Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[O:16]=[C:17]1[NH:22][C:21](=[O:23])[C:20]([CH:24]=O)=[CH:19][NH:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C.C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[CH:10]1[CH2:11][CH2:12][N:13]([CH2:24][C:20]2[C:21](=[O:23])[NH:22][C:17](=[O:16])[NH:18][CH:19]=2)[CH2:14][CH2:15]1
Reactant: Fc1ccccc1/C=C/C1CCNCC1
Reactant: O=Cc1c[nH]c(=O)[nH]c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=c1[nH]cc(CN2CCC(/C=C/c3ccccc3F)CC2)c(=O)[nH]1
Reaction time: 20 h
Yield: 56.1 %

Procedure:
After dissolving 100 mg of (E)-4-[2-(2-fluorophenyl)vinyl]piperidine in 3 ml of tetrahydrofuran, 116 mg of 2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxaldehyde, 0.05 ml of acetic acid and 198 mg of sodium triacetoxyborohydride were added while stirring, and the stirring was continued for 20 hours at room temperature. An additional 200 mg of sodium triacetoxyborohydride was then added and the mixture was stirred overnight at room temperature. Aqueous sodium carbonate solution was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: tetrahydrofuran/methanol). Ethyl acetate was added and the mixture was filtered to obtain the title compound (90 mg, 38% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[C:12]([C@@H:18]2[O:23][CH2:22][C@@H:21]3[CH2:24][NH:25][CH2:26][CH2:27][N:20]3[CH2:19]2)=[CH:11][CH:10]=1.[N:28]1([C:33]2[CH:34]=[CH:35][C:36]([CH2:39][C:40](O)=[O:41])=[N:37][CH:38]=2)[CH:32]=[N:31][N:30]=[N:29]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[Cl-].[Na+].O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:28]1([C:33]2[CH:34]=[CH:35][C:36]([CH2:39][C:40]([N:25]3[CH2:26][CH2:27][N:20]4[C@H:21]([CH2:22][O:23][C@@H:18]([C:12]5[C:13]([CH3:17])=[C:14]([C:9]([F:8])=[CH:10][CH:11]=5)[C:15]#[N:16])[CH2:19]4)[CH2:24]3)=[O:41])=[N:37][CH:38]=2)[CH:32]=[N:31][N:30]=[N:29]1
Reactant: O=C(O)Cc1ccc(-n2cnnn2)cn1
Reactant: Cc1c([C@H]2CN3CCNC[C@H]3CO2)ccc(F)c1C#N
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1c([C@H]2CN3CCN(C(=O)Cc4ccc(-n5cnnn5)cn4)C[C@H]3CO2)ccc(F)c1C#N
Reaction time: 0.08 h

Procedure:
6-Fluoro-2-methyl-3-((3S,9aS)-octahydropyrazino[2,1-c][1,4]oxazin-3-yl)benzonitrile 2,2,2-trifluoroacetate (1.06 g, 2.71 mmol) was suspended in DCM (20 mL) and TEA (1.13 ml, 8.13 mmol) was added. The mixture was stirred for 5 min and then 2-(5-(1H-tetrazol-1-yl)pyridin-2-yl)acetic acid (0.555 g, 2.71 mmol), HOBT (0.623 g, 4.07 mmol) and EDC (1.039 g, 5.42 mmol) were added and the mixture was stirred for 4 h. The reaction mixture was poured into brine/NaHCO3 mixture. The DCM layer was separated and dried over Na2SO4, then was filtered and concentrated. The residue was purified by chromatography using a 120 g ISCO Redisep column eluting with a 5% (NH4OH: MeOH 1:9)/95% DCM solvent system to yield 3-((3S,9aS)-8-(2-(5-(1H-tetrazol-1-yl)pyridin-2-yl)acetyl)-octahydropyrazino[2,1-c][1,4]oxazin-3-yl)-6-fluoro-2-methylbenzonitrile: LC-MS: M+1=463.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=O)[CH2:6][CH:5]1[CH3:15])(=[O:3])[CH3:2].[NH2:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][CH:23]=[N:22][C:21]=2[CH:25]=1.C(N(CC)CC)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[N:16][C:17]2[CH:18]=[CH:19][C:20]3[O:24][CH:23]=[N:22][C:21]=3[CH:25]=2)[CH2:6][CH:5]1[CH3:15])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccccc2C(=O)CC1C
Reactant: Nc1ccc2ocnc2c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1c2ccccc2C(=Nc2ccc3ocnc3c2)CC1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
[Step 1] 177 mg of 1-acetyl-4-oxo-2-methyl-1,2,3,4-tetrahydroquinoline and 77 mg of 5-aminobenzoxazole were dissolved in 2 mL of methylene chloride, and 0.32 mL of triethylamine and 0.57 mL of titanium tetrachloride (1.0 M dichloromethane solution) were added to the solution under ice cooling. The mixture was stirred for 16 hours at room temperature. After completion of the reaction, the reaction liquid was filtered through Celite, and was concentrated under reduced pressure. Thus, a crude product of 1-acetyl-4-[(benzoxazol-5-yl)imino]-2-methyl-1,2,3,4-tetrahydroquinoline was obtained as a pale brown solid.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].C[O:7][C:8]1[C:13]2=[CH:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][N+:20]=3[C:21]([CH3:22])=[C:12]2[CH:11]=[CH:10][CH:9]=1>Br.O>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[OH:7][C:8]1[C:13]2=[CH:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][N+:20]=3[C:21]([CH3:22])=[C:12]2[CH:11]=[CH:10][CH:9]=1
Reactant: COc1cccc2c(C)[n+]3ccccc3cc12
Agent: Br
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Product: Cc1c2cccc(O)c2cc2cccc[n+]12
Temperature: 100 °C
Yield: 90.9 %

Procedure:
A mixture of 2.3 g of 10-methoxy-6-methylbenzo[b]quinolizinium perchlorate in 35 mL of 48% HBr was heated at 100° C. for 14 h, cooled to room temperature, and was diluted with water. The resulting mixture was heated to dissolve the solid product, filtered while hot, and the filtrate was treated with 20 g of sodium perchlorate. The precipitated solid product was filtered, washed with ether, air dried to afford 2 g (90.9%) of 10-hydroxy-6-methyl-benzo[b]quinolizinium perchlorate (Formula II: R1 =H; R2 =CH3 ; R7 =10--OH; X- --ClO4-), m.p. 246°-248° C. (d).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[O:7]=[C:8]([CH3:23])[CH2:9][C:10]([O:12][C:13]([CH3:22])([CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH:14]=[CH2:15])=[O:11].[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CC(C)=O>[O:7]=[C:8]([CH3:23])[CH:9]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:10]([O:12][C:13]([CH3:22])([CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH:14]=[CH2:15])=[O:11]
Reactant: C=CC(C)(CCC=C(C)C)OC(=O)CC(C)=O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CC(C)(CCC=C(C)C)OC(=O)C(Cc1ccccc1)C(C)=O

Procedure:
Potassium carbonate (3.92 g, 0.028 mol), 3,7-dimethyl-1,6-octadien-3-yl 3-oxo-butyrate (4.80 g, 0.030 mol), benzyl chloride (4.80 g, 0.038 mol) and acetone (15 mL) are placed in a 50 mL round-bottomed flask fitted with a magnetic stirrer, condenser and argon inlet. The mixture is heated to reflux for 18 h. The cooled mixture is filtered and concentrated by rotary evaporation. The resulting oil is purified on silica gel to yield the desired compound. Structure is confirmed by thin layer chromatography and 1H and 13C NMR.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([OH:38])[C:19]3[CH:20]=[CH:21][C:22]([O:24][CH2:25][O:26][CH3:27])=[CH:23][C:18]=3[O:17][CH2:16][CH:15]2[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][O:36][CH3:37])=[CH:30][CH:29]=2)=[CH:10][CH:9]=1.[I-:39].[Na+].O>C(C(C)=O)C>[OH:38][C:14]1([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][I:39])=[CH:9][CH:10]=2)[C:19]2[CH:20]=[CH:21][C:22]([O:24][CH2:25][O:26][CH3:27])=[CH:23][C:18]=2[O:17][CH2:16][CH:15]1[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][O:36][CH3:37])=[CH:30][CH:29]=1
Reactant: COCOc1ccc(C2COc3cc(OCOC)ccc3C2(O)c2ccc(OCCCCCCl)cc2)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCC(C)=O
Product: COCOc1ccc(C2COc3cc(OCOC)ccc3C2(O)c2ccc(OCCCCCI)cc2)cc1
Temperature: 25 °C
Yield: 74.6 %

Procedure:
4-[4-(5-Chloropentyloxy)phenyl]-4-hydroxy-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-2,3-dihydro-4H-benzopyran (167 mg, 0.3 mmol) and sodium iodide (139 mg, 0.9 mmol) were dissolved in methyl ethyl ketone (5 ml) and then refluxed for 12 hours. The reaction solution was cooled to room temperature and, after adding water, extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure to remove the organic solvent. The concentrate was subjected to column chromatography (n-hexane:ethyl acetate=4:1) to obtain 142 mg (yield: 75%) of the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][OH:10]>>[CH3:9][O:10][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1
Reactant: CO
Reactant: Nc1ccnc(Cl)c1
Product: COc1cc(N)ccn1

Procedure:
Na (0.7 g, 30 mmol) was added to methanol (10 mL) at room temperature. Once all Na had dissolved, 2-chloro-4-aminopyridine (0.5 g, 3.9 mmol) was added. The solution was heated to reflux for 16 hours. After the reaction solution cooled to room, it was partitioned between ethyl acetate and water. The aqueous layer was extracted twice with additional ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated under vacuum to give the title product. MS (DCI) m/e 125 (M+H)+.
Reaction SMILES: ClC1C=CC=CC=1OC.Cl[C:11]1[C:16]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[N:15][NH:14][C:13](=[O:26])[CH:12]=1.[NH:27]1C(=O)C=CC=[N:28]1.O.NN>>[NH:27]([C:11]1[C:16]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[N:15][NH:14][C:13](=[O:26])[CH:12]=1)[NH2:28]
Reactant: COc1ccc(Cl)cc1-c1n[nH]c(=O)cc1Cl
Reactant: O=c1cccn[nH]1
Agent: COc1ccccc1Cl
Agent: NN
Solvent: O
Product: COc1ccc(Cl)cc1-c1n[nH]c(=O)cc1NN
Yield: 90 %

Procedure:
A mixture of 1.5 g (0.005 mol) of 5-chloro-6-(2'-methoxy-5'-chlorophenyl)-3-pyridazinone chloroanisole-6-pyridazinone and 25 ml of hydrazine hydrate was heated at reflux for 4 hours. The solution was cooled and the white solid which formed was separated, washed with water (30 ml) and dried at 40° in a vacuum oven overnight to give 1.2 g (81%) of a colorless solid product, m.p. 285°-290°.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.[F:29][C:30]([F:58])([F:57])[O:31][C:32]1[CH:37]=[CH:36][C:35](Br)=[CH:34][C:33]=1[NH:39][C:40]1[N:49]=[CH:48][C:47]2[CH2:46][CH2:45][C:44]3[C:50]([C:54]([NH2:56])=[O:55])=[N:51][N:52]([CH3:53])[C:43]=3[C:42]=2[N:41]=1.[Li]N([Si](C)(C)C)[Si](C)(C)C.[CH2:69]([N:71]1[CH2:76][CH2:75][NH:74][CH2:73][CH2:72]1)[CH3:70]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:69]([N:71]1[CH2:76][CH2:75][N:74]([C:35]2[CH:36]=[CH:37][C:32]([O:31][C:30]([F:58])([F:57])[F:29])=[C:33]([NH:39][C:40]3[N:49]=[CH:48][C:47]4[CH2:46][CH2:45][C:44]5[C:50]([C:54]([NH2:56])=[O:55])=[N:51][N:52]([CH3:53])[C:43]=5[C:42]=4[N:41]=3)[CH:34]=2)[CH2:73][CH2:72]1)[CH3:70]
Reactant: CCN1CCNCC1
Reactant: Cn1nc(C(N)=O)c2c1-c1nc(Nc3cc(Br)ccc3OC(F)(F)F)ncc1CC2
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CCN1CCN(c2ccc(OC(F)(F)F)c(Nc3ncc4c(n3)-c3c(c(C(N)=O)nn3C)CC4)c2)CC1
Temperature: 25 °C
Yield: 21.7 %

Procedure:
Tris(dibenzilideneacetone)dipalladium, Pd2(dba)3, (9.1 mg, 0.01 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)-biphenyl (7.8 mg, 0.02 mmol), 8-[2-trifluoromethoxy-5-bromo-phenylamino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (200 mg, 0.41 mmol) in THF (4.5 mL) were charged in a round-bottom flask flushed with argon. The flask was evacuated and backfilled with argon. LiN(TMS)2 solution (1M in THF, 2.7 mL) and N-ethylpiperazine (0.125 mL, 0.98 mmol) were added and the reaction mixture refluxed for 3 h. The reaction mixture was then allowed to cool to room temperature and concentrated. The crude solid was purified by flash chromatography on silica gel (eluant: DCM/EtOH 90/10) to afford 46 mg (52% yield) of the title compound.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22](=O)[CH3:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[OH-].[K+].NN>C(O)COCCO>[CH2:22]([C:19]1[CH:20]=[CH:21][C:16]([C@H:13]2[CH2:14][CH2:15][C@H:10]([C@H:7]3[CH2:8][CH2:9][C@H:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]3)[CH2:11][CH2:12]2)=[CH:17][CH:18]=1)[CH3:23]
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(C(C)=O)cc3)CC2)CC1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(CC)cc3)CC2)CC1
Reaction time: 4 h

Procedure:
A mixture of 32.6 g of p-(trans-4-(trans-4-propylcyclohexyl)-cyclohexyl)-acetophenone, 15 g of KOH, 25 ml of 85% hydrazine and 250 ml of diethylene glycol is warmed to 100° for 1 hour. The temperature is increased slowly until the hydrazone formed decomposes, and is boiled for another 4 hours, cooled and worked up in the customary manner to give trans-1-p-ethylphenyl-4-(trans-4-propylcyclohexyl)-cyclohexane.
Reaction SMILES: [NH2:1][C:2]1[C:20]([NH2:21])=[CH:19][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([F:18])([F:17])[F:16])[CH2:11][CH2:10]2)=[O:7])=[C:4]([Cl:22])[CH:3]=1.[N:23]([C:26]1[CH:27]=[C:28]([CH:37]=[CH:38][C:39]=1[O:40][CH3:41])[CH2:29][N-:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[C:24]=S>>[F:18][C:15]([F:16])([F:17])[C@H:12]1[CH2:11][CH2:10][C@H:9]([NH:8][C:6]([C:5]2[C:4]([Cl:22])=[CH:3][C:2]3[NH:1][C:24]([NH:23][C:26]4[CH:27]=[C:28]([CH2:29][NH:30][C:31]([C:32]([CH3:33])([CH3:35])[CH3:34])=[O:36])[CH:37]=[CH:38][C:39]=4[O:40][CH3:41])=[N:21][C:20]=3[CH:19]=2)=[O:7])[CH2:14][CH2:13]1
Reactant: COc1ccc(C[N-]C(=O)C(C)(C)C)cc1N=C=S
Reactant: Nc1cc(Cl)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N
Product: COc1ccc(CNC(=O)C(C)(C)C)cc1Nc1nc2cc(C(=O)N[C@H]3CC[C@H](C(F)(F)F)CC3)c(Cl)cc2[nH]1

Procedure:
The compound was prepared from 4,5-diamino-2-chloro-N-(trans-4-trifluoromethyl-cyclohex-1-yl)-benzamide and N-(3-isothiocyanato-4-methoxy-benzyl)-pivaloylamide in analogy to example 72a.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:13]=[C:12]([NH:14][C:15](=[O:24])[C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])[C:6]2[O:7][C:8]([CH3:11])=[C:9]([CH3:10])[C:5]=2[CH:4]=1.ClC(Cl)(Cl)[C:27]([N:29]=C=O)=[O:28]>C(N(CC)CC)C>[Cl:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=1[C:15]([NH:14][C:12]1[C:6]2[O:7][C:8]([CH3:11])=[C:9]([CH3:10])[C:5]=2[CH:4]=[C:3]([NH:2][C:27]([NH2:29])=[O:28])[CH:13]=1)=[O:24]
Reactant: Cc1oc2c(NC(=O)c3c(Cl)cccc3Cl)cc(N)cc2c1C
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1oc2c(NC(=O)c3c(Cl)cccc3Cl)cc(NC(N)=O)cc2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
A mixture of 5-amino-7-(2,6-dichlorobenzoylamino)-2,3-dimethylbenzo[b]furan hydrochloride (155 mg), triethylamine (61 mg) and trichloroacetyl isocyanate (115 mg) was stirred at ambient temperature for 1 hour. Then, the mixture was concentrated in vacuo and to the residue was added methanol (3 ml) and aqueous 1N-sodium hydroxide (2 ml). The mixture was stirred at 60° C. for 15 minutes and the methanol was evaporated in vacuo. The separated solid was collected, washed with water and dried to give 7-(2,6-dichlorobenzoylamino)-2,3-dimethyl-5-ureidobenzo[b]furan (130 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[N+:12]([O-])([OH:14])=[O:13]>O>[OH:1][C:2]1[CH:7]=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccccc1O
Reactant: O=[N+]([O-])O
Solvent: O
Product: O=C(O)Cc1ccc([N+](=O)[O-])cc1O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a suspension of o-hydroxy phenylacetic acid (15.0 g, 0.099 mol) in H2O (39 mL) at 0° C. was added a solution of nitric acid (12 mL of 65% in 8 mL H2O) slowly via pipette. The solution was stirred for an additional 1.5 h at 0° C. The mixture was then warmed to ambient temperature and allowed to stir for an additional 0.5 h. The heterogeneous solution was poured over ice (10 g) and filtered to remove the insoluble ortho-nitro isomer. The reddish solution was concentrated under reduced pressure, and the thick residue was redissolved in 6N HCl and filtered through celite. The solvent was again removed under reduced pressure to provide the desired 2-hydroxy-4-nitro-phenylacetic acid as a light, brownish-red solid (40% yield). The product (IV-a) was used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]([CH3:12])[CH3:11])=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:15][C:16](=[O:27])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([Cl:26])[CH:20]=1)C>>[Cl:26][C:21]1[CH:20]=[C:19]([CH2:18][CH2:17][C:16]([OH:27])=[O:15])[CH:24]=[CH:23][C:22]=1[O:25][CH2:2][C:3]1[C:4]([S:9][CH:10]([CH3:12])[CH3:11])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCc1ccc(O)c(Cl)c1
Reactant: CC(C)Sc1ncccc1CCl
Product: CC(C)Sc1ncccc1COc1ccc(CCC(=O)O)cc1Cl
Yield: 101.9 %

Procedure:
3-Chloromethyl-2-isopropylsulfanyl-pyridine (23 mg, 0.11 mmol) obtained in Step C of Preparation Example 1 and 3-(3-chloro-4-hydroxy-phenyl)-propionic acid ethyl ester (29 mg, 0.12 mmol) obtained in Step C of Preparation Example 42 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (41 mg, 93%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([CH:12]1[CH2:17][CH2:16][O:15][C:14]([CH3:19])([CH3:18])[CH2:13]1)[CH2:6][C:5]2=O.[CH3:21][C:22]([S:25]([NH2:27])=[O:26])([CH3:24])[CH3:23].C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([CH:12]1[CH2:17][CH2:16][O:15][C:14]([CH3:19])([CH3:18])[CH2:13]1)[CH2:6][C:5]2=[N:27][S:25]([C:22]([CH3:24])([CH3:23])[CH3:21])=[O:26]
Reactant: CC1(C)CC(C2CC(=O)c3cc(Br)ccc3O2)CCO1
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC[O-]
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)CC(C2CC(=NS(=O)C(C)(C)C)c3cc(Br)ccc3O2)CCO1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 94.5 %

Procedure:
Titanium (IV) ethoxide (6.18 mL, 29.48 mmol) was added to a solution of 6-bromo-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)chroman-4-one (Intermediate 28, 4 g, 11.79 mmol) in dry THF (150 mL) under argon. The solution was stirred 5 min before addition of 2-methylpropane-2-sulfinamide (1.715 g, 14.15 mmol) was made in one portion. The reaction was refluxed over the weekend (˜70 h) with a heating bath temperature of 80° C. The reaction was cooled to r.t., and diluted with EtOAc (300 mL). Saturated NaHCO3 (150 mL) was added under vigorous stirring. After 5 min diatomaceous earth was added and the mixture was stirred for another 10 min. The slurry was filtered through diatomaceous earth (washed with EtOAc) and the filtrate was evaporated at reduced pressure. Purification by flash chromatography (EtOAc/heptane) on silica gel gave the title compound (4.93 g, 95% yield): MS (ES+) m/z 442 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH2:12]([O:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19])[CH2:13][CH3:14]>>[CH3:11][C:10]1[C:2]([NH:1][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[O:15][CH2:12][CH2:13][CH3:14])=[C:3]([CH:7]=[CH:8][CH:9]=1)[C:4]([NH2:6])=[O:5]
Reactant: CCCOc1ccccc1C(=O)Cl
Reactant: Cc1cccc(C(N)=O)c1N
Product: CCCOc1ccccc1C(=O)Nc1c(C)cccc1C(N)=O

Procedure:
The title compound was prepared from 2-amino-3-methylbenzamide and 2-n-propoxybenzoyl chloride following the procedure of Preparation 5 and was obtained as a colourless solid (71%), m.p. 140-142° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[O:24])[CH2:19][CH2:18]3)=[CH:7][C:8]([C:12]([O:14]CC)=[O:13])=[N:9]2)=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[O:24])[CH2:19][CH2:18]3)=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(N2CCN(C(=O)Nc3ccc(F)cc3)CC2)c2ccc(Cl)cc2n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(N2CCN(C(=O)Nc3ccc(F)cc3)CC2)c2ccc(Cl)cc2n1
Reaction time: 4 h

Procedure:
A solution of ethyl 7-chloro-4-[4-(4-fluorophenylaminocarbonyl)piperazin-1-yl]quinoline-2-carboxylate (389 mg, 0.85 mmol) in THF-water 3:1 (5 mL) is treated with LiOH x H2O (126 mg, 3 mmol) and stirred at room temp. for 4 h. The reaction mixture is concentrated and acidified with 1 N HCl (pH 4). The colorless precipitate is collected by filtration yielding the title product.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[CH:28]=O.[BH3-]C#N.[Na+]>CO.CN1C(=O)N(C)CC1>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([NH:1][CH2:28][C:27]4[CH:30]=[C:31]([O:35][CH3:36])[C:32]([O:33][CH3:34])=[C:25]([O:24][CH3:23])[CH:26]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CN1CCN(C)C1=O
Product: COc1cc(CNc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc(OC)c1OC

Procedure:
Analogously to Example 21, 1.00 mmol of 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine in 26 ml of methanol, 13 ml of DMEU and 3.0 mmol of acetic acid are first reacted with 3,4,5-trimethoxy-benzaldehyde and then reduced with 7.00 mmol of NaCNBH3 (5-7 days). 4-(3-Chloro-phenylamino)-3-(3,4,5-trimethoxybenzylamino)-1H-pyrazolo[3,4-d]pyrimidine is obtained; m.p. 240-245° C. HPLC: TRet (Grad5-40)=22.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH2:12](Br)[CH:13]=[CH2:14]>>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:14][CH:13]=[CH2:12])=[CH:6][CH:5]=1
Reactant: C=CCBr
Reactant: COC(=O)c1ccc(O)cc1
Product: C=CCOc1ccc(C(=O)OC)cc1
Reaction time: 16 h
Yield: 91 %

Procedure:
4-Allyloxybenzoic acid methyl ester was prepared by reacting 4-hydroxybenzoic acid methyl ester with allyl bromide following Method C in 91% yield. The reaction was conducted at room temperature for 16 h and the resulting product was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][N:14]1[C:19](=[O:20])[CH2:18][CH2:17][CH2:16][C:15]1=[O:21].Cl.N.CS(C)=[O:26]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:26])[CH:6]2[CH2:12][CH2:13][N:14]1[C:15](=[O:21])[CH2:16][CH2:17][CH2:18][C:19]1=[O:20]
Reactant: CS(C)=O
Reactant: COc1ccc2[nH]cc(CCN3C(=O)CCCC3=O)c2c1
Agent: Cl
Agent: N
Product: COc1ccc2c(c1)C(CCN1C(=O)CCCC1=O)C(=O)N2

Procedure:
145 mg of N-[2-(5-methoxyindol-3-yl)ethyl]glutarimide are dissolved in DMSO (30 μl) in a round-bottomed flask and concentrated HCl (72 μl) is added with stirring. The mixture is stirred overnight at room temperature. The crude product is neutralized with NH3 and then extracted with EtOAc. After separation on a silica plate, N-[2-(5-methoxy-2-oxo-2,3-dihydroindol-3-yl)ethyl]glutarimide is obtained.