Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7](=[O:25])[N:8]([CH3:24])[C:9]([CH:18]([OH:23])[C:19]([O:21][CH3:22])=[O:20])=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[C:5]=2[CH:4]=[CH:3]1.C(O[C:30]([CH3:33])([CH3:32])[CH3:31])(=O)C.Cl(O)(=O)(=O)=O>>[C:30]([O:23][CH:18]([C:9]1[N:8]([CH3:24])[C:7](=[O:25])[C:6]2[N:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1)[C:19]([O:21][CH3:22])=[O:20])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)C(O)c1c(-c2ccc(C)cc2)c2ccn(C)c2c(=O)n1C
Agent: [O-][Cl+3]([O-])([O-])O
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)cc2)c2ccn(C)c2c(=O)n1C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 73.2 %

Procedure:
An ice cold solution of methyl 2-(1,6-dimethyl-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-hydroxyacetate (28 mg, 0.082 mmol) in tert-butyl acetate (1111 μl, 8.23 mmol) was treated with perchloric acid (7.07 μl, 0.082 mmol), and stirred for 20 min. The reaction was then kept in the refrigerator without stirring for 2 days. The reaction was quenched with sat. NaHCO3 at 0° C., extracted with EtOAc 2×, washed with Brine, dried with Na2SO4, filtered, and concentrated. Purification with column chromatography (0-100% EtOAc/Hexane) gave methyl 2-(tert-butoxy)-2-(1,6-dimethyl-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (23.6 mg, 0.060 mmol, 72.4% yield). The intermediate was dissolved in Methanol (500 μl) and Tetrahydrofuran (THF) (500 μl), treated with 2M LiOH (174 μl, 0.348 mmol), and stirred at 60° C. for 4 hours. The mixture was concentrated and purified with reverse phase chromatography (20-100% MeCN/H2O-0.1% TFA, 12 min) to give title compound (19.6 mg, 0.051 mmol, 87% yield) as white solid: 1H NMR (400 MHz, CHLOROFORM-d) ppm 0.99 (s, 9H), 2.43 (s, 3H), 3.66 (s, 3H), 4.20 (s, 3H), 5.45 (s, 1H), 5.98 (d, J=2.7 Hz, 1H), 6.96 (d, J=2.7 Hz, 1H), 7.24-7.31 (m, 2H), 7.31-7.38 (m, 1H), 7.49-7.57 (m, 1H); LCMS (m/z) ES+=383 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[Se:9][C:10]([CH2:13][OH:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:18]1[CH:24]2[CH2:25][CH:21]([CH2:22][CH2:23]2)[C:20](=[O:26])[CH:19]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[Se:9][C:10]([CH2:13][O:14][C:18]3[CH:24]4[CH2:25][CH:21]([CH2:22][CH2:23]4)[C:20](=[O:26])[CH:19]=3)=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: OCc1cnc(-c2ccc(Cl)cc2)[se]1
Reactant: O=C1C=C(Cl)C2CCC1C2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1C=C(OCc2cnc(-c3ccc(Cl)cc3)[se]2)C2CCC1C2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 63.7 %

Procedure:
To a solution of [2-(4-chlorophenyl)selenazol-5-yl]methanol (300 mg, 1.1 mmol) in dry tetrahydrofuran (5 ml) is added, in one portion, sodium hydride (60% dispersion in mineral oil, 44 mg, 1.1 mmol). The reaction mixture is stirred for 5 minutes at room temperature and 4-chlorobicyclo[3.2.1]oct-3-en-2-one (172 mg, 1.1 mmol) is added in one-portion. The reaction mixture is stirred at room temperature overnight. Silica gel is added to the crude reaction mixture, the solvent is evaporated under reduced pressure and the residue is purified by flash chromatography on silica gel to give 4-[2-(4-chlorophenyl)selenazol-5-ylmethoxy]bicyclo[3.2.1]oct-3-en-2-one (275 mg).
Reaction SMILES: ClC1C=C2C(C=CC(C)=N2)=CC=1O.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:22]([O:32]C)=[C:23]([CH3:31])[CH:24]=[C:25]3[C:30]=2[N:29]=[CH:28][CH:27]=[CH:26]3)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[C:22]([OH:32])=[C:23]([CH3:31])[CH:24]=[C:25]3[C:30]=2[N:29]=[CH:28][CH:27]=[CH:26]3)=[CH:19][CH:20]=1
Reactant: COc1c(C)cc2cccnc2c1-c1ccc(Cl)cc1
Agent: Cc1ccc2cc(O)c(Cl)cc2n1
Product: Cc1cc2cccnc2c(-c2ccc(Cl)cc2)c1O

Procedure:
Compound 4C was prepared following the procedure used to prepare compound 1C of Example 1, except that 8-(4-chlorophenyl)-7-methoxy-6-methylquinoline (4B) was used instead of compound 1B. LCMS-ESI+ (m/z): 270.2, 272.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=[CH:3]1.C([O:18][C:19](=[O:25])[CH2:20][NH:21][C:22](=[O:24])[CH3:23])C.C(O)C.[OH-].[Na+].Cl>O.C1COCC1>[CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[O:8])=[CH:5][CH:4]=[CH:3]1.[C:22]([NH:21][CH2:20][C:19]([OH:25])=[O:18])(=[O:24])[CH3:23]
Reactant: CCOC(=O)CNC(C)=O
Agent: Cc1ccc(C(=O)c2cccn2C)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture consisting of 4.45 grams (0.013 moles) of 1-methyl-5-p-toluoylpyrrole-2-acetamidoacetic acid ethyl ester (1-b), 50 ml of ethanol, 25 ml of THF and 19.5 ml (0.0195 moles) of 1N NaOH was kept under stirring at room temperature (20°-25° C.) for 1.5 hours. The mixture was then diluted with water to 300 ml and slowly acidified with 37% HCl. A solid product precipitated which, after filtration and drying, weighed 3.4 grams and was crystallized from ethanol thus giving 2.3 grams of a compound of formula ##STR23## having the following chemico-physical characteristics: Formula: C17H18N2O4.
Reaction SMILES: C[CH2:2][N:3](C(C)C)C(C)C.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.Br[C:45]1[CH:54]=[CH:53][C:52]([N+:55]([O-:57])=[O:56])=[C:51]2[C:46]=1[CH:47]=[CH:48][CH:49]=[N:50]2.O>CN(C=O)C.[C-]#N.[C-]#N.[Zn+2]>[N+:55]([C:52]1[C:51]2[N:50]=[CH:49][CH:48]=[CH:47][C:46]=2[C:45]([C:2]#[N:3])=[CH:54][CH:53]=1)([O-:57])=[O:56]
Reactant: O=[N+]([O-])c1ccc(Br)c2cccnc12
Reactant: CCN(C(C)C)C(C)C
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc([N+](=O)[O-])c2ncccc12
Temperature: 100 °C
Yield: 73.1 %

Procedure:
Zn(CN)2 (739 mg, 6.3 mmol), DIPEA (0.41 ml, 2.37 mmol), X-phos (225 mg, 0.47 mmol) and Pd2 (dba)2 (90 mg, 0.16 mmol) were added to a degassed (with argon) solution of 5-bromo-8-nitroquinoline 470 (400 mg, 1.58 mmol) in DMF (4 ml) and the mixture was heated at 100° C. in microwave for 20 min. After cooling, the mixture was poured into water and the aqueous phase was extracted with EtOAc. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with n-hexane/EtOAc (96:4) as the eluent to give the title compound (230 mg, 63%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[S:17](Cl)(=[O:19])=[O:18]>>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][S:17]([C:11]2[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=2[F:9])(=[O:19])=[O:18])[CH:5]=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Reactant: Nc1cncc(Br)c1
Product: O=S(=O)(Nc1cncc(Br)c1)c1ccc(F)cc1F
Yield: 102.1 %

Procedure:
5-Bromopyridin-3-amine (500 mg, 2.89 mmol) was treated with 2,4-difluorobenzene-1-sulfonyl chloride (390 μl, 2.90 mmol) according to the method described in Preparation 15b to give 1.03 g (100% yield) of the title compound as an oil. Purity 74%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH3:18])=[C:5]2[CH2:19][C:20]([NH2:22])=[O:21].[H-].[Na+].I[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>N1C=CC=CC=1.C(OCC)(=O)C.Cl>[CH3:18][C:6]1[N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]2[C:4]([C:5]=1[CH2:19][C:20]([NH2:22])=[O:21])=[CH:3][C:2]([O:1][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[CH:10][CH:9]=2
Reactant: Cc1c(CC(N)=O)c2cc(O)ccc2n1Cc1ccccc1
Reactant: Ic1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1c(CC(N)=O)c2cc(Oc3ccccc3)ccc2n1Cc1ccccc1
Reaction time: 0.17 h
Yield: 3 %

Procedure:
5-Hydroxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetamide (1.2 g, 4.1 mmol) was dissolved in 40 mL of pyridine, 90 mg (2.2 mmol) of 60% NaH/mineral oil added, stirred 0.17 hours, 315 mg of CuO added, stirred 0.17 hours and 0.5 (4.1 mmol) mL of iodobenzene added. The mixture was heated to maintain reflux for 24 hours, cooled, and diluted with ethyl acetate and 1N HCl. The mixture was filtered thru a celite pad and the organic material separated, washed with brine, dried (Na2SO4) and concentrated at reduced pressure. The residue was chromatographed on silica gel and eluted with 1% MeOH/methylene chloride→3% MeOH/methylene chloride to give 40 mg (3% yield) of 2-methyl-5-phenoxy-1-(phenylmethyl)-1H-indole-3-acetamide.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:28][C:12]2=[CH:13][C:14]3[C:15](=[O:27])[N:16]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[C:17](=[O:21])[C:18]=3[C:19]([CH3:20])=[C:11]2[N:10]=1.[F:29][C:30]1[CH:31]=[CH:32][C:33]([CH3:40])=[C:34]([CH2:36][CH:37]([NH2:39])[CH3:38])[CH:35]=1>C(O)CCC>[CH3:25][N:24]([CH3:26])[CH2:23][CH2:22][N:16]1[C:15](=[O:27])[C:14]2[CH:13]=[C:12]3[NH:28][C:9]([C:3]4[C:4](=[O:8])[NH:5][CH:6]=[CH:7][C:2]=4[NH:39][CH:37]([CH3:38])[CH2:36][C:34]4[CH:35]=[C:30]([F:29])[CH:31]=[CH:32][C:33]=4[CH3:40])=[N:10][C:11]3=[C:19]([CH3:20])[C:18]=2[C:17]1=[O:21]
Reactant: Cc1c2c(cc3[nH]c(-c4c(Cl)cc[nH]c4=O)nc13)C(=O)N(CCN(C)C)C2=O
Reactant: Cc1ccc(F)cc1CC(C)N
Solvent: CCCCO
Product: Cc1ccc(F)cc1CC(C)Nc1cc[nH]c(=O)c1-c1nc2c(C)c3c(cc2[nH]1)C(=O)N(CCN(C)C)C3=O
Yield: 55 %

Procedure:
A mixture of 2-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-(dimethylamino)ethyl)-4-methylimidazo[4,5-f]isoindole-5,7(1H,6H)-dione (0.48 g, 1.20 mmol), 1-(5-fluoro-2-methylphenyl)propan-2-amine (0.24 g, 1.44 mmol), Hunig,s base (0.78 g, 6.00 mmol), and 10 mL of anhydrous 1-butanol was heated at reflux for 12-13 h under an argon atmosphere. Product was purified by a silica gel column using methylene chloride and methanol (9:1 v/v) as eluent to afford 0.35 g of the designed compound as yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 13.36 (s, 1H, NH), 11.24 (d, J=6.0 Hz, 1H, NH), 11.02 (d, J=8.5 Hz, 1H, NH), 7.99 (s, 1H, ArH), 7.32 (t, J=6.5 Hz, 1H, ArH), 7.15-7.08 (m, 2H, ArH), 6.91-6.87 (m, 1H, ArH), 6.16 (d, J=7.5 Hz, 1H, ArH), 4.22-4.18 (m, 1H, CH), 3.73-3.71 (m, 2H, CH2), 2.97-2.96 (m, 2H, CH2), 2.86 (s, 3H, CH3), 2.72-2.68 (m, 2H, CH2), 2.36 (s, 6H, 2×CH3), 2.27 (s, 3H, CH3), 1.34 (d, J=6.5 Hz, 3H, CH3); Mass (ESI, negative) m/z 529.0 [M−H]−.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9]2)=[CH:4][CH:3]=1.N1CCCCC1.[O:25]1[CH2:37][CH:26]1[CH2:27][CH2:28][CH2:29][O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1>C1(C)C=CC=CC=1>[O:32]1[CH2:33][CH2:34][CH2:35][CH2:36][CH:31]1[O:30][CH2:29][CH2:28][CH2:27][CH:26]([OH:25])[CH2:37][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9]2)=[CH:4][CH:3]=1
Reactant: O=c1cc(-c2ccccc2)oc2cc(O)ccc12
Reactant: C1CCC(OCCCC2CO2)OC1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: O=c1cc(-c2ccccc2)oc2cc(OCC(O)CCCOC3CCCCO3)ccc12
Temperature: 100 °C

Procedure:
A solid mixture of 7-hydroxyflavone (32.0 g, 0.134 mol), piperidine (0.5 ml), and 2-(4,5-epoxypent-1-oxy)tetrahydropyran (50 g, 0.268 mol) was stirred and heated under nitrogen at 100° C. for 14 hours; it became a stirrable mixture after 6 hours heating at 100° C. The cooled reaction mixture was purified through a pad of silica gel eluting with CH2Cl2 initially and then CH2Cl2 --EtOAc (1:1). The resulting solid was stirred with ether and filtered, giving 43.9 g (77% crude yield) of an off-white solid; pure white crystals, mp 110°-112° C., were obtained from recrystallization from toluene.
Reaction SMILES: [C:1]([C:4]1[C:16]([OH:17])=[C:15]([CH2:18][CH3:19])[CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])(=O)[CH3:2].[O-]CC.[Na+].Cl>C(O)C>[CH3:2][C:1]1[C:4]2[C:16]([OH:17])=[C:15]([CH2:18][CH3:19])[CH:14]=[CH:13][C:5]=2[O:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)COc1ccc(CC)c(O)c1C(C)=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1oc2ccc(CC)c(O)c2c1C
Temperature: 25 °C
Yield: 50.2 %

Procedure:
To a solution of 1.92 g (7.22 mmol) of ethyl (2-acetyl-4-ethyl-3-hydroxyphenoxy)acetate in 35 mL of absolute ethanol was added 0.54 g (7.94 mmol) of sodium ethoxide. The reaction was heated at reflux for 3 h and then cooled to room temperature, acidified with 1N HCl, and concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The organics were washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/heaxnes (1:9) to provide 0.9 g of ethyl 3-methyl-4-hydroxy-5-ethylbenzofuran-2-carboxylate.
Reaction SMILES: [C:1]([C:4]1([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH2:7][CH2:6][CH2:5]1)(=O)[CH3:2].Cl.[NH2:17][OH:18].O.O.O.C([O-])(=O)C.[Na+]>O>[C:1](=[N:17][OH:18])([C:4]1([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH2:7][CH2:6][CH2:5]1)[CH3:2]
Reactant: CC(=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(=NO)C1(c2ccc(Cl)c(Cl)c2)CCC1

Procedure:
A mixture of 1-acetyl-1-(3,4-dichlorophenyl)cyclobutane (4.86 g) prepared as described in Example 1, hydroxylamine hydrochloride (1.6 g), sodium acetate trihydrate (3.3 g), industrial methylated spirit (15 ml) and water (2 ml) was heated under reflux for twenty hours. The cooled reaction mixture was poured into water and the oil which separated was cooled to give a solid which was recrystallised from industrial methylated spirit to give 1-acetyl-1-(3,4-dichlorophenyl)cyclobutane oxime (m.p. 120°-121° C.).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[CH3:9][N:10]([CH3:32])[CH:11]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)=[CH:18][CH:17]=2)[CH2:12]1>>[CH3:9][N:10]([CH3:32])[CH:11]1[CH2:15][CH2:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:31])[C:24]3[CH:25]=[CH:26][C:27]([O:30][C:2]4[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=4)=[CH:28][CH:29]=3)=[CH:20][CH:21]=2)[CH2:12]1
Reactant: Fc1ccc(Cl)nc1
Reactant: CN(C)C1CCN(c2ccc(NC(=O)c3ccc(O)cc3)cc2)C1
Product: CN(C)C1CCN(c2ccc(NC(=O)c3ccc(Oc4ccc(F)cn4)cc3)cc2)C1

Procedure:
2-Chloro-5-fluoropyridine was reacted with N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-4-hydroxybenzamide by method R. This resulted in the product with the molecular weight of 420.2 (C24H25FN4O2); MS (ESI): 421 (M+H+) as hydrotrifluoroacetate.
Reaction SMILES: Cl[CH:2]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:3]([NH:5][C:6]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:9]=[CH:8][C:7]=1[C:16](=[O:26])[CH2:17][C:18]([NH:20][C:21]1[S:22][CH:23]=[CH:24][N:25]=1)=[O:19])=O>CN(C)C1C=CN=CC=1.O1CCCC1>[C:27]1([CH:2]2[C:3]3=[N:5][C:6]4[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:9]=[CH:8][C:7]=4[C:16]([OH:26])=[C:17]3[C:18](=[N:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)[O:19]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(CC(=O)c1cccc(C(F)(F)F)c1NC(=O)C(Cl)c1ccccc1)Nc1nccs1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: Oc1c2c(nc3c(C(F)(F)F)cccc13)C(c1ccccc1)OC2=Nc1nccs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.3 %

Procedure:
1.82 g of 4-dimethylamino-pyridine were added to a solution of 6 g of the product of Step B in 150 ml of tetrahydrofuran and the mixture was stirred at room temperature for 16 hours and was evaporated to dryness under reduced pressure. The residue was extracted with 100 ml of water and 3 ml of hydrochloric acid were added to the aqueous extract which was stirred at room temperature for 15 minutes and was vacuum filtered. The product was washed with water and dried under reduced pressure at 90° C. to obtain 5.34 g of 1,3-dihydro-3-phenyl-1-[(2-thiazolyl)-imino]-5-trifluoromethyl-furo[3,4-b] quinoline-9-ol melting at 270° C. (decomposition).
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]([C:7]([O:9][CH3:10])=[O:8])[CH:4]([C:11]2[C:16]([O:17][CH3:18])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][C:12]=2[O:21][CH3:22])[CH:3]1C(OC)=O.[Cl-].[Na+].O>CN1CCCC1=O>[O:1]=[C:2]1[NH:6][CH:5]([C:7]([O:9][CH3:10])=[O:8])[CH:4]([C:11]2[C:12]([O:21][CH3:22])=[CH:13][C:14]([O:19][CH3:20])=[CH:15][C:16]=2[O:17][CH3:18])[CH2:3]1
Reactant: COC(=O)C1NC(=O)C(C(=O)OC)C1c1c(OC)cc(OC)cc1OC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)C1NC(=O)CC1c1c(OC)cc(OC)cc1OC
Temperature: 170 °C

Procedure:
(+)-Dimethyl 5-oxo-3-(2,4,6-trimethoxyphenyl)pyrrolidine-2,4-dicarboxylate (4.0 g, 0.0109 mol) was dissolved in N-methylpyrrolidone (15 mL). Sodium chloride (0.631 g, 0.0109 mol) and water (0.196 mL, 0.0109 mol) were added and the reaction mixture was heated to 170° C. for 5 hours. The reaction mixture was poured on ice (50 g) and the solid was filtered and dried.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[NH2:13])[CH:5]=[CH:6][CH:7]=1.C1CCN2C(=NCCC2)CC1.[CH:25]([S:28](Cl)(=[O:30])=[O:29])([CH3:27])[CH3:26]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH:13][S:28]([CH:25]([CH3:27])[CH3:26])(=[O:30])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCCC1c1cccc(F)c1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1cccc(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 100 mL round bottom flask equipped with a magnetic stirrer was charged with (+,−) cis-[2-(3-fluoro-phenyl)-cyclopentylamine (650 mg, 3.63 mmol) from preparation 14, methylene chloride (15.0 mL) and the solution cooled to 0° C. DBU (0.65 mL, 4.35 mmol) and isopropylsulfonyl chloride (0.49 mL, 4.35 mmol) were added. The reaction was then stirred at 0° C. for 60.0 minutes and brought to room temperature with stirring overnight. The reaction was diluted with methylene chloride and washed with 1N HCl, brine and the organic layer dried over sodium sulfate. The title compound.was purified by radial chromatography eluting with methylene chloride to give 573 mg (55%) of the purified title compound as a white solid. The nmr was consistent with the assigned structure.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:5]=1[NH2:6].Cl[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1>CN(C=O)C>[Cl:3][C:4]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:5]=1[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Nc1cc(I)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(I)ccc2Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under argon, 12.62 g (316.16 mmol, 60% in mineral oil) of sodium hydride were suspended in 250 ml of abs. DMF and cooled to 0° C. 32 g (126.3 mmol) of 2-chloro-5-iodoaniline, dissolved in 80 ml of abs. DMF, were then slowly added dropwise, and the mixture was stirred at 0° C. for 30 min. 41 ml (303 mmol) of 1-(chloromethyl)-4-methoxybenzene were then slowly added to the reaction mixture, and the mixture was subsequently warmed to room temperature. The mixture was stirred at RT overnight and then carefully poured into 150 ml of ice-water. The organic phase was separated off, and the aqueous phase was then extracted three more times with diethyl ether. The combined organic phases were dried over magnesium sulphate. After filtration, the solvent was removed under reduced pressure. The crude product obtained was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 40:1). This gave 59 g of the title compound (94% of theory).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].[F:10][C:11]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:12]=1[C:13](Cl)=[O:14]>>[OH:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[NH:1][C:13](=[O:14])[C:12]1[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:11]=1[F:10]
Reactant: Cc1ccc(O)c(N)c1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1F
Product: Cc1ccc(O)c(NC(=O)c2cc([N+](=O)[O-])ccc2F)c1

Procedure:
Prepared by the method of Example 15a), from 2-amino-4-methylphenol (283 mg, 2.3 mmol) and 2-fluoro-5-nitrobenzoyl chloride (468 mg, 2.3 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:5]2[N:15]=[C:16]([CH3:19])[C:17]([I:18])=[C:4]2[N:3]=1.CCN(C(C)C)C(C)C.[NH:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[CH2:34][OH:35]>C(#N)C>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]3[N:15]=[C:16]([CH3:19])[C:17]([I:18])=[C:4]3[N:3]=[C:2]([N:29]3[CH2:33][CH2:32][CH2:31][C@H:30]3[CH2:34][OH:35])[CH:7]=2)=[CH:9][CH:10]=1
Reactant: Cc1nn2c(-c3ccc(F)cc3)cc(Cl)nc2c1I
Reactant: OC[C@@H]1CCCN1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nn2c(-c3ccc(F)cc3)cc(N3CCC[C@H]3CO)nc2c1I
Yield: 61.2 %

Procedure:
5-Chloro-7-(4-fluorophenyl)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidine (241 mg), DIPEA (0.2 mL) and (S)-2-pyrrolidinemethanol (152 mg) are stirred at 90° C. for 16 hours in an acetonitrile (60 mL) solvent. The reaction solvent is removed by distillation under reduced pressure. The remainder is purified by column chromatography to yield the target compound (172 mg). 1H NMR (CDCl3, 300 MHz); δ 7.92 (m, 2H), 7.22 (m, 2H), 6.10 (s, 1H), 4.45 (br, 1H), 3.85-3.57 (m, 4H), 2.38 (s, 3H), 2.08-2.01 (m, 3H), 1.72 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][S:9]([CH3:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12][NH:13][CH3:14]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]=[S:9]([CH3:11])([N:13]([CH3:14])[CH3:12])=[O:10])=[CH:4][CH:3]=1
Reactant: CS(=O)Nc1ccc(Cl)nc1
Reactant: CNC
Product: CN(C)S(C)(=O)=Nc1ccc(Cl)nc1

Procedure:
The title compound is prepared from N-(6-chloropyridin-3-yl)methanesulfinamide and dimethylamine following a procedure analogous to that described for Intermediate 3 (Step 2). LC (method 1): tR=0.78 min; Mass spectrum (ESI+): m/z=234 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[C:21]([C:22]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:23]=2[CH2:24][CH2:25][NH:26][CH:27]3[CH3:32])=[CH:20][CH:19]=[CH:18][N:17]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[CH:29][CH:30]=[CH:31][C:22]=4[C:21]4[C:16]([O:15][CH3:14])=[N:17][CH:18]=[CH:19][CH:20]=4)[CH:27]3[CH3:32])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: COc1ncccc1-c1cccc2c1CCNC2C
Product: COc1ncccc1-c1cccc2c1CCN(C(=O)c1cc3ncc(Br)cn3n1)C2C

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-(2-Methoxy-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [Cl:1][C:2]1[C:10](C(F)(F)F)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:6])=[O:5].[Cl:15]C1C=C(Cl)C=CC=1C(O)=O.ClC1C(C(F)(F)F)=CC=CC=1C(O)=O>>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:15])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:6])=[O:5]
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Agent: O=C(O)c1cccc(C(F)(F)F)c1Cl
Product: O=C(Cl)c1ccc(Cl)cc1Cl

Procedure:
The title compound was prepared in a manner analogous to Intermediate 12 substituting 2,4-dichlorobenzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid.
Reaction SMILES: [NH2:1][C:2]1[O:6][C:5]([CH:7]([NH:16]C(=O)OCC2C=CC=CC=2)[CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:4][N:3]=1>CO.[Pd]>[NH2:16][CH:7]([C:5]1[O:6][C:2]([NH2:1])=[N:3][N:4]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1nnc(C(CCc2ccccc2)NC(=O)OCc2ccccc2)o1
Agent: [Pd]
Solvent: CO
Product: Nc1nnc(C(N)CCc2ccccc2)o1
Reaction time: 3 h

Procedure:
0.33 g of benzyl [1-(5-amino-[1,3,4]oxadiazol-2-yl)-3-phenylpropyl]carbamate were dissolved in 50 ml of dry methanol at RT, treated under argon with hydrogenation catalyst (10% palladium on carbon), and hydrogenated at RT for 3 h. The reaction mixture was filtered off through Celite, the filtrate was concentrated under reduced pressure, and the residue was dried under high vacuum. 5-(1-Amino-3-phenylpropyl)-[1,3,4]oxadiazol-2-ylamine was obtained, which was employed in the next stage without further purification.