Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1N2CN3CN(C2)C[N:2]1C3.Br[CH2:12][CH2:13][N:14]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[O:16][C:15]1=[O:23]>C(Cl)(Cl)Cl>[NH2:2][CH2:12][CH2:13][N:14]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[O:16][C:15]1=[O:23]
Reactant: O=c1oc2cccnc2n1CCBr
Reactant: C1N2CN3CN1CN(C2)C3
Solvent: ClC(Cl)Cl
Product: NCCn1c(=O)oc2cccnc21

Procedure:
0.013 mol of hexamethylenetetramine, dissolved beforehand in 20 cm3 of chloroform, and 0.01 mol of 3-(2-bromoethyl)-3H-oxazolo[4,5-b]pyridin-2-one, dissolved beforehand in 15 cm3 of chloroform, are introduced into a round-bottomed flask placed under argon and surmounted by a condenser. The mixture is heated to reflux for one week. The product is drained and dried. The precipitate is introduced into a ground-necked 250-cm3 flask equipped with a reflux condenser, and 50 cm3 of absolute alcohol and 10 cm3 of concentrated hydrochloric acid are added. The mixture is heated to reflux for two hours with magnetic stirring. The solvent is evaporated off on a water bath under vacuum and the product is recrystallized in alcohol at 95° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([C:22]2[N:30]=[C:29]([NH:31][C@H:32]4[CH2:37][CH2:36][C@H:35]([NH:38]C(OC(C)(C)C)=O)[CH2:34][CH2:33]4)[N:28]=[C:27]4[C:23]=2[N:24]=[CH:25][N:26]4C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl>CO>[NH2:38][C@H:35]1[CH2:34][CH2:33][C@H:32]([NH:31][C:29]2[N:28]=[C:27]3[C:23]([N:24]=[CH:25][NH:26]3)=[C:22]([N:18]3[C:19]4[C:15](=[CH:14][C:13]([NH:12][C:10]([NH:9][C:4]5[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=5)=[O:11])=[CH:21][CH:20]=4)[CH2:16][CH2:17]3)[N:30]=2)[CH2:37][CH2:36]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2nc(N3CCc4cc(NC(=O)Nc5ccc(Cl)c(Cl)c5)ccc43)c3ncn(C(=O)OC(C)(C)C)c3n2)CC1
Agent: Cl
Solvent: CO
Product: N[C@H]1CC[C@H](Nc2nc(N3CCc4cc(NC(=O)Nc5ccc(Cl)c(Cl)c5)ccc43)c3nc[nH]c3n2)CC1
Reaction time: 48 h

Procedure:
The product obtained in stage 1 is dissolved in 5 ml of methanol. 5 ml of a 2N solution of hydrochloric acid in methanol are added. Stirring is carried out for 48 hours at ambient temperature, followed by evaporation to dryness. The residue is chromatographed on an Xterra LCMSprep column, eluting with acetonitrile/ammonium hydrogen carbonate buffer at 0.2% as a gradient. 30 mg of expected product, example 43, are thus recovered.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:10]([OH:12])=O)[NH:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:13][C:14]1[CH:15]=[C:16]([C:21]2[O:25][C:24]([CH2:26][CH2:27][NH2:28])=[CH:23][CH:22]=2)[CH:17]=[CH:18][C:19]=1[Cl:20]>>[Cl:13][C:14]1[CH:15]=[C:16]([C:21]2[O:25][C:24]([CH2:26][CH2:27][NH:28][C:10]([C:7]3[NH:8][N:9]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=3)=[O:12])=[CH:23][CH:22]=2)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1
Reactant: CC(C)(C)c1cc(C(=O)O)[nH]n1
Product: CC(C)(C)c1cc(C(=O)NCCc2ccc(-c3ccc(Cl)c(Cl)c3)o2)[nH]n1
Yield: 33 %

Procedure:
The title compound was synthesized as in Example 17 starting from 5-tert-butyl-2H-pyrazole-3-carboxylic acid and 2-(5-(3,4-dichlorophenyl)furan-2-yl)ethanamine. Crude product was purified by chromatography (silica column, eluent: 3% MeOH/DCM) to give 53 mg (33%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.27 (s, 9H), 2.97 (t, 2H), 3.54 (q, 2H), 6.33 (m, 1H), 6.39 (br s, 1H), 7.02 (d, 1H), 7.62 (m, 2H), 7.86 (d, 1H), 8.20 (s, 1H), 12.88 (s, 1H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]([CH3:17])[CH:14]=[C:13]([OH:18])[C:12]2=[O:19].[OH-].[Na+]>O>[CH3:1][S:2]([O:18][C:13]1[C:12](=[O:19])[C:11]2[C:16](=[C:7]([F:6])[CH:8]=[CH:9][CH:10]=2)[N:15]([CH3:17])[CH:14]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1cc(O)c(=O)c2cccc(F)c21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1cc(OS(C)(=O)=O)c(=O)c2cccc(F)c21
Reaction time: 0.33 h

Procedure:
Methanesulphonyl chloride (1.1 g) d to a solution of 8-fluoro-3-hydroxy-1 -methyl-4-quinolone (1.83 g) and sodium hydroxide (0.6 g) in water (15 ml) and the resultant mixture stirred at 0 to 5° for 3 hours with the pH being adjusted to 9 after 20 minutes using aqueous sodium hydroxide (5M, 2 ml). Further methanesulphonyl chloride (1.1 g) was then added and the mixture stirred for 105 minutes whilst maintaining the pH at 9 by the addition of aqueous sodium hydroxide (5M, 2ml). The resultant solid was collected by filtration, washed with water (20 ml) and crystallised from industrial methylated spirit (100 ml) to give the novel compound 8-fluoro-1-methyl-4-oxo-1,4-dihydroquinol-3-yl methanesulphonate, m.p. 207°-209°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][CH3:16]>>[CH2:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)[CH2:15][CH3:16]
Reactant: CCCOCCCCCl
Reactant: O=C1CCNCC1
Product: CCCOCCCCN1CCC(=O)CC1

Procedure:
1-(4-Propoxybutyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-4-propoxybutane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9](=O)[CH:10]=[CH:11][N:12](C)[CH3:13])=[C:4]([F:16])[CH:3]=1.C[NH:18]N>CO>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[CH:10]=[CH:11][N:12]([CH3:13])[N:18]=2)=[C:4]([F:16])[CH:3]=1
Reactant: CNN
Reactant: CN(C)C=CC(=O)c1c(F)cc(Br)cc1F
Solvent: CO
Product: Cn1ccc(-c2c(F)cc(Br)cc2F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(4-bromo-2,6-difluorophenyl)-3-(dimethylamino)-2-propene-1-one (i.e. the product of Step A, 2.39 g, 8.24 mmol) and methylhydrazine (0.42 g, 9.05 mmol) in methanol (50 mL) was stirred at room temperature overnight. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by medium pressure liquid chromatography on silica gel eluted with 0 to 100% ethyl acetate in hexanes to yield the title compound (0.86 g).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[C:14]([O:16]C1C=CC([N+]([O-])=O)=CC=1)=O)=[O:7])([CH3:4])[CH3:3].[NH2:37][C@H:38]([C:41]([NH:43][C@H:44]([C:50]([NH:52][C@H:53]([C:57]([N:59]1[CH2:100][CH2:99][CH2:98][C@H:60]1[C:61]([NH:63][C@H:64]([C:69]([NH:71][C@H:72]([C:76]([NH:78][C@H:79]([C:83]([NH:85][C@H:86]([C:91]([O:93][C:94]([CH3:97])([CH3:96])[CH3:95])=[O:92])[CH2:87][CH:88]([CH3:90])[CH3:89])=[O:84])[C@@H:80]([CH3:82])[OH:81])=[O:77])[CH:73]([CH3:75])[CH3:74])=[O:70])[CH2:65][CH:66]([CH3:68])[CH3:67])=[O:62])=[O:58])[C@@H:54]([CH3:56])[OH:55])=[O:51])[CH2:45][CH2:46][C:47](=[O:49])[NH2:48])=[O:42])[CH2:39][OH:40]>CN(C=O)C>[NH:26]([C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28])[C@H:13]([C:14]([NH:37][C@H:38]([C:41]([NH:43][C@H:44]([C:50]([NH:52][C@H:53]([C:57]([N:59]1[CH2:100][CH2:99][CH2:98][C@H:60]1[C:61]([NH:63][C@H:64]([C:69]([NH:71][C@H:72]([C:76]([NH:78][C@H:79]([C:83]([NH:85][C@H:86]([C:91]([O:93][C:94]([CH3:96])([CH3:95])[CH3:97])=[O:92])[CH2:87][CH:88]([CH3:89])[CH3:90])=[O:84])[C@@H:80]([CH3:82])[OH:81])=[O:77])[CH:73]([CH3:74])[CH3:75])=[O:70])[CH2:65][CH:66]([CH3:67])[CH3:68])=[O:62])=[O:58])[C@@H:54]([CH3:56])[OH:55])=[O:51])[CH2:45][CH2:46][C:47](=[O:49])[NH2:48])=[O:42])[CH2:39][OH:40])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7]
Reactant: CC(C)C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CO)[C@@H](C)O)C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C)[C@@H](C)O)C(C)C
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)[C@@H](C)O)C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C)[C@@H](C)O)C(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.35 g Z-Lys(Boc)-ONp (2.7 mmol) and 2.42 g (2.64 mmol) H-Ser-Gln-Thr-Pro-Leu-Val-Thr-Leu-OtBu (F. 1) are dissolved in 35 ml DMF. After stirring at room temperature for 18 hours the reaction mixture is evaporated to dryness.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.[NH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[O:17])=[CH:13][CH:12]=2)=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: Nc1cccnc1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Product: O=C(Nc1cccnc1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
320 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 400 mg of 4-(methoxycarbonyl)benzoic acid via Procedure G to give methyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoate. 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoate was then hydrolyzed via Procedure M to give 550 mg of 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid. 50 mg of 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 3-aminopyridine via Procedure G. The organic layer was evaporated to dryness and purified on reverse phase HPLC to yield N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(pyridin-3-yl)terephthalamide. MS (Q1) 429 (M)+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][C:8]=1[C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=O)=O.[OH:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[OH:31][C:32]1[CH:33]=[C:34]([C:7]2[C:16]3[C:11](=[C:12]([C:17]([F:19])([F:18])[F:20])[CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][C:8]=2[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:28])[CH:35]=[CH:36][CH:37]=1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1cccc(O)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Yield: 86 %

Procedure:
A solution of 3-benzoyl-8-(trifluoromethyl)quinolin-4-yl trifluoromethanesulfonate (1.6 g, 3.6 mmol), 3-hydroxyphenylboronic acid (0.60 g, 4.3 mmol), and K3PO4 (3.0 g) in dioxane (50 ml) was heated to reflux. After, 4 hr, the reaction was cooled, filtered, concentrated to give a solid which was triturated with 10% EtOAc/hexane to give a white solid (1.2 g Yield=86%); MS (ESI) m/z 394 ([M+H]+; 1H NMR (DMSO) δ 9.54 (s, 1H), 9.11 (s, 1H), 8.339 (d, 1h, J=7.0 Hz), 8.01(d, 1H, J=8.0 Hz), 7.83-7.79 (m, 1H), 7.64-7.61 (m, 2h), 7.55-7.51 (m, 1H), 7.39 (t, 2H, J=7.8 Hz), 7.13 (t, 1H, =7.8 Hz), 6.72-6.68 (m, 3H); Anal. Calcd for C23H14F3NO2: C, 70.23; H, 3.59; N, 3.56. Found: C, 69.67; H, 3.43; N, 3.51.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][O:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.O>C(Cl)Cl.N1C=CC=CC=1>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[CH2:9][O:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc(OCc2cc(Cl)ccc2N)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(OCc2cc(Cl)ccc2NS(=O)(=O)c2ccc(Cl)cc2)cc1
Reaction time: 21 h
Yield: 43.1 %

Procedure:
To a solution of methyl 4-(2-amino-5-chlorophenylmethoxy)benzoate (450 mg; prepared in Reference Example 10.) in methylene chloride (4 ml), pyridine (0.24 ml) and 4-chlorobenzenesulfonylchloride (380 mg) were added. The mixture was stirred for 21 hour. To the reaction mixture, water was added. The mixture was extracted with ethyl acetate. The organic layer was washed, dried over and concentrated under the reduced pressure. The residue was purified by recrystallization from hexane-AcOEt mixture solvent to give the title compound (310 mg) having the following physical data.
Reaction SMILES: [C:1]1([C:7]2[N:8]([CH2:19][C:20]([OH:22])=O)[C:9](=[O:18])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:25])=O>C(Cl)Cl>[C:1]1([C:7]2[N:8]([CH2:19][C:20]([Cl:25])=[O:22])[C:9](=[O:18])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cn1c(-c2ccccc2)c(-c2ccccc2)oc1=O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)Cn1c(-c2ccccc2)c(-c2ccccc2)oc1=O
Temperature: 25 °C

Procedure:
A mixture of 4,5-diphenyl-2-oxo-4-oxazolin-3-ylacetic acid (2.1 g, 7.1 mmol) [J. Org. Chem., 38, 3034 (1973)], thionyl chloride (5 ml) and methylene chloride (20 ml) is refluxed for 2.5 hours. After cooling to room temperature the solvent is removed in vacuo and resulting oil crystallizes on standing. The product is triturated with ether-hexane to give the title compound; 2.0 g mp 104°-112°.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:33]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)[C:14](=[O:32])[N:15]([CH2:24][CH:25]([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[N:18]=2)=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>ClCCl>[NH2:33][C@@H:13]([CH2:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:11][CH:10]=1)[C:14]([N:15]([CH2:24][CH:25]([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[N:18]=1)=[O:32]
Reactant: CCOC(CN(Cc1cccc(F)n1)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21)OCC
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CCOC(CN(Cc1cccc(F)n1)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1)OCC
Yield: 95.4 %

Procedure:
To a mixed solution of 9H-fluoren-9-ylmethyl N-((1S)-2-(4-(tert-butoxy)phenyl)-1-((2,2-diethoxyethyl)((6-fluoropyridin-2-yl)methyl)carbamoyl)ethyl)carbamate (1.37 g, 2.00 mmol) described in Production Example 2-1 and dichloromethane (7.0 mL) was added piperidine (7.0 mL) at room temperature. The resultant mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under a reduced pressure, and the resultant residue was purified by NH silica gel column chromatography (ethyl acetate) to give the title compound (881 mg, yield: 95%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=1.[CH3:17][CH2:18][O-:19].[Na+].CCO>CN(C=O)C.CCOC(C)=O>[CH2:18]([O:19][C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=1)[CH3:17]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1N1CCCCC1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1ccc([N+](=O)[O-])c(N2CCCCC2)c1
Yield: 54 %

Procedure:
To 1-(5-chloro-2-nitro-phenyl)-piperidine (197 mg, 0.810 mmol, as prepared in Example 3, step (a)) in 1.5 mL of DMF was added 4 mL of 0.5 M NaOEt in EtOH (1.94 mmol). The resultant solution was heated at 90° C. for 24 h. The reaction was diluted with EtOAc (50 mL) and washed with water (50 mL), dried (Na2SO4) and concentrated in vacuo. Purification by preparative tic (20% EtOAc-hexane) gave 110 mg (54%) of the title compound. Mass spectrum (ESI, m/z): Calcd. for C13H18N2O3, 251.1 (M+H), found 251.1.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.Cl[C:34]([C:36]1([O:39]C(=O)C)[CH2:38][CH2:37]1)=[O:35]>>[OH:39][C:36]1([C:34]([N:2]2[CH2:6][CH2:5][C@H:4]([NH:7][C:8]([C:10]3[C:14]4[N:15]=[CH:16][N:17]=[C:18]([C:19]5[C:27]6[O:26][CH2:25][O:24][C:23]=6[CH:22]=[CH:21][C:20]=5[O:28][CH2:29][CH:30]5[CH2:32][CH2:31]5)[C:13]=4[NH:12][CH:11]=3)=[O:9])[CH2:3]2)=[O:35])[CH2:38][CH2:37]1
Reactant: O=C(N[C@H]1CCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CC(=O)OC1(C(=O)Cl)CC1
Agent: Cl
Product: O=C(N[C@H]1CCN(C(=O)C2(O)CC2)C1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12

Procedure:
Starting from 4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (S)-pyrrolidin-3-ylamide hydrochloride (example A143) and acetic acid 1-chlorocarbonyl-cyclopropyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[CH:16][N:17]2[CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27].[C:30](Cl)(=[O:34])[C:31](Cl)=[O:32]>>[CH3:27][Si:26]([CH3:29])([CH3:28])[CH2:25][CH2:24][O:23][CH2:22][N:17]1[C:18]2[C:14](=[C:13]([N:12]3[C:3]4[CH:4]=[CH:5][C:6]5[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=5[C:2]=4[NH:1][C:31](=[O:32])[C:30]3=[O:34])[CH:21]=[CH:20][CH:19]=2)[CH:15]=[CH:16]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Nc3ccc4c(c3N)CCCC4)cccc21
Reactant: O=C(Cl)C(=O)Cl
Product: C[Si](C)(C)CCOCn1ccc2c(-n3c(=O)c(=O)[nH]c4c5c(ccc43)CCCC5)cccc21

Procedure:
1-Amino-2-[1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-4-yl]amino-5,6,7,8-tetrahydronaphthalene and oxalyl chloride were used in a process similar to Example 1(3) to give the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][Br:10]
Reactant: Cc1ccc(F)cc1Br
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(CBr)c(Br)c1
Yield: 87.1 %

Procedure:
Combine 2-bromo-4-fluoro-1-methyl-benzene (15 g, 79.3 mmol), N-bromosuccinimide (18.08 g, 101.6 mmol), and 2,2-azobisisobutyronitrile (3.9 g, 23.8 mmol) in carbon tetrachloride (150 mL) in a round bottom flask fitted with a reflux condensor. Heat the mixture at reflux for 21 h. Cool the mixture and remove the solvent under reduced pressure. Suspend the crude mixture in DCM and wash with water. Wash the organics with aqueous saturated sodium chloride and dry over sodium sulfate. Filter and remove the solvent under reduced pressure to obtain the crude product. Purify by column chromatography (1% ethyl acetate in hexane→10% ethyl acetate in hexanes) to give the title compound as an oily white solid (18.5 g, 87%). GCMS m/z 268 [M]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[CH2:9]1.[H-].[Na+].Cl[CH2:19][C:20](=O)[CH3:21]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[C:11]2[C:20]([CH3:21])=[CH:19][O:15][C:10]=2[CH2:9]1
Reactant: O=C1CC(=O)CC(c2ccccc2F)C1
Reactant: CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1coc2c1C(=O)CC(c1ccccc1F)C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-(2-fluorophenyl)cyclohexane-1,3-dione (mp180-181° C.; 1.03 g) in DMF (20 ml) was added 60% sodium hydride (0.22 g), and the mixture was stirred, under argon atmosphere, at room temperature for 15 minutes. To the mixture was added chloroacetone (0.45 ml), and the mixture was stirred at 150° C. overnight (14 hours). The reaction solution was cooled and concentrated under reduced pressure. To the residue was added ice-water, and the mixture was extracted with ethyl acetate. The upper layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure, and the residue was subjected to silica gel chromatography and eluted with ethyl acetate/hexane to give 6-(2-fluorophenyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.22 g).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1>>[CH3:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[O:8])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Product: COc1ccc(NC(=O)c2cccnc2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from nicotinoyl chloride and 4-methoxy-2-nitroaniline and was obtained as an orange solid as described in Example 1. 1H NMR (DMSO-d6): 10.74 (s, 1H), 9.10 (d, J=2.4, 1H), 8.80-8.78 (m, 1H), 7.62-7.54 (m, 3H), 7.39-7.35 (m, 1H), 3.87 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[C:4]([C:15]2[O:16][C:17]([CH2:20][OH:21])=[CH:18][CH:19]=2)[CH:3]=1.Cl.[N:23](OCC)=[O:24].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[C:4]([C:15]2[O:16][C:17]([CH2:20][OH:21])=[CH:18][CH:19]=2)[C:3]=1[N:23]=[O:24]
Reactant: CCON=O
Reactant: Nc1cc(-c2ccc(CO)o2)nn1Cc1ccccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Nc1c(N=O)c(-c2ccc(CO)o2)nn1Cc1ccccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 g (34.8 mmol) of 5-amino-1-(2-fluorobenzyl)-3-(5-hydroxymethyl-2-furyl)-pyrazole are initially introduced in a mixture of 66 ml of ethanol and 26.7 ml of 5% strength aqueous hydrochloric acid, treated in the course of 5 minutes with 26.4 ml of a 15% strength ethanolic solution of ethyl nitrite and stirred at room temperature for 1 h. The deep violet reaction solution is added to aqueous potassium carbonate solution and extracted with ethyl acetate. After evaporating the organic phase in vacuo, 8 g of the residue are obtained, which can be immediately reacted further. (Rf=0.17, T1E1, SiO2).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=2)=[O:13])[N:3]=1.[CH3:21][C:22]1[NH:26][N:25]=[C:24]([NH2:27])[CH:23]=1.CCN(C(C)C)C(C)C.[I-].[K+]>CN(C)C=O.O>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]([C:4]2[N:3]=[C:2]([NH:27][C:24]3[CH:23]=[C:22]([CH3:21])[NH:26][N:25]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[O:13])=[N:15][CH:16]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: O=C(c1ccc(F)cn1)c1nc(Cl)c2ccccc2n1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(C(=O)c3ccc(F)cn3)nc3ccccc23)n[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 6.6 %

Procedure:
To a stirred mixture of (4-chloroquinazolin-2-yl)(5-fluoropyridin-2-yl)methanone (244 mg, 0.85 mmol) and 5-methyl-3-aminopyrazole (99 mg, 1.02 mmol) in N,N-dimethylformamide (3 mL) were added DIEA (0.3 mL, 4.22 mmol) and potassium iodide (141 mg, 0.85 mmol) and the mixture was stirred at rt for 15 h and then at 60° C. for 2.5 h. The mixture was allowed to cool to rt, and then water was added. The precipitated solid was collected by filtration. A portion of the solid (180 mg) was purified by preparative reverse-phase HPLC eluting with 30% to 70% acetonitrile/0.05% aq HOAc to afford (5-fluoropyridin-2-yl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone (19.6 mg). 1H NMR (300 MHz, CDCl3) δ 12.19 (s, 1H), 10.65 (s, 1H), 8.72-8.69 (m, 2H), 8.26 (m, 1H), 8.00 (td, J=3 Hz, J=8.7 Hz, 1H), 7.92-7.80 (m, 2H), 7.66 (t, J=7.5 Hz, 1H), 6.34 (s, 1H), 2.16 (s, 3H); LC-MS (ESI) m/z 349 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH:7]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9]2)=[CH:4][CH:3]=1.Cl>[Pd].CCO>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(=O)c2ccc(O)cc2o1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1CCc2ccc(O)cc2O1

Procedure:
To a large hydrogenation vessel were added ethyl 7-hydroxychromone-2-carboxylate (=ethyl 7-hydroxy-4-oxo-4H-chromene-2-carboxylate) (675.4 g, 2.88 mol), EtOH 4 liters, conc. hydrochloric acid 40 ml. The resulting suspension was combined with 5% Pd/C 68 g, and subjected to hydrogenation condition (H2, 40 psi, rt) overnight. The reaction mixture was filtered through a pad of celite to remove the catalyst. The filtrate was concentrated to give thick oily material, which solidified upon standing. Tan solid 630.1 g (98%).