Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[CH2:24][NH:25][CH2:26][CH3:27])[CH:7]=1)[CH3:2].[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[CH2:24][N:25]([C:32]([CH:29]2[CH2:31][CH2:30]2)=[O:33])[CH2:26][CH3:27])[CH:7]=1)[CH3:2]
Reactant: CCNCc1cc([N+](=O)[O-])ccc1Oc1cc(CC(=O)OCC)ccc1OC
Reactant: O=C(Cl)C1CC1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2CN(CC)C(=O)C2CC2)c1

Procedure:
Prepared according to the procedure described in Example 42, Step 3, using the following starting materials: [3-(2-ethylaminomethyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and cyclopropanecarbonyl chloride.
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][O:8][C:9]1[N:10]=[C:11]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]1[O:16][CH2:15][CH:14]([C@H:23]3[CH2:28][CH2:27][C@H:26]([N:29]4[C:37](=[O:38])[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[C:30]4=[O:39])[CH2:25][CH2:24]3)[NH:13][C:12]2=1.IC>CN(C)C=O>[CH3:7][O:8][C:9]1[N:10]=[C:11]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]1[O:16][CH2:15][CH:14]([C@H:23]3[CH2:24][CH2:25][C@H:26]([N:29]4[C:30](=[O:39])[C:31]5[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=5)[C:37]4=[O:38])[CH2:27][CH2:28]3)[N:13]([CH3:1])[C:12]2=1
Reactant: COc1ccc2ncc3c(c2n1)NC([C@H]1CC[C@H](N2C(=O)c4ccccc4C2=O)CC1)CO3
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc2ncc3c(c2n1)N(C)C([C@H]1CC[C@H](N2C(=O)c4ccccc4C2=O)CC1)CO3
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Cesium carbonate (119 mg, 0.36 mmol, 1.0 eq) is added at room temperature to a stirred solution of 2-[trans-4-(6-methoxy-3,4-dihydro-2H-1-oxa-4,5,9-triaza-phenanthren-3-yl)-cyclohexyl]-isoindole-1,3-dione (190 mg, 0.36 mmol, 1.0 eq) in N,N-dimethylformamide (3 mL), followed by iodomethane (23 μL, 0.36 mmol, 1.0 eq). After 5 hours stirring at room temperature, one additional equivalent of iodomethane is added to the reaction mixture and, after 2 hours stirring, solvent is removed to give a residue that is extracted with ethyl acetate (3×10 mL) and water (10 mL). The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: cyclohexane:ethyl acetate:methanol, 1:3:0 to 0:1:0 to 0:9:1, v/v/v) to afford 2-[trans-4-(6-methoxy-4-methyl-3,4-dihydro-2H-1-oxa-4,5,9-triaza-phenanthren-3-yl)-cyclohexyl]-isoindole-1,3-dione as an orange solid (113 mg, 54% yield).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1>CN1CCCC1=O>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1
Reactant: Nc1ccc(O)cc1
Reactant: Clc1nc2ccccc2s1
Solvent: CN1CCCC1=O
Product: Oc1ccc(Nc2nc3ccccc3s2)cc1

Procedure:
The solution of 2-chlorobenzothiazole (2.47 mL, 20 mmol) and 4-aminophenol (2.18 g, 20.0 mmol) in N-methylpyrrolidone (16 mL) was heated at 160° C. for 7 h. The reaction mixture was quenched with aqueous 2N NaOH and then extracted with EtOAc. The organic layer was washed with 2N NaOH. To the combined aqueous layer was added aqueous 5N HCl until pH 6, then the product was extracted with EtOAc (2×), dried (Na2SO4) and concentrated. The crude product was dissolved in MeOH and treated with SiO2. Chromatography through a Redi-Sep® pre-packed silica gel column (120 g), eluting with a gradient of 0% to 50% EtOAc in hexane, provided 4-(benzo[d]thiazol-2-ylamino)phenol as a tan solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[C:4]([CH:11]=[CH2:12])[N:3]=1.[F:13][C:14]1[CH:35]=[CH:34][C:17]([O:18][C:19]2[CH:24]=[CH:23][C:22](B3OC(C)(C)C(C)(C)O3)=[CH:21][CH:20]=2)=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>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:13][C:14]1[CH:35]=[CH:34][C:17]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:2]3[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[C:4]([CH:11]=[CH2:12])[N:3]=3)=[CH:21][CH:20]=2)=[CH:16][CH:15]=1
Reactant: C=Cc1cc(C(=O)O)nc(Cl)n1
Reactant: CC1(C)OB(c2ccc(Oc3ccc(F)cc3)cc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C=Cc1cc(C(=O)O)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Temperature: 90 °C
Yield: 82 %

Procedure:
As shown in Scheme 4, a suspension of 2-chloro-6-vinylpyrimidine-4-carboxylic acid (9) (4.38 g, 0.02 mol), 2-(4-(4-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (22) (7.45 g, 0.02 mol), Na2CO3 (5.3 g, 0.05 mol), and PdCl2(PPh3)2 (Aldrich, 701 mg, 1.0 mmol) in dimethoxy ethane(DME)/EtOH/H2O (500 mL, 2:1:2 ratio) was degassed by repeating with Ar2/vacuum cycles. The mixture was heated at 90° C. for 23 h. Upon cooling to the room temperature, the mixture was poured into DCM. The solids were filtered off and the filtrates were washed with H2O and the aqueous phase was extracted with EtOAc. The combined organic layers were dried with anhydrous MgSO4 and concentrated to give 2-(4-(4-fluorophenoxy)phenyl)-6-vinylpyrimidine-4-carboxylic acid (23) pale yellow oil which was then purified by column chromatography (EtOAc:Hexanes=1:1) to give 6.5 g (82% yield), Rf=0.3 (DCM:MeOH=9:1); LC/MS: m/z=337 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[N:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:13]([N+:21]([O-])=O)=[C:12]([NH:24][CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[N:11]=3)[C:6]=2[CH:31]=1.[H][H]>C(O)C.[Pd]>[NH2:21][C:13]1[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:15][C:10]([N:7]2[C:6]3[CH:31]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)=[N:11][C:12]=1[NH:24][CH:25]1[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1
Reactant: CCOC(=O)c1nc(-n2cnc3ccc(F)cc32)nc(NC2CCOCC2)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1nc(-n2cnc3ccc(F)cc32)nc(NC2CCOCC2)c1N
Reaction time: 10 h
Yield: 76.6 %

Procedure:
Hydrogenation of ethyl 2-(6-fluoro-1H-benzo[d]imidazol-1-yl)-5-nitro-6-(tetrahydro-2H-pyran-4-ylamino)pyrimidine-4-carboxylate (310 mg, 0.717 mmol) was performed in ethanol, using Pd/C (10%), under a positive pressure of hydrogen. After 10 h, the catalyst was filtered, washed with portions of methylene chloride, and the combined filtrate concentrated to give the desired amine as a white solid (220 mg, 78% yield). 1H NMR (400 MHz, DMSO-d6) δ, ppm: 8.97 (s, 1H), 8.47 (dd, J=2.6, 2.2 Hz, 1H), 7.74 (m, 1H), 7.60 (d, J=8.9 Hz, 2H), 7.16 (m, 1H), 6.74 (d, J=8.3 Hz, 1H), 4.37-4.32 (m, 3H), 3.94 (d, J=10.4 Hz, 2H), 3.55 (t, J=10.4 Hz, 2H), 2.01 (m, 2H), 1.58 (m, 2H), 1.42 (t, J=7.1 Hz, 3H); LCMS (EI) m/z 401 (MH)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[C:4]([C:12]2[NH:20][C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[CH:13]=2)=[CH:3]1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:8][CH:9]=2)[C:4]([C:12]2[NH:20][C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[CH:13]=2)=[CH:3]1
Reactant: Cn1cc(-c2cc3cccnc3[nH]2)c2cc(N)ccc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(-c2cc3cccnc3[nH]2)c2cc(NS(C)(=O)=O)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indol-5-ylamine [52.4 mg, Example 18] in dichloromethane (5 mL) was treated with triethylamine (30 μl) followed by methane sulfonyl chloride (17 μl). After stirring at ambient temperature for 16 hours the reaction mixture was diluted with dichloromethane (10 mL), then washed with water (10 mL), then washed with brine (10 mL), then dried over magnesium sulfate and then evaporated. The residual solid was triturated with diethyl ether to give the title compound as a yellow solid, m.p. 223-224° C. MS: 341 (MH+).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[C:3]=1[C:17]([OH:19])=O.Cl.C(N=C=NCCCN(C)C)C.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:37]=[CH:38][CH:39]=1>ClCCl>[CH3:32][O:33][C:34]1[CH:35]=[C:36]([N:40]2[CH2:45][CH2:44][N:43]([C:17]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[O:19])[CH2:42][CH2:41]2)[CH:37]=[CH:38][CH:39]=1
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: Cc1onc(-c2cccc(C(F)(F)F)c2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1cccc(N2CCN(C(=O)c3c(-c4cccc(C(F)(F)F)c4)noc3C)CC2)c1
Yield: 74.5 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-methyl-3-(3-(trifluoromethyl)phenyl)isoxazol-4-carboxylic acid (500 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3-methoxyphenyl)piperazine (354 mg, 1.84 mmol), a gel-like required compound (602 mg, 1.37 mmol, 75%) was obtained.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].C[N:9](C)[CH2:10][CH2:11][NH2:12].CN1CCOCC1>ClCCl>[CH:3]([CH2:2][C:1]([NH:9][CH2:10][CH2:11][NH2:12])=[O:6])([CH3:5])[CH3:4]
Reactant: CC(C)CC(=O)Cl
Reactant: CN(C)CCN
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)CC(=O)NCCN
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Isovaleroyl chloride (5 g, 38 mmole) in dichloromethane was added dropwise to a stirred solution of N,N-dimethylethylene diamine (3,38 g, 38 mmole) and NMM (7.75 g, 76.7 mmoles) in CH2Cl2 at 0° C. The reaction mixture was stirred at room temperature for four hours when the solvent was evaporated. The residue was taken up in 5 M NaOH (50 ml) and extracted with ethyl acetate (2×100 ml). The ethyl acetate was washed with a saturated aqueous solution of sodium chloride, dried (Na2SO4) and evaporated. The residue was dissolved in diethyl ether and 5 M HCl in ethyl acetate (10 ml) added. The resulting solid was filtered, washed with diethyl ether (5+10 ml) and dried under high vacuum.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[C:15]1(O)[CH2:24][CH2:23][C:18]2([O:22][CH2:21][CH2:20][O:19]2)[CH2:17][CH2:16]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[C:15]1[CH2:24][CH2:23][C:18]2([O:19][CH2:20][CH2:21][O:22]2)[CH2:17][CH:16]=1
Reactant: COCOc1ccc(C2(O)CCC3(CC2)OCCO3)c(OCOC)c1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COCOc1ccc(C2=CCC3(CC2)OCCO3)c(OCOC)c1
Yield: 70.7 %

Procedure:
8-[2,4-Bis(methoxymethoxy)phenyl]-1,4-dioxaspiro[4.5]decan-8-ol (1.40 g, 3.95 mmol) was placed in a 50 ml round bottomed flask equipped with magnetic stirrer and Dean-Stark apparatus. Toluene (30 ml) was added, followed by camphor sulphonic acid (10 mg). The stirred solution was then heated under reflux for 1 hr, cooled and saturated aqueous sodium bicarbonate solution (10 ml) added. The mixture was poured into a separating funnel and the phases separated. The aqueous phase was extracted with ethyl acetate (2×15 ml) and the combined organics were washed with brine (15 ml), dried over anhydrous magnesium sulphate, filtered and then concentrated in vacuo yielding an orange oil which was purified by flash column chromatography (SiO2, ethyl acetate/petroleum ether, 45:55, v/v) to afford the title product (0.94 g) as a colourless oil. δH (CDCl3) 1.84 (2H, t), 2.41-2.43 (2H, m), 2.56-2.62 (2H, m), 3.47 (6H, s), 3.98-4.02 (4H, m), 5.13 (4H, s), 5.58-5.63 (1H, m), 6.64 (1H, dd), 6.78 (1H, d), 7.08 (1H, d).
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].Br[CH2:15][C:16]1[CH:35]=[CH:34][C:19]2/[C:20](=[C:30](/[CH3:33])\[C:31]#[N:32])/[C:21]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=3[O:23][CH2:24][C:18]=2[CH:17]=1.O>C1COCC1>[C:31](/[C:30](=[C:20]1/[C:21]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=2[O:23][CH2:24][C:18]2[CH:17]=[C:16]([CH2:15][CH:3]([C:2](=[O:1])[CH2:9][CH2:10][CH3:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:35]=[CH:34][C:19]/1=2)/[CH3:33])#[N:32]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCC(=O)C(Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
[step 1] Ethyl 3-oxohexanoate (883 mg, 5.58 mmol) was dissolved in THF (9 mL), sodium hydride (60% w/w, 190 mg, 4.75 mmol) was added, and the mixture was stirred at room temperature for 30 min. To the mixture was added dropwise a solution (9 mL) of (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (1.0 g, 2.79 mmol) obtained in Reference Example 1 in tetrahydrofuran, and the mixture was stirred at room temperature overnight. Water was added to the mixture, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1 v/v) to give (E)-ethyl 2-{[11-(1-cyanoethylidene)-3-fluoro-6,11-dihydrodibenzo[b,e]oxepin-8-yl]methyl}-3-oxohexanoate (1.19 g, 98%).
Reaction SMILES: [CH:1]1([C:4]2[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH3:13])[C:5]=2[CH:6]=[O:7])[CH2:3][CH2:2]1.Cl([O-])=[O:15].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.CC(=CC)C.O>[CH:1]1([C:4]2[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH3:13])[C:5]=2[C:6]([OH:15])=[O:7])[CH2:2][CH2:3]1
Reactant: [O-][Cl+][O-]
Reactant: CCc1cccc(C2CC2)c1C=O
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCc1cccc(C2CC2)c1C(=O)O
Temperature: 25 °C

Procedure:
2-Cyclopropyl-6-ethyl-benzaldehyde (CAS 945408-11-7) (500 mg, 2.9 mmol) was dissolved in 3.5 mL tert butanol and 1.7 mL 2-methyl-2-butene. At 0° C. a solution of sodium chlorite (80% purity, 422 mg, 3.8 mmol) and sodium dihydrogenphosphate (452 mg, 3.8 mmol) in 3 mL water was added slowly. The reaction mixture was stirred at room temperature over night. The solvents were evaporated off. The residue was taken up in 1N sodium hydroxide solution and was extracted with tert butyl methylether. The aqueous phase was adjusted at pH 1 with 25% HCl and extracted twice with tert butyl methylether. The combined organic phases were dried on sodium sulfate, filtered and evaporated. The crude product was used without any further purification, white solid (412 mg, 75%), MS: m/e=189.3 [(M−H)−].
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH3:27][CH:28]([OH:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:35][CH:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH3:27])[CH:7]=1
Reactant: CC(O)c1ccccc1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Product: CC(Oc1cc(F)ccc1-c1ncnc(Nc2cccc(CS(C)(=O)=O)c2)n1)c1ccccc1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (50 mg; 0.129 mmol), intermediate 42.1, and DL-1-phenylethanol (63 mg; 0.515 mmol), example 68 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [C:1]([O:20][CH2:21][CH:22]([OH:44])[CH2:23][O:24][C:25]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:45][C:46]1[CH:51]=[CH:50][C:49](O)=[CH:48][CH:47]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[I:45][C:46]1[CH:51]=[CH:50][C:49]([O:44][CH:22]([CH2:21][O:20][C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:23][O:24][C:25]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:48][CH:47]=1
Reactant: OC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Oc1ccc(I)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Ic1ccc(OC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 8 h
Yield: 89.9 %

Procedure:
Compound 1 (5.0 g, 8.67 mmol), 4-iodophenol (2.10 g, 9.54 mmol) and triphenyl phosphine (2.5 g, 9.5 mmol) were dissolved in dry THF (35 mL). Diisopropyl azodicarboxylate (1.88 mL, 9.5 mmol) was added dropwise during 15 min, and the reaction was allowed to proceed overnight at RT. All volatiles were removed in vacuo. Purification on silica gel (eluent, petroleum ether, bp 40-60° C.: dichloromethane, 1:1, v/v) yielded 6.07 g of the title compound. 1H NMR (CDCl3): 7.49 (2H, d, J 9.1); 7.37-7.21 (30H); 6.62 (2H, d, J 9.1). 4.43 (1H, m); 3.40 (4H, m).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:12][CH2:13][CH3:14])=[CH:8][NH:9]2)=[CH:5][CH:4]=1)=[O:2].[H-].[Na+].Br[CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][C:20]=1[O:29][CH3:30]>CN(C)C=O>[CH3:30][O:29][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:19]=1[CH2:18][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([CH:1]=[O:2])[CH:11]=2)[C:7]([CH2:12][CH2:13][CH3:14])=[CH:8]1)[C:23]([O:25][CH3:26])=[O:24]
Reactant: CCCc1c[nH]c2cc(C=O)ccc12
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1cn(Cc2ccc(C(=O)OC)cc2OC)c2cc(C=O)ccc12
Reaction time: 1 h
Yield: 97.6 %

Procedure:
6-Formyl-3-propylindole (1.0 g) in N,N-dimethylformamide (DMF) (10 ml) was added slowly to a stirred suspension of sodium hydride (0.128 g, oil-free) in dry DMF (30 ml) at 0° under an atmosphere of nitrogen. The mixture was stirred at 0° for 60 min and methyl 4-bromomethyl-3-methoxybenzoate (1.38 g) in dry DMF (10 ml) was added dropwise. The cooling bath was removed, the mixture stirred for 3.5 hr, then poured into 1N hydrochloric acid (75 ml), and extracted with ethyl acetate (15 ml). The organic extract was washed (water (twice), brine), dried (MgSO4) and evaporated to give a dark oil. The product was purified by flash chromatography, eluting with 55:40:5 hexane:methylene chloride:ethyl acetate, to give methyl 3-methoxy-4-(6-formyl-3-propylindol-1-ylmethyl)benzoate (1.9 g, 97%) as a yellow oil; partial NMR(250 MHz, DMSO-d6): 0.95(t, 3H, CH2CH3), 1.65(m, 2H, CH2CH3), 2.70(t, 2H, CH2CH2CH3), 3.83(s, 3H, OCH3), 3.95(s, 3H, OCH3), 5.50(s, 2H, NCH2), 9.96(s, 1H, CHO).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C(Cl)(=O)C(Cl)=O.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][NH2:33])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>ClCCl>[C:18]([O:22][C:23]([N:25]1[CH2:26][CH2:27][N:28]([CH2:31][CH2:32][NH:33][C:9](=[O:11])[CH:8]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:29][CH2:30]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C(O)C=Cc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCN(CCN)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(CCNC(=O)C=Cc2cccnc2)CC1

Procedure:
Batch size: 36.1 g (242 mmol) 3-(3-pyridyl)-acrylic acid, 23.1 ml (264 mmol) oxalyl chloride, 50 g (15.4 mmol) 2-[4-(tert-but-oxycarbonyl)-piperazin-1-yl]-ethylamine and 30.4 ml (220 mmol) TEA in 400 ml absolute dichloromethane.
Reaction SMILES: C(O)(=[O:3])C.O.[C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])[CH3:7]>O1CCOCC1>[O:8]=[C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:7]=[O:3]
Reactant: CC(=O)O
Reactant: CC(=O)c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: O=CC(=O)c1ccccc1
Temperature: 80 °C
Yield: 142 %

Procedure:
Add SeO2 (4.6 g; 0.042 mol; 1.0 equiv), acetic acid (1.2 mL; 0.021 mol; 0.5 equiv), water (1.5 mL; 0.083 mol; 2.0 equiv) in 1,4-dioxane (15 mL) and stir at 80° C. until the solution becomes clear. Cool the reaction to RT, add acetophenone (5.0 g; 0.042 mol; 1.0 equiv) and stir at 80° C. for 18 h. Cool the reaction to RT, filter through Celite®, wash the residue with EA, and dry over anhydrous sodium sulfate. Evaporate the organic layer, purify over 50 g silica using EA in hexane to produce the title compound (4.0 g, 72.7%). MS (ES+): m/z=135 (M+H)
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[CH3:11][C:12]([CH3:26])([CH2:23][CH2:24]C)[CH2:13][NH:14][C:15]1[N:16]([CH3:22])[N:17]=[C:18]([CH3:21])[C:19]=1[NH2:20].[K+].[Br-]>>[CH3:26][C:12]([CH3:11])([CH2:23][CH3:24])[CH2:13][NH:14][C:15]1[N:16]([CH3:22])[N:17]=[C:18]([CH3:21])[C:19]=1[NH:20][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: CCCC(C)(C)CNc1c(N)c(C)nn1C
Reactant: N#Cc1ccc(C=O)cc1
Agent: [Br-]
Agent: [K+]
Product: CCC(C)(C)CNc1c(NCc2ccc(C#N)cc2)c(C)nn1C
Yield: 19 %

Procedure:
The title compound was prepared according to the procedure of Example 1, Step 5 except that 4-cyanobenzaldehyde was used in place of 4-pyridinecarboxaldehyde and N(3)-(2,2-dimethyl-pentyl)-2,5-dimethyl-2H-pyrazole-3,4-diamine was used in place of N(3)-(2,2-dimethyl-propyl)-2,5-dimethyl-2H-pyrazole-3,4-diamine. Yellow oil, yield: 19%, 1H NMR (300 MHz, CDCl3): δ0.83 (t, 3H), 0.89 (s, 6H), 1.28 (q, 2H), 2.10 (s, 3H), 2.61 (s, 2H), 3.59 (s, 3H), 4.04 (s, 2H), 7.42 (d, 2H), 7.61 (d, 2H), IR (KBr, cm−1): 3340m, 2961s, 2877m, 2226s, 1588m, 1565m, 1537m, 1462m, 1378m, 1365m, 1296w, 821w, MS (ES) m/z (relative intensity): 326 (M+H+, 100).
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2]O.[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([NH2:16])[CH:10]=1)([O-:8])=[O:7].[OH-].[Na+]>Cl.O>[N+:6]([C:9]1[CH:14]=[CH:13][C:12]2[NH:15][C:2]([CH2:1][OH:5])=[N:16][C:11]=2[CH:10]=1)([O-:8])=[O:7]
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: O=C(O)CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc2[nH]c(CO)nc2c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
6.2 g (81.5 mmol) glycolic acid is added to a solution of 6.24 g (40.8 mmol) 4-nitro-o-phenylenediamine in 80 mL semiconcentrated HCl. The reaction solution is refluxed for 4 h and the solvent is eliminated i.vac. The residue is taken up in water and made basic with 2 N NaOH. The product precipitates out and is stirred for another 1 hour in the ice bath. The precipitate is suction filtered and washed successively with water and PE. The product is dried at 40° C. This still contains 40% 4-nitro-o-phenylenediamine. It is again taken up in semiconcentrated HCl and after the addition of 6.5 mL glycolic acid (57% in water) it is refluxed for 3 h and heated for a further 12 h at 80° C. The solvent is eliminated i.vac. and the residue is dissolved in water and made alkaline with 6 N NaOH, during which time the product is precipitated. The precipitate is suction filtered and washed successively with water and PE. The product is dried in the circulating air dryer at 50° C.