Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[CH3:17][O:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[CH3:17][O:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:22]
Reactant: COc1ccccc1C(=O)Cl
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Product: COc1ccccc1C(=O)Nc1cccc(C(=O)C2CCN(C)CC2)c1
Yield: 77.6 %

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (50 mg, 0.229 mmol) and 2-methoxybenzoyl chloride (102 μl, 0.685 mmol), 62.6 mg (78%) of the title compound were recovered.
Reaction SMILES: [CH:1]([C:4]1[N:8]2[N:9]=[CH:10][C:11]3[C:16]([C:7]2=[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]=1[CH2:23]/[CH:24]=[CH:25]/[OH:26])=[CH:15][CH:14]=[CH:13][CH:12]=3)([CH3:3])[CH3:2]>C(OCC)C.[O-2].[O-2].[Mn+4]>[CH:1]([C:4]1[N:8]2[N:9]=[CH:10][C:11]3[C:16]([C:7]2=[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]=1/[CH:23]=[CH:24]/[CH:25]=[O:26])=[CH:15][CH:14]=[CH:13][CH:12]=3)([CH3:3])[CH3:2]
Reactant: CC(C)c1c(C/C=C/O)c(-c2ccccc2)c2c3ccccc3cnn12
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOCC
Product: CC(C)c1c(/C=C/C=O)c(-c2ccccc2)c2c3ccccc3cnn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
A mixture of activated manganese dioxide (2.18 g) and (E)-3-(3-isopropyl-1-phenylpyrrolo[2,1-a]-phthalazin-2-yl)propen-1-ol (0.77 g) in anhydrous diethyl ether (50 ml) was stirred at the ambient temperature under an atmosphere of argon for 2 hours. The suspension was then filtered and the solid was washed thoroughly with diethyl ether (4×25 ml). The filtrate was evaporated, to give a yellow oil, which was triturated with a mixture of petroleum ether (b.p. 40°-60° C.) and diethyl ether (5 ml; 3:1 v/v) and the solid which separated was collected, to give (E)-3-(3-isopropyl-1-phenylpyrrolo[2,1-a]phthalazin-2-yl)propenal (0.56 g) in the form of a yellow solid, m.p. 162°-164° C. [Elemental analysis: C., 81.5; H, 6.07; N, 8.2%; calculated: C, 81.1; H, 5.92; N, 8.2%; NMR (in CDCl3): 1.6 (6H, d, J=7 Hz), 3.89 (1H, septet J=7 Hz), 5.83 (1H, dd, J=16 Hz, 8 Hz), 7.13-7.68 (10H, m), 8.29 (1H, s), 9.41 (1H, d, J=8 Hz); Mass spectrum (electron impact) m/z=340].
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:4][CH2:3]1.[C:19]1([CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:11][C:10]([O:9][C:7]([NH:6][C@H:5]([CH2:4][CH2:3][C:2](=[O:1])[C:30]1[CH:31]=[CH:32][C:27]([O:26][CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:28][CH:29]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:8])([CH3:13])[CH3:12]
Reactant: Ic1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Product: CCOC(=O)[C@@H](CCC(=O)c1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized (2.9 g, 16%) following a similar procedure as set out earlier in Description 6 starting from 1-(1,1-dimethylethyl) 2-ethyl (2R)-5-oxo-1,2-pyrrolidinedicarboxylate (D32, 10.5 g 40.8 mmol) and 4-iodophenyl phenylmethyl ether (13.34 g, 43 mmol); Rt (HPLC): 6.37 min; MS: (ES/+) 464 m/z: [M+Na+], C25H31NO6 requires 441; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.92 (d, 2H); 7.29-7.45 (m, 5H); 6.99 (d, 2H); 5.18 (bs, 1H); 5.12 (s, 2H); 4.29-4.4 (bm, 1H); 4.20 (q, 2H); 2.94-3.16 (m, 2H); 2.22-2.33 (m, 1H); 2.00-2.15 (m, 1H); 1.39 (s, 9H); 1.28 (t, 3H).
Reaction SMILES: [CH2:1]([C:4]([N:23]=C(C1C=CC=CC=1)C1C=CC=CC=1)([CH2:10][CH2:11][CH2:12][CH2:13][B:14]1[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:22])([CH3:21])[O:15]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:2]=[CH2:3].Cl>C(OCC)C>[CH2:1]([C:4]([NH2:23])([CH2:10][CH2:11][CH2:12][CH2:13][B:14]1[O:15][C:16]([CH3:22])([CH3:21])[C:17]([CH3:20])([CH3:19])[O:18]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCC(CCCCB1OC(C)(C)C(C)(C)O1)(N=C(c1ccccc1)c1ccccc1)C(=O)OCC
Agent: Cl
Solvent: CCOCC
Product: C=CCC(N)(CCCCB1OC(C)(C)C(C)(C)O1)C(=O)OCC
Reaction time: 16 h
Yield: 94.6 %

Procedure:
A solution of ethyl 2-allyl-2-(diphenylmethyleneamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (0.32 g, 0.65 mmol) in diethyl ether (3.4 mL, 0.2 M) was treated with 1N HCl (3 mL). After stirring 16 h, the layers were separated and the aqueous phase was diluted with saturated aqueous K2CO3 and extracted with chloroform to give ethyl 2-allyl-2-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate as a colorless oil (0.20 g, 94%). Rf 0.62 (10% methanol in dichloromethane); 1H NMR (CDCl3, 300 MHz) δ 5.76-5.60 (m, 1H), 5.18-5.07 (m, 2H), 4.15 (q, J=7.2 Hz, 2H), 2.54 (ddt, J1=13.5 Hz, J2=6.3 Hz, J3=1.2 Hz, 1H), 2.23 (dd, J1=13.5 Hz, J2=8.7 Hz, 1H), 1.8-1.68 (m, 2H), 1.70-1.60 (m, 1H), 1.60-1.46 (m, 2H), 1.46-1.32 (m, 3H), 1.24 (s, 12H), 1.20-1.06 (m, 1H), 0.766 (t, J=7.8 Hz, 2H); ESI-LCMS m/z calcd for C17H32BNO4: 325.2. found 326.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[C:11]([CH:12]=1)=[N:10][C:9](=O)[N:8]1[NH:14][CH:15]=[N:16][C:7]=21.O(Cl)[Cl:20].CN(C)C1C=CC=CC=1>>[Cl:20][C:9]1[N:8]2[N:14]=[CH:15][N:16]=[C:7]2[C:6]2[CH:5]=[C:4]([O:17][CH3:18])[C:3]([O:2][CH3:1])=[CH:12][C:11]=2[N:10]=1
Reactant: ClOCl
Reactant: COc1cc2nc(=O)n3[nH]cnc3c2cc1OC
Solvent: CN(C)c1ccccc1
Product: COc1cc2nc(Cl)n3ncnc3c2cc1OC

Procedure:
300 mg of 8,9-Dimethoxy-1,2,4-triazolo-[1,5-c]quinazoline-5-one is refluxed with 5 ml Phospherous oxychloride and a catalytic amount of N,N-dimethylamline for 18 hours. The reaction mixture is then evaporated in vacuo to dryness; the residue taken up in methylene chloride and the methylene chloride layer extracted several times with cold sodium bicarbonate solution, with water, dried and then avaporated in vacuo to dryness. The residue is crystallized from methylene chloride/diethyl ether to give 5-chloro-8,9-dimethoxy-1,2,4-triazolo-[1,5-c]-quinazoline, m.p. 258°-260°.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=1)[C:4]#[C:5][CH3:6].[CH2:19]([O:21][C:22]([C:24]1[C:25](Cl)=[C:26]2[C:32]([CH3:33])=[N:31][O:30][C:27]2=[N:28][CH:29]=1)=[O:23])[CH3:20]>CN1CCCC1=O>[CH2:19]([O:21][C:22]([C:24]1[C:25]([N:17]([S:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH2:3][C:4]#[C:5][CH3:6])=[CH:9][CH:10]=2)(=[O:15])=[O:16])[CH3:18])=[C:26]2[C:32]([CH3:33])=[N:31][O:30][C:27]2=[N:28][CH:29]=1)=[O:23])[CH3:20]
Reactant: CCOC(=O)c1cnc2onc(C)c2c1Cl
Reactant: CC#CCOc1ccc(S(=O)(=O)NC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC#CCOc1ccc(S(=O)(=O)N(C)c2c(C(=O)OCC)cnc3onc(C)c23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
To a suspension of 0.105 g (0.63 mmol) of 60% sodium hydride in 8 mL of 1-methyl-2-pyrrolidinone was added 0.628 g (2.63 mmol) of the product of Example 5 and the resulting mixture was stirred for 30 minutes at room temperature. A solution of 0.601 g (2.50 mmol) of ethyl-4-chloro-3-methylisoxazolo[5,4-b]pyridine-5-carboxylate in 7 mL of 1-methyl-2-pyrrolidinone was added and the reaction was heated to 80-90° C. for 48 h. The reaction mixture was then concentrated in vacuo and the residue was diluted with dichloromethane. The organics were washed with water, 2N citric acid solution and brine, dried over Na2SO4, filtered through Magnesol® and concentrated in vacuo. The residue was triturated with ethyl acetate/hexanes and the resulting solid was filtered and dried in vacuo to provide 1.0 g (90%) of the product as a solid; m.p.85-90° C. Electrospray Mass Spec: 444 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]1>>[Br:1][C:2]1[C:3]([N:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:22]2)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1cccnc1
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccnc4)c23)C1
Yield: 34 %

Procedure:
Solid (R)-tert-butyl 1-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (52 mg, 34% yield) was prepared as described in Example 1, Step J, using N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (100 mg, 0.298 mmol, Example 1, Step I) and substituting (R)-tert-butyl piperidin-3-ylcarbamate (179 mg, 0.895 mmol) for tert-butyl piperidin-3-ylcarbamate.
Reaction SMILES: O[C@@H]([C@@H](CCCC1C=CC=CC=1)C(O)=O)C(N1CCOCC1)=O.C[O:25][C:26](=[O:47])[C@@H:27]([CH:37]([F:46])[C:38]([N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)=[O:39])[CH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[F:46][CH:37]([C@@H:27]([CH2:28][CH2:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:26]([OH:47])=[O:25])[C:38]([N:40]1[CH2:41][CH2:42][O:43][CH2:44][CH2:45]1)=[O:39]
Reactant: COC(=O)[C@H](CCCc1ccccc1)C(F)C(=O)N1CCOCC1
Agent: O=C(O)[C@H](CCCc1ccccc1)[C@H](O)C(=O)N1CCOCC1
Product: O=C(O)[C@H](CCCc1ccccc1)C(F)C(=O)N1CCOCC1

Procedure:
It is similarly prepared according to the procedure of (22), but using (S)-2-(1-Fluoro-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid methyl ester (6a).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[O:13][C:12]([CH:14]=[O:15])=[CH:11][CH:10]=1.[CH3:16][Mg]Cl.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CC(OC)(C)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[O:13][C:12]([CH:14]([OH:15])[CH3:16])=[CH:11][CH:10]=1
Reactant: C[Mg]Cl
Reactant: O=Cc1ccc(COC2CCCCO2)o1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: COC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1ccc(COC2CCCCO2)o1
Temperature: 1 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
Crude 5-(tetrahydro-pyran-2-yloxymethyl)-furan-2-carbaldehyde (171 g) was dissolved in THF (1 L) and cooled to 1° C. Methylmagnesium chloride (3 M in THF, 325 mL, 0.97 mol) was then added while keeping the internal temperature below 5° C. After the addition, the reaction mixture was stirred at rt for 1 h. Water (1 L), TBME (1 L) and 40% aq. citric acid (200 mL) were added, the layers separated and the org. layer washed with water (500 mL) and evaporated to dryness to give 174 g of crude 1-[5-(tetrahydro-pyran-2-yloxymethyl)-furan-2-yl]-ethanol (95% yield). Part of the crude material (96 g, 0.43 mol) was dissolved in CH2Cl2 (1 L) and treated with MnO2 (371 g, 4.26 mol) at rt. The reaction mixture was heated to 45° C. and stirred at this temperature for 24 h. The mixture was then filtered over celite and the filter cake washed with CH2Cl2. The filtrate was evaporated to dryness to give crude 1-[5-(tetrahydro-pyran-2-yloxymethyl)-furan-2-yl]-ethanone (89 g, 93%) as a yellow oil.
Reaction SMILES: [C:1]([C:3]1([CH2:19][CH2:20]Br)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][CH2:6][C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]1=2)#[N:2].[ClH:22].[CH:23]12[CH2:30][CH2:29][CH:26]([CH2:27][CH2:28]1)[CH2:25][NH:24]2.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>C(OCC)C.C(Cl)Cl.C(O)(C)C.O>[ClH:22].[C:1]([C:3]1([CH2:19][CH2:20][N:24]2[CH2:25][CH:26]3[CH2:29][CH2:30][CH:23]2[CH2:28][CH2:27]3)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][CH2:6][C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]1=2)#[N:2]
Reactant: C1CC2CCC1CN2
Reactant: N#CC1(CCBr)c2ccccc2CCCc2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CCOCC
Solvent: O
Product: N#CC1(CCN2CC3CCC2CC3)c2ccccc2CCCc2ccccc21
Temperature: 100 °C

Procedure:
3.1 Parts 12-cyano-12-(2-bromoethyl)-5,6,7,12-tetrahydrodibenzo[a,d]cyclooctene, 1.8 parts 2-azabicyclo[2.2.2]octane hydrochloride, 1.8 parts potassium carbonate, 44 parts dimethylsulfoxide and 10 parts water are combined, heated at 100° C. for about 4 hours, and then poured into an ice-water mixture. The resulting gummy precipitate is dissolved in a mixture of ethyl ether and methylene chloride. The organic phase is separated, washed three times with water, dried with sodium sulfate, filtered, and the solvents removed to leave an oil. This oil is dissolved with a solution of HC1 in isopropanol, and precipitated with ethyl ether to give 12-cyano12-[2-(2-azabicyclo[2.2.2]oct-2-yl)ethyl]-5,6,7,12-tetrahydrodibenzo[a,d]cyclooctene hydrochloride. This compound is represented by the following structural formula. ##STR17##
Reaction SMILES: [OH:1][NH:2][C:3]([NH2:5])=[O:4].C(O[CH:9](OCC)[CH2:10][CH:11](OCC)OCC)C.[ClH:21]>>[ClH:21].[N+:2]1([O-:1])[C:3]([OH:4])=[N:5][CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(CC(OCC)OCC)OCC
Reactant: NC(=O)NO
Agent: Cl
Product: [O-][n+]1cccnc1O
Temperature: 1.5 °C

Procedure:
0.261 mol (19.85 g) hydroxy urea have been dissolved in 390 ml 1 M HCl and 0.235 mol (51.77 g) 1,1,3,3-tetraethoxypropane were added dropwise under ice cooling, with the internal temperature being maintained at 1-2° C. The solution was thawed in an ice bath to room temperature and stirred over night, then evaporated to dryness. The residue was suspended with 250 ml of acetone, the mixture was cooled in an ice/ethanol bath, the solid filtered off and washed with a little ice-cold acetone. After drying, 24.5 g of crude product were obtained. The crude product was recrystallized with 460 ml of methanol from the boiling heat, cooled in an ice/ethanol bath, filtered off and dried. The mother liquor was concentrated on a rotary evaporator until again product started to precipitate, then a second fraction was crystallized similarly. After drying 11.8 g (1. fraction) and 5.9 g (2. fraction) the title compound were obtained.
Reaction SMILES: C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[CH3:16][O:17][C:18]1[CH:19]=[C:20](/[CH:30]=[CH:31]/[C:32]([OH:34])=O)[CH:21]=[CH:22][C:23]=1[N:24]1[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]1.[NH2:35][N:36]1[CH2:41][CH2:40][CH2:39][CH:38]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[Br:48])[C:37]1=[O:49].O>CN(C=O)C.C(OCC)(=O)C>[Br:48][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=1[CH:38]1[CH2:39][CH2:40][CH2:41][N:36]([NH:35][C:32](=[O:34])/[CH:31]=[CH:30]/[C:20]2[CH:21]=[CH:22][C:23]([N:24]3[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]3)=[C:18]([O:17][CH3:16])[CH:19]=2)[C:37]1=[O:49]
Reactant: NN1CCCC(c2ccccc2Br)C1=O
Reactant: COc1cc(/C=C/C(=O)O)ccc1-n1cnc(C)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(/C=C/C(=O)NN2CCCC(c3ccccc3Br)C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.3 %

Procedure:
BOPCl (1.48 g) was added to a suspension of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (1.0 g), 1-amino-3-(2-bromophenyl)piperidin-2-one (1.26 g) and TEA (1.1 mL) in DMF (20 mL), and the reaction solution was stirred at room temperature for three hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The resulting organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: ethyl acetate-methanol system) to obtain 1.130 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)=[O:2].[CH2:12]=[O:13].C(N(CC)CC)C>CC(C)=O>[CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][OH:13])[CH:4]=1)=[O:2]
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: C=O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=Cc1cn(CO)c2ccccc12
Temperature: 120 °C
Reaction time: 3 h
Yield: 43.9 %

Procedure:
The mixture of 5.81 g of 3-formyl-1H-indole, 1.80 g of paraformaldehyde and 0.40 g of triethylamine was stirred at 120 ° C. for 3 hours. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture. The mixture was filtered, and then the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 3.08 g of 3-formyl-1H-indole-1-ylmethanol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>>[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:29])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[CH:12][N:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)=[CH:23][C:22]=1[C:30]([F:31])([F:32])[F:33]
Reactant: Cc1ccc(N=C=O)cc1C(F)(F)F
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Product: Cc1ccc(NC(=O)Nc2ccc(-c3c(C(N)=O)[nH]c4cnccc34)cc2)cc1C(F)(F)F

Procedure:
61 mg of pale yellow solid 3-{4-[3-(4-methyl-3-trifluoromethylphenyl)ureido]-phenyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxamide are prepared as described in Example 1 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide and 4-methyl-3-trifluoromethylphenyl isocyanate.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C@@H:13]1[C@@H:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[C:16]2([O:33][CH2:32][CH2:31][O:30]2)[CH2:15][O:14]1.C(N(CC)CC)C>C(Cl)Cl.O>[CH:12]([C@@H:13]1[C@@H:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH:27]([CH3:28])[CH3:29])=[O:25])[C:16]2([O:30][CH2:31][CH2:32][O:33]2)[CH2:15][O:14]1)=[O:11]
Reactant: CC(C)OC(=O)CCCCCC[C@@H]1[C@@H](CO)OCC12OCCO2
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)CCCCCC[C@@H]1[C@@H](C=O)OCC12OCCO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87.8 %

Procedure:
A solution of oxalyl chloride (2.0 mL, 2.0M in CH2Cl2, 4.0 mmol) in 15 mL of CH2Cl2 was cooled to -78° C., and to it a solution of DMSO (0.5 mL, 7.8 mmol) in 1.0 mL of CH2Cl2 was added dropwise. The resulting solution was stirred for 3 min, at which time a solution of the alcohol 6 (0.88 g, 2.6 mmol) in 15 mL of CH2Cl2 was introduced via cannula. Stirring was continued at -78° C. for 15 min and then triethyl amine (1.8 mL, 13 mmol) was added. The mixture was allowed to warm to room temperature over a period of 10 min and was then poured into 50 mL of water. The layers were separated and the aqueous layer was extracted with 25 mL of CH2Cl2. Combined organic extracts were washed with water, brine and dried (MgSO4) and processed in the normal manner. The crude material was subjected to chromatography on silica gel to yield the aldehyde 7 (0.75 g, 88% yield) as a pale yellow liquid: Rf 0.4 (60% EtOAc/hexane); 1H-NMR (d6 -DMSO) δ9.58 (d, J=1.3 Hz, 1H), 4.85 (septet, J=6.2 Hz, 1H), 4.05 (m, 1H), 3.84 (broad m, 4H), 3.66 (s, 2H), 3.50 (m, 1H), 2.20 (m, 4H), 1.47 (m, 4H), 1.22 (broad m, 6H), 1.16 (d, J=7.2 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][CH:8]2[C:13]([OH:15])=O.[CH2:16]([N:18]1[CH:22]=[C:21]([CH2:23][NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)[CH:20]=[N:19]1)[CH3:17]>>[CH2:16]([N:18]1[CH:22]=[C:21]([CH2:23][N:24]([C:25]2[CH:26]=[CH:27][C:28]([CH:31]([CH3:32])[CH3:33])=[CH:29][CH:30]=2)[C:13]([CH:8]2[C:9]3[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][CH:10]=3)[CH2:5][CH2:6][CH2:7]2)=[O:15])[CH:20]=[N:19]1)[CH3:17]
Reactant: CCn1cc(CNc2ccc(C(C)C)cc2)cn1
Reactant: COc1cccc2c1CCCC2C(=O)O
Product: CCn1cc(CN(C(=O)C2CCCc3c(OC)cccc32)c2ccc(C(C)C)cc2)cn1
Yield: 80.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.31 g) and [(1-ethylpyrazol-4-yl)methyl] (4-isopropylphenyl)amine (0.37 g) as starting materials, N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-5-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.52 g) was obtained.
Reaction SMILES: Cl.[CH:2]([N:5]1[C:9]([C:10]2[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[C:13]([O:19]COC)=[CH:12][C:11]=2[O:23]COC)=[N:8][NH:7][C:6]1=[O:27])([CH3:4])[CH3:3].C(=O)([O-])O.[Na+]>CO>[OH:23][C:11]1[CH:12]=[C:13]([OH:19])[C:14]([CH:16]([CH3:18])[CH3:17])=[CH:15][C:10]=1[C:9]1[N:5]([CH:2]([CH3:4])[CH3:3])[C:6](=[O:27])[NH:7][N:8]=1
Reactant: COCOc1cc(OCOC)c(C(C)C)cc1-c1n[nH]c(=O)n1C(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(C)c1cc(-c2n[nH]c(=O)n2C(C)C)c(O)cc1O
Reaction time: 8 h
Yield: 74.3 %

Procedure:
5 N hydrochloric acid (7 mL) was added to a methanol (13 mL) solution of 4-isopropyl-5-(5-isopropyl-2,4-bis-methoxymethoxyphenyl)-2,4-dihydro-[1,2,4]triazol-3-one (F63-06, 1.03 g, 2.82 mmol) and the mixture was stirred overnight. After cooling to ice cold conditions, the reaction mixture was neutralized by adding saturated aqueous sodium hydrogencarbonate. The solution was extracted with ethyl acetate, and the extract was washed with water and then with saturated sodium chloride solution. After drying the extract over anhydrous sodium, sodium sulfate was removed by filtration and the solvent was distilled off under reduced pressure to obtain white solids. After crude purification by silica gel column chromatography (chloroform, methanol), the solids were further purified by silica gel column chromatography (NHsilica, diethyl ether, methanol) to obtain 5-(2,4-dihydroxy-5-isopropylphenyl)-4-isopropyl-2,4-dihydro-[1,2,4]triazol-3-one (OH-a21, white solids, 581 mg, 74%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[C:24]#[N:25])=[CH:4][C:5](=[O:16])[N:6]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:7]=1.FC(F)(F)S(O[CH2:32][CH2:33][O:34][C:35]([F:38])([F:37])[F:36])(=O)=O>>[Cl:1][C:2]1[C:3]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[C:24]#[N:25])=[CH:4][C:5](=[O:16])[N:6]([CH:8]([CH2:32][CH2:33][O:34][C:35]([F:38])([F:37])[F:36])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:7]=1
Reactant: CC(C)(C)OC(=O)Cn1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: O=S(=O)(OCCOC(F)(F)F)C(F)(F)F
Product: CC(C)(C)OC(=O)C(CCOC(F)(F)F)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
300 mg (0.79 mmol) of tert-butyl [5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]acetate in the presence of 0.95 ml (0.95 mmol, 1.2 eq.) of bis(trimethylsilyl)lithium amide (1M in THF) and 207 mg (0.79 mmol, 1.0 eq.) of 2-(trifluoromethoxy)ethyl trifluoromethanesulphonate were reacted according to General Method 7B. Yield: 244 mg (purity 92%, 58% of theory)
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH2:6][CH2:7]Cl)[CH3:4].[S:9]([O-])([O-])(=O)=[S:10].[Na+].[Na+].Cl.[OH-].[Na+]>O>[CH3:2][N:3]([CH3:4])[CH2:5][CH2:6][CH2:7][S:10][S:9][CH2:7][CH2:6][CH2:5][N:3]([CH3:4])[CH3:2]
Reactant: O=S([O-])([O-])=S
Reactant: CN(C)CCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)CCCSSCCCN(C)C
Reaction time: 2 h

Procedure:
In a 300 ml round-bottom flask were charged 31.6 g of N,N-dimethyl-3-chloropropylamine hydrochloride, 34.8 g of sodium thiosulfate and 100 ml of distilled water. The mixture was heated under reflux and stirred for 2 hours and then continuously heated under reflux for further 1 hour after the addition of 22.3 g of 36% hydrochloric acid. Under cooling in an ice bath, 25.3 g of 95% sodium hydroxide was slowly added to adjust pH to the alkaline range, and the mixture was subjected to extraction three times with 30 ml of tetrahydrofuran. Most of the water was removed with potassium hydroxide pellets. The extract was further dehydrated with anhydrous potassium carbonate, and the solvent was removed by distillation and distilled under reduced pressure to give a transparent colorless bis(N,N-dimethyl-3-aminopropyl)disulfide as the precursor of the mercaptoalkylamine desired in an amount of 22.5 g.