporated to dryness.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][OH:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Se](=O)=O>O1CCOCC1.ClCCl>[C:1]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH:11]=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccnc(CO)c1
Agent: O=[Se]=O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)c1ccnc(C=O)c1
Temperature: 82.5 °C
Yield: 95.8 %

Procedure:
4-t-Butyl-2-hydroxymethyl-pyridine (4.13 g, 25 mmole) is dissolved in 75 ml dioxane in a 200 ml one neck round bottom flask under nitrogen. The solution is treated with selenium dioxide (1.53 g, 13.75 mmole) and the reaction is warmed to 80-85° C. for 1 h. The mixture is cooled, diluted with dichloromethane, and is filtered through celite. The filter cake is washed well with dichloromethane and the filtrate is concentrated to an amber oil. The crude oil is passed through a 50 g plug of silica gel (230-400 mesh), eluting with 20% acetone/hexane, while collecting 100 ml fractions. Fractions 1-3 are combined and concentrated to give 3.91 g (96%) of 4-t-Butyl-2-pyridine-carboxaldehyde as a light amber oil.
Reaction SMILES: [Br:1][C:2]#[C:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[CH:6][CH:5]=1.[OH-].[Na+]>CO.C1COCC1.O>[Br:1][C:2]#[C:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C#CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(C#CBr)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
To a solution of methyl 4-(bromoethynyl)benzoate (67 g, 280 mmol) in CH3OH/THF/H2O=5/5/1 (1100 mL) was added NaOH (44.84 g) and the reaction mixture was stirred at 25° C. for 3 hr. The volatiles were removed under reduced pressure and the resulting solution was neutralized with 1 N HCl to pH 3-5. Solids were collected by filtration, washed with water and dried at 50° C. for 5 hr to yield 4-(bromoethynyl)benzoic acid (INT-1) (61 g, 96%).
Reaction SMILES: [OH:1][CH:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][N:4]1[C:8]2[N:9]=[CH:10][NH:11][C:12](=O)[C:7]=2[CH:6]=[N:5]1.C1C(=O)N([Br:27])C(=O)C1.CN(C)P(N(C)C)N(C)C.[Li+].[Br-]>C(#N)C>[Br:27][C:12]1[N:11]=[CH:10][N:9]=[C:8]2[N:4]([CH2:3][CH:2]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[OH:1])[N:5]=[CH:6][C:7]=12
Reactant: O=c1[nH]cnc2c1cnn2CC(O)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: CN(C)P(N(C)C)N(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: CC#N
Product: OC(Cn1ncc2c(Br)ncnc21)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
To a cold (−20° C.) suspension of 10 (2.56 g, 10 mmol) and NBS (7.12 g, 40 mmol) in dry acetonitrile (20 mL), hexamethylphosphorous triamide (HT) (6.53 g, 40 mmol) was added dropwise. After addition, the cold bath was removed and the reaction mixture stirred at room temperature for 0.5 h. LiBr (3.44 g, 40 mmol) was added and the mixture was heated at 70° C. for 5 h. The mixture was evaporated under reduced pressure. The dark oil was purified by column chromatography (Silica Gel, 100 Mesh) using CHCl3 as the eluant, to afford the pure product 11 (1.40 g, 44%) as a white solid: mp 146-147° C. 1H NMR: δ 3.46-3.53 (br s, 1H, OH, disappears with D2O), 4.57-4.79 (m, 2H, CH2N), 5.18-5.29 (m, 1H, CHO), 7.30-7.52 (m, 5H Ar), 8.01 (s, 1H, H-3), 8.48 (s, 1H, H-6). IR cm−1: 3240-2500 (OH). Anal. (C13H11N4OBr) C, H, N.