Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)([O-:14])=[O:13]>ClCCl>[CH:1]([NH:4][S:21]([C:18]1[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:20][CH:19]=1)(=[O:22])=[O:23])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.7 %

Procedure:
To a stirred solution of isopropylamine (6.8 mL, 79.6 mmol) and triethylamine (16.6 mL, 119.4 mmol) in dichloromethane (300 mL) was added the solution of 4-nitro-benzenesulfonyl chloride (8.8 g, 39.8 mmol) in dichloromethane (50 mL) at 0° C. The mixture solution stirred at room temperature for 4 h. The mixture solution was stirred at room temperature for 4 h and then washed with brine (50 mL×2) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to afford N-isopropyl-4-nitro-benzenesulfonamide (9.3 g, 96%) as a white powder: MS (ESI) M+1=245.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH:7]([CH3:11])[C:8]([OH:10])=O)=[O:4].[CH2:12]([O:19][C:20](=[O:24])[C@H:21]([CH3:23])[NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:12]([O:19][C:20](=[O:24])[C@H:21]([CH3:23])[NH:22][C:8](=[O:10])[CH:7]([CH3:11])[CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)CCC(C)C(=O)O
Reactant: C[C@H](N)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: COC(=O)CCC(C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
4-methoxycarbonyl-2-methylbutanoic acid (3.1 g.), L-alanine benzyl ester (3.58 g.) and hydroxybenzotriazole (2.7 g.) are dissolved in dichloromethane. The solution is chilled in the ice bath and dicyclohexylcarbodiimide (4.12 g.) is added. After stirring 15 minutes in the ice bath and 18 hours at room temperature the precipitate is filtered off and the filtrate is concentrated to dryness. The residue is dissolved in ethyl acetate and washed neutral. The organic phase is dried over magnesium sulfate and concentrated to dryness to yield N-(4-methoxycarbonyl-2-methylbutanoyl)-L-alanine benzyl ester.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C[Al](C)C.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:20]#[N:21]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:16][C:17]1[CH:18]=[C:19]([C:20](=[NH:21])[NH:9][C:8]2[CH:10]=[CH:11][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: COc1ccc(C#N)cc1Cl
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline (10 mmol) in toluene (100 mL), trimethylaluminum (2M solution in toluene, 15 mmol) is added over 15 minutes. The reaction mixture is warmed to room temperature and stirred for 2.5 hours. A solution of 3-chloro-4-methoxybenzonitrile (20 mmol) in toluene (50 mL) is added over 10 minutes and the reaction mixture is heated to 80°-85° C. After 20 hours, the reaction mixture is cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue is washed with a mixture of methylene chloride/methanol (2/1). The combined filtrates are concentrated in vacuo and the resulting yellowish solid is stirred with a mixture of hexane/ether (2/1, 1000 mL). The intermediate is filtered and washed with more of hexane/ether (2/1). The pale yellow solid 3-chloro-4-methoxy-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide is used in the next reaction without further purification.
Reaction SMILES: C(OC(=O)CN(C(OC(C)(C)C)=O)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11](CO)[N:10]=1)(C)(C)C.[S:25]1[CH:29]=[CH:28][N:27]=[C:26]1[C:30]1[CH:46]=[CH:45][C:33]([CH2:34][NH:35][S:36](C2C=CC=CN=2)(=[O:38])=[O:37])=[CH:32][CH:31]=1>>[S:25]1[CH:29]=[CH:28][N:27]=[C:26]1[C:30]1[CH:31]=[CH:32][C:33]([CH2:34][NH:35][S:36]([C:12]2[CH:11]=[N:10][CH:9]=[CH:14][CH:13]=2)(=[O:38])=[O:37])=[CH:45][CH:46]=1
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(CO)n1
Reactant: O=S(=O)(NCc1ccc(-c2nccs2)cc1)c1ccccn1
Product: O=S(=O)(NCc1ccc(-c2nccs2)cc1)c1cccnc1

Procedure:
Reaction and post-treatment were carried out in the same manner as in Example 2-(a) except for using tert-butyl[tert-butoxycarbonyl(6-hydroxymethylpyridin-2-yl)amino]acetate (279 mg, 0.824 mmol) obtained in Reference Example 3-(b), and using N-[4-(thiazol-2-yl)benzyl]pyridin-2-ylsulfonamide (275 mg, 0.830 mmol) obtained in Reference Example 5 in place of N-[4-(thiazol-2-yl)benzyl]pyridin-3-ylsulfonamide to afford the title compound (496 mg) as a white foam. (Yield: 92%) Mass spectrum (FAB, m/z): 652 (M++1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16](O)[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:27][N:28]([CH3:32])[C:29](Cl)=[O:30]>CN(C)C=O.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:29]([N:28]([CH3:32])[CH3:27])=[O:30])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1
Reactant: CN(C)C(=O)Cl
Reactant: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)C(=O)c1cc(C#N)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 140 °C
Yield: 6.3 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (39 mg, 0.15 mmol), potassium carbonate (32 mg, 0.30 mmol) and dimethylcarbamyl chloride (27 μL, 0.30 mmol) in N,N-dimethylformamide (1 mL) was heated in a sealed vial at 140° C. for 2 hours. The reaction was cooled, diluted with dichloromethane, washed with water (3×) and saturated brine, filtered and concentrated. Silica gel chromatography using hexanes:ethyl acetate:dichloromethane 3.5:0.5:4 afforded 3 mg (29%) of 3-(2-pyridyl)-5-(3-cyano-5-(dimethylamino)carbonylphenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.85 (d, 1H), 8.40 (s, 1H), 8.29 (s, 1H), 8.22 (d, 1H), 7.89 (m, 1H), 7.73 (s, 1H), 7.48 (dd, 1H), 3.14 (s, 3H), 3.06 (s, 3H).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:5]P(=O)(OC)OC.[CH:17]([C:19]1[O:20][C:21]([CH2:37][O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:22][C:23](=[O:36])[C:24]=1[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=O.C(O)(=O)C>C1COCC1>[O:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])/[CH:5]=[CH:17]/[C:19]1[O:20][C:21]([CH2:37][O:38][C:39](=[O:44])[C:40]([CH3:41])([CH3:42])[CH3:43])=[CH:22][C:23](=[O:36])[C:24]=1[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCOC(=O)CCCCCOc1c(C=O)oc(COC(=O)C(C)(C)C)cc1=O
Reactant: CCCCCC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCCC(=O)/C=C/c1oc(COC(=O)C(C)(C)C)cc(=O)c1OCCCCCC(=O)OCC
Reaction time: 1 h
Yield: 22.1 %

Procedure:
To a solution, under nitrogen, of 0.206 g (4.3 mmole) of sodium hydride (50% dispersion in mineral oil) in 15 ml of dry THF was added dropwise 1.04 g (4.69 mmole) of dimethyl (2-oxoheptyl)-phosphonate. The heterogeneous mixture was stirred for 1.0 hour then a solution of 1.55 g (3.9 mmole) of 2-formyl-3-(5-carboethoxypentyloxy)-6-(trimethylacetoxymethyl)-4-pyrone in 5 ml of THF was added. The mixture was stirred for 15 min then was neutralized to pH 7 with glacial acetic acid. The neutralized solution was concentrated by rotary evaporation and the residue dissolved in methylene chloride. The organic solution was washed with saturated brine solution and dried over magnesium sulfate. Removal of the solvent left an oil which was purified by chromatography on silica gel using ether as the eluent. Concentration of the fractions containing product furnished 0.425 g (22%) of pure 2-(3-oxo-trans-1-octenyl)-3-(5-carboethoxypentyloxy)-6-(trimethylacetoxymethyl)-4-pyrone as an oil. NMR (CDCl3): δ0.88 (3H, t, J=5 Hz); 1.25 (9H, s), 2.27 (2H, t, J=6.5 Hz); 2.60 (2H, t, J=6.5 Hz); 4.91 (2H, s).
Reaction SMILES: [C:1]([O:5][P:6]([O-:13])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N+](CCCC)(CCCC)CCCC)CCC.[NH2:31][C:32]1[N:41]=[C:40]([C:42]([N:44]2[CH2:52][C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH2:45]2)=[O:43])[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([C:53]3[CH:58]=[C:57]([F:59])[C:56]([F:60])=[CH:55][C:54]=3[CH2:61]Cl)[CH:38]=2)[N:33]=1>C(#N)C>[P:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([O:13][CH2:61][C:54]1[CH:55]=[C:56]([F:60])[C:57]([F:59])=[CH:58][C:53]=1[C:37]1[CH:38]=[C:39]2[C:34](=[CH:35][CH:36]=1)[N:33]=[C:32]([NH2:31])[N:41]=[C:40]2[C:42]([N:44]1[CH2:45][C:46]2[C:51](=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:52]1)=[O:43])=[O:7]
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)c(F)cc3CCl)ccc2n1
Reactant: CC(C)(C)OP(=O)([O-])OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: CC(C)(C)OP(=O)(OCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1)OC(C)(C)C
Temperature: 80 °C

Procedure:
800 mg of tetrabutylammonium di-tert-butylphosphate are added to 270 mg of [2-amino-6-(2-chloromethyl-4,5-difluorophenyl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone dissolved in 20 ml of acetonitrile, and the solution obtained is heated at 80° C. for 2 h. After cooling to 25° C., undissolved material is filtered off, and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in 1 ml of dimethyl sulfoxide and purified by chromatography (reversed phase).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:20][CH2:19][CH:18]([NH:21][CH3:22])[CH2:17][CH2:16]3)=[O:14])[N:10]=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:38]1([C:42](Cl)=[O:43])[CH2:41][CH2:40][CH2:39]1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:16][CH2:17][CH:18]([N:21]([CH3:22])[C:42]([CH:38]4[CH2:41][CH2:40][CH2:39]4)=[O:43])[CH2:19][CH2:20]3)=[O:14])[N:10]=[C:9]([C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)[CH:8]=2)=[CH:29][CH:30]=1
Reactant: O=C(Cl)C1CCC1
Reactant: CNC1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)C1CCC1)C1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1
Reaction time: 0.17 h

Procedure:
To a solution of 1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}-N-methylpiperidin-4-amine (150 mg, 0.37 mmol) in DCM (3 mL) at room temperature was added triethylamine (56 μL, 0.40 mmol) followed by cyclobutanecarbonyl chloride (42 μL, 0.37 mmol) and the solution stirred for 10 minutes. The solution was then loaded directly onto a pre-wetted Biotage 25M column for flash chromatography and eluted with 2-8% MeOH/DCM to yield the title compound as a white solid, 154 mg, 85%; 1H NMR (mix of rotomers, 400 MHz, DMSO-D6) δ ppm 8.52 (2 H, d, J=6.06 Hz), 7.66 (2 H, d, J=6.06 Hz), 7.30 (2 H, dd, J=8.46, 5.68 Hz), 7.15 (2 H, t, J=8.97 Hz), 6.52 (1 H, s), 5.08-5.33 (2 H, m), 4.42-4.57 (0.5 H, m), 4.38 (1 H, d, J=13.39 Hz), 3.95 (3 H, s), 3.64-3.79 (0.5 H, m), 3.36-3.48 (0.5 H, m), 3.24-3.34 (0.5 H, m), 3.03-3.20 (1 H, m), 2.55-2.76 (4 H, m), 2.01-2.28 (4 H, m), 1.39-1.99 (6 H, m); m/z (APCI+) for C28H32N5O2F 490.2 (M+H)+.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:2]1.[Cl:19]N1C(=O)CCC1=O.O>C(#N)C>[Cl:19][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[NH:1][CH2:2][CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH2:4]2
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2C1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1CNc2ccc(Cl)cc2C1
Reaction time: 6 h
Yield: 32.9 %

Procedure:
To a solution of tert-butyl 1,2,3,4-tetrahydroquinolin-3-yl-carbamate (28.3 g, 114 mmol), prepared as described in Example 1A, in acetonitrile (240 mL) at RT was added dropwise a solution of N-chlorosuccinimide (15.22 g, 114 mmol) in acetonitrile (240 mL). After addition, the reaction mixture was stirred for 6 h, then water (500 mL) added. The mixture was extracted with EtOAc (2×500 mL). The combined organics were washed with saturated aqueous NaCl, dried Na2SO4) and concentrated. The residue was chromatographed (silica gel) eluting with EtOAc/hexanes (1:5 ratio) to give the title compound (10.6 g, 58% yield) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8](B3OC(C)(C)C(C)(C)O3)[CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:20].Br[C:22]1[CH:23]=[N:24][CH:25]=[C:26]([F:30])[C:27]=1[CH:28]=[O:29].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:30][C:26]1[CH:25]=[N:24][CH:23]=[C:22]([C:8]2[CH:9]=[CH:10][C:5]3[O:4][C:3](=[O:20])[N:2]([CH3:1])[C:6]=3[CH:7]=2)[C:27]=1[CH:28]=[O:29]
Reactant: O=Cc1c(F)cncc1Br
Reactant: Cn1c(=O)oc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)oc2ccc(-c3cncc(F)c3C=O)cc21
Temperature: 100 °C
Yield: 34.5 %

Procedure:
A mixture of 3-Methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-benzooxazol-2-one (138 mg, 0.5 mmol), 3-Bromo-5-fluoro-pyridine-4-carbaldehyde (102 mg, 0.5 mmol), Na2CO3 (2 M in water, 0.75 mL, 1.5 mmol) and PdCl2(PPh3)2 (17 mg, 0.03 mmol) in DMF (3 mL) was heated at 100° C. for 4 hrs. After concentration, the residue was diluted with DCM and saturated NH4Cl solution. After filtration and concentration, the residue was purified by flash column (MeOH—CH2Cl2, v/v, 0-1.5%) and afforded the title compound (47 mg, 35%). 1H NMR (400.3 MHz, CDCl3): δ 3.45 (s, 3H), 6.96 (d, J=1.7 Hz, 1H), 7.08 (dd, J=8, 1.7 Hz, 1H), 7.32 (d, J=8 Hz, 1H) 8.59 (s, 1H), 8.68 (d, J=1.3 Hz, 1H), 10.07 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[CH:13]([NH2:16])([CH3:15])[CH3:14]>CN(C=O)C>[CH:13]([NH:16][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])([CH3:15])[CH3:14]
Reactant: CC(C)N
Reactant: COC(=O)c1cccc(CBr)c1
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CNC(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
A mixture of 2.00 g of methyl 3-(bromomethyl)benzoate, 1.55 g of isopropylamine, and 10 mL of DMF was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 1.20 g of methyl 3-[(isopropylamino)methyl]benzoate as a colorless solid.
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][N:14]2[C:18](=[O:19])[CH2:17][CH2:16][CH:15]2[CH2:20][CH2:21][CH:22]([OH:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:7][CH:6]=1)C.[OH-].[Na+]>>[OH:30][CH:22]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:21][CH2:20][CH:15]1[CH2:16][CH2:17][C:18](=[O:19])[N:14]1[CH2:13][CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([OH:31])=[O:3])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(OCCN2C(=O)CCC2CCC(O)Cc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(OCCN2C(=O)CCC2CCC(O)Cc2ccccc2)cc1
Yield: 85.6 %

Procedure:
Analogous to the procedure described for Example 1A, Step F, 4-{2-[2-(3-hydroxy-4-phenyl-butyl)-5-oxo-pyrrolidin-1-yl]-ethoxy}-benzoic acid ethyl ester (52 mg, 0.122 mmol) was hydrolyzed with 6N NaOH (1 mL) to yield the title compound (41.5 mg). 1H NMR (CDCl3) δ7.98 (d, 2H), 7.32–7.16 (m, 5H), 6.85 (m, 2H), 4.13 (m, 2H), 3.92 (m, 1H), 3.81 (m, 1H), 3.75 (m, 1H), 3.40 (m, 1H), 2.82 (m, 1H), 2.66 (m, 1H), 2.36 (m, 2H), 2.10 (m, 2H), 1.70–1.34 (m, 5H); MS 398.4 (M+1), 396.3 (M−1).
Reaction SMILES: [F:1][C:2]1[C:3]([O:30][CH3:31])=[CH:4][C:5]([CH2:25][C:26]([F:29])([F:28])[F:27])=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:23]#[N:24])=[N:13][N:14]3[CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[CH:10][CH:9]=2)[CH:7]=1.[CH3:32][O-:33].[Na+]>CO>[CH3:32][O:33][C:23]([C:12]1[C:11]2[C:15](=[CH:16][C:8]([C:6]3[CH:7]=[C:2]([F:1])[C:3]([O:30][CH3:31])=[CH:4][C:5]=3[CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:9][CH:10]=2)[N:14]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[N:13]=1)=[NH:24]
Reactant: C[O-]
Reactant: COc1cc(CC(F)(F)F)c(-c2ccc3c(C#N)nn(C4CCCCO4)c3c2)cc1F
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1nn(C2CCCCO2)c2cc(-c3cc(F)c(OC)cc3CC(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.1 %

Procedure:
To a solution of 6-[5-fluoro-4-methoxy-2-(2,2,2-trifluoro-ethyl)-phenyl]-1-(tetrahydro-pyran-2-yl)-1H-indazole-3-carbonitrile (Preparation 37, 1.737 g, 4.00 mmol) in methanol (40 mL) was added sodium methoxide (648 mg, 12.0 mmol) and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between EtOAc (50 mL) and water (50 mL) and the aqueous layer was extracted with further EtOAc (2×50 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the title compound as an oily solid (1.64 g) in an 88% yield.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:24])=[C:8]2[CH:14]=[CH:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])C.[NH2:25][CH2:26][C:27]([OH:29])=[O:28].C[O-].[Na+].CO>>[OH:24][C:7]1[C:6]([C:4]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:5])=[N:11][CH:10]=[C:9]2[N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=3)[CH:13]=[CH:14][C:8]=12
Reactant: CCOC(=O)c1ncc2c(ccn2Cc2cccc(OC)c2)c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(Cn2ccc3c(O)c(C(=O)NCC(=O)O)ncc32)c1

Procedure:
Prepared in analogy to that of Example 1(e) from 1-(3-methoxy-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 356 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1.C(N(CC)C(C)C)(C)C.Cl[C:29]1[N:34]=[C:33]([Cl:35])[N:32]=[C:31]([Cl:36])[C:30]=1[Cl:37]>C1COCC1>[CH2:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:29]2[C:30]([Cl:37])=[C:31]([Cl:36])[N:32]=[C:33]([Cl:35])[N:34]=2)[CH2:4][CH2:5]1)=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Clc1nc(Cl)c(Cl)c(Cl)n1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(CNc2nc(Cl)nc(Cl)c2Cl)CC1
Reaction time: 0.75 h

Procedure:
To a solution of benzyl 4-(aminomethyl)piperidine-1-carboxylate (EXAMPLE 13, Step 1) and N,N-diisopropylethylamine (2.6 g, 20 mmol) in THF (40 mL) at −78° C. was added a solution of tetrachloropyrimidine (4.4 g, 20 mmol). The cooling bath was removed and the solution was stirred for 45 min. The solution was concentrated and purified by filtering through a pad of silica gel using ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH2:7][C:6]2([CH3:16])[CH3:15].FC(F)(F)[C:19](O)=[O:20].C1N2CN3CN(C2)CN1C3>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH:19]=[O:20])[N:9]([CH3:13])[C:8](=[O:14])[CH2:7][C:6]2([CH3:16])[CH3:15]
Reactant: COc1ccc2c(c1)C(C)(C)CC(=O)N2C
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: COc1cc2c(cc1C=O)N(C)C(=O)CC2(C)C
Temperature: 25 °C

Procedure:
To a flame dried round bottom flask equipped with a nitrogen cap was added 83 mg (0.38 mmol) 6-methoxy-1,4,4-trimethyl-3,4-dihydro-1H-quinolin-2-one, 3 ml of trifluoroacetic acid and 53 mg (0.38 mmol) of hexamethylene tetraamine. The mixture was stirred under reflux for 1.5 hours and then cooled to ambient temperature. The reaction mixture was quenched with 30 ml of saturated aqueous bicarbonate solution and extracted with ethyl acetate (3×30 ml). The combined organics were then washed with brine followed by drying over sodium sulfate and evaporation in vacuo. The crude residue (64 mg; 68%) was used directly in the following step. Mass spectrum APCI m/e 248 (p+1).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=2)[N:3]=1.[C:23]1([CH3:35])[CH:28]=[CH:27][C:26]([S:29]([N:32]=[C:33]=[O:34])(=[O:31])=[O:30])=[CH:25][CH:24]=1>ClCCl>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:33]([NH:32][S:29]([C:26]3[CH:27]=[CH:28][C:23]([CH3:35])=[CH:24][CH:25]=3)(=[O:31])=[O:30])=[O:34])=[CH:18][CH:19]=2)[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: Cc1nn(-c2ccc(CCN)cc2)c(C)c1-c1ccccc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(-n3nc(C)c(-c4ccccc4)c3C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.5 %

Procedure:
To a solution of 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylamine (step 3, 166 mg, 0.57 mmol) in dichloromethane (10 ml) was added p-toluenesulfonyl isocyanate (135 mg, 0.68 mmol). The resulting mixture was stirred at room temperature for 30 min. The reaction mixture washed with water and the organic phase was dried (Na2SO4). After removal of the solvent, the crude product was purified by TLC with dichloromethane/methanol (10:1) to afford 110 mg (39%) of the title compound as yellow solids: MS (ESI) m/z 489 [M+H]+, 487 [M−H]−, 1H-NMR (CDCl3) δ 7.77 (2H, d, J=8.0 Hz), 7.45-7.16 (11H, m), 6.54 (1H, br.s), 3.36 (2H, br.s), 2.73 (2H, br.s), 2.31 (3H, s), 2.28 (3H, s), 2.20 (3H, s).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([CH2:15]O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:18].O.[OH-].[Na+]>C(Cl)(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([CH2:15][Br:18])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: OCC1CCCCN(Cc2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: BrCC1CCCCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
8.3 g (0.038 mol) of 1-benzyl-3-hydroxymethyl-hexahydroazepine are dissolved in 200 ml of carbon tetrachloride and 16 ml of phosphorus tribromide are added. The mixture is stirred for 6 hours at ambient temperature, water is then added whilst the mixture is cooled with ice and it is made slightly alkaline with 2-molar sodium hydroxide solution. The aqueous solution is separated off and extracted twice with methylene chloride. The organic phases are combined, dried over magnesium sulphate and concentrated by evaporation in vacuo. Yield: 8.9 g (82% of theory).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:24])[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][Si](C)(C)C)=[CH:8][C:7]=1[CH2:18][N:19]([CH:21]1[CH2:23][CH2:22]1)[CH3:20])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[CH:1]([O:4][C:5](=[O:24])[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[CH:13])=[CH:8][C:7]=1[CH2:18][N:19]([CH:21]1[CH2:23][CH2:22]1)[CH3:20])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)c1ccc(C#C[Si](C)(C)C)cc1CN(C)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(C(=O)OC(C)C)c(CN(C)C2CC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.4 %

Procedure:
A solution 2-[(cyclopropyl-methyl-amino)-methyl]-4-trimethylsilanylethynyl-benzoic acid isopropyl ester (Intermediate 121, 0.34 g, 1 mmol) in methanol (2 mL) was treated with potassium carbonate (0.207 g, 1.5 mmol) and the resulting reaction mixture was stirred at ambient temperature for 4 h. The volatiles were evaporated in vacuo, the residue was diluted with water and extracted with diethyl ether, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title compound as an oil (0.21 g, 78%).