Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].[Br:13]Br.Br>C(Cl)(Cl)Cl>[Br:13][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:11])[C:2]2([CH3:12])[CH3:1]
Reactant: CC1(C)C(=O)Nc2ccccc21
Reactant: BrBr
Agent: Br
Solvent: ClC(Cl)Cl
Product: CC1(C)C(=O)Nc2ccc(Br)cc21
Temperature: 25 °C

Procedure:
3,3-Dimethyl-1,3-dihydro-2H-indol-2-one (1.12 g, 0.00695 mol) was dissolved in chloroform and stirred at room temperature under nitrogen. Bromine (1.12 g) was added and the mixture was heated under reflux until HBr evolution ceased and the bromine colour was discharged from the solution. The solution was washed with sodium metabisulphite solution and sodium hydrogen carbonate solution, dried (MgSO4), filtered and concentrated to dry under reduced pressure to give 5-bromo-3,3-dimethyl-1,3-dihydro-2H-indol-2-one as a yellow solid. 1H NMR (CDCl3) 1.39 (6H s), 6.8 (1H d), 7.3 (2H m), 7.9 (1H broad).
Reaction SMILES: FC1C=CC([S:8]([Cl:11])(=[O:10])=[O:9])=CC=1OC.N[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([O:23][CH2:24][CH3:25])[CH:16]=1>>[C:19]([C:18]1[CH:21]=[CH:22][C:15]([S:8]([Cl:11])(=[O:10])=[O:9])=[CH:16][C:17]=1[O:23][CH2:24][CH3:25])#[N:20]
Reactant: COc1cc(S(=O)(=O)Cl)ccc1F
Reactant: CCOc1cc(N)ccc1C#N
Product: CCOc1cc(S(=O)(=O)Cl)ccc1C#N

Procedure:
The titled compound is prepared analogously to 4-fluoro-3-methoxy-benzenesulfonyl chloride (Intermediate 102a) by replacing 4-fluoro-3-methoxyaniline with 4-amino-2-ethoxy-benzonitrile.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:7])=[CH:5][N:6]=1.Br[CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15]>>[CH3:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][N:6]1[CH:5]=[C:4]([CH3:7])[S:3][C:2]1=[NH:1]
Reactant: COCCOCCBr
Reactant: Cc1cnc(N)s1
Product: COCCOCCn1cc(C)sc1=N
Yield: 83.8 %

Procedure:
A mixture of 2-amino-5-methylthiazole (1.5 g, 13.0 mmol) and 1-bromo-2-(2-methoxyethoxy)ethane (Aldrich, 2.0 mL, 14.5 mmol) was processed as in Example 157A to afford the title compound (2.2 g, 10.9 mmol, 78% yield). 1H NMR (300 MHz, CD3OD) δ ppm 2.29 (d, J=1.36 Hz, 3H) 3.34 (s, 3H) 3.49-3.54 (m, 2H) 3.60-3.66 (m, 2H) 3.80 (t, J=5.10 Hz, 2H) 4.13 (t, J=4.80 Hz, 2H) 6.99-7.04 (m, 1H); MS (DCI/NH3) m/z 217 (M+H)+.
Reaction SMILES: [CH:1]12[CH:7]([NH:8][C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[NH:14][N:13]=[CH:12]4)[CH:4]([CH2:5][CH2:6]1)[CH2:3][NH:2]2.[OH:18][CH2:19][CH2:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[CH3:30])[CH:25]=O>>[NH:14]1[C:15]2[C:11](=[CH:10][C:9]([NH:8][CH:7]3[CH:4]4[CH2:5][CH2:6][CH:1]3[N:2]([CH2:25][C:24]3[CH:27]=[CH:28][C:29]([CH3:30])=[C:22]([CH:23]=3)[O:21][CH2:20][CH2:19][OH:18])[CH2:3]4)=[CH:17][CH:16]=2)[CH:12]=[N:13]1
Reactant: c1cc2[nH]ncc2cc1NC1C2CCC1NC2
Reactant: Cc1ccc(C=O)cc1OCCO
Product: Cc1ccc(CN2CC3CCC2C3Nc2ccc3[nH]ncc3c2)cc1OCCO

Procedure:
Reaction of Intermediate 23 with 3-(2-hydroxyethoxy)-4-methylbenzaldehyde affords the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1.[OH:26][C:27]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:15][C:14]([F:17])([F:16])[C:13]([C:6]1[C:7]([CH3:12])=[N:8][C:9]2[C:4]([C:5]=1[C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)=[CH:3][C:2]([N:30]1[CH2:31][CH2:32][C:27]([OH:26])([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:28][CH2:29]1)=[CH:11][CH:10]=2)=[O:18]
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(F)cc2)c1C(=O)C(F)(F)F
Product: Cc1nc2ccc(N3CCC(O)(c4ccccc4)CC3)cc2c(-c2ccc(F)cc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 32 %

Procedure:
The title compound was prepared from 1-[6-Bromo-4-(4-fluoro-phenyl)-2-methyl-quinolin-3-yl]-2,2,2-trifluoro-ethanone [example 24] and 4-hydroxy-4-phenylpiperidine according to the procedure of example 25, except that the reaction time was of 16 h. Yield: 32%; MS: m/z=509 (M+H).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]2[CH2:9][CH2:10][O:11][C:12]3[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:13]=3[C:14]=2[N:15]=1)=[O:5])C.[OH-].[Na+].Cl>O1CCCC1.O>[Br:20][C:18]1[CH:17]=[CH:16][C:13]2[C:14]3[N:15]=[C:6]([C:4]([OH:5])=[O:3])[S:7][C:8]=3[CH2:9][CH2:10][O:11][C:12]=2[CH:19]=1
Reactant: CCOC(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reaction time: 2 h

Procedure:
To a solution of 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid ethyl ester from Example 21 (518 mg) in tetrahydrofuran (10 ml) was added a solution of sodium hydroxide (117 mg) in water (2 mL) Methanol (5 mL) was also added to aid dissolution. After 2 hours, the reaction mixture was acidified with HCl (2M) and the reaction mixture was then extracted with dichloromethane, dried (MgSO4) and the solvent removed in vacuo to yield 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid.
Reaction SMILES: C([SnH](CCCC)CCCC)CCC.Br[CH:15]1[CH:20]([OH:21])[CH2:19][CH2:18][CH2:17][CH:16]1[N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32].N(C(C)(C)C#N)=NC(C)(C)C#N>C1(C)C=CC=CC=1.CO>[OH:21][CH:20]1[CH2:19][CH2:18][CH2:17][CH:16]([N:22]2[C:23](=[O:32])[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]2=[O:31])[CH2:15]1
Reactant: O=C1c2ccccc2C(=O)N1C1CCCC(O)C1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1C1CCCC(O)C1
Temperature: 80 °C
Reaction time: 64 h
Yield: 79.7 %

Procedure:
Tri-n-butyltin hydride (430 g, 1.48 mol) was added to a stirred solution of 2-(2-bromo-3-hydroxy-cyclohexyl)-isoindole-1,3-dione (400 g, 1.23 mol) and 2,2′-azobis(2-methylpropionitrile) (20 g) in toluene (4000 mL) and methanol (400 mL) and the reaction mixture was stirred at 80° C. for 64 h. The reaction mixture was concentrated to give the crude product. The crude product was washed with petroleum ether and ethyl acetate (1:1) to give 2-(3-hydroxy-cyclohexyl)-isoindole-1,3-dione (240 g, 0.98 mol) as a white solid. 1H NMR (CD3OD, 400 MHz): δ ppm 7.82 (m, 4H), 4.16 (m, 1H), 3.63 (m, 1H), 2.13 (m, 2H), 1.98 (d, 2H), 1.89 (m, 1H),1.68 (t, 1H), 1.46 (m, 1H),1.31 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1[N:7]=[C:8]([NH2:11])[S:9][CH:10]=1)[CH3:2].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([O:37][CH3:38])=[C:18]([S:20]([N:23]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]3[CH:30]=[CH:31][C:32]([C:34](O)=[O:35])=[CH:33][C:24]2=3)(=[O:22])=[O:21])[CH:19]=1>>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:34]([C:32]2[CH:31]=[CH:30][C:25]3[CH2:26][CH2:27][CH2:28][CH2:29][N:23]([S:20]([C:18]4[CH:19]=[C:14]([Cl:13])[CH:15]=[CH:16][C:17]=4[O:37][CH3:38])(=[O:21])=[O:22])[C:24]=3[CH:33]=2)=[O:35])[S:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCCCc2ccc(C(=O)O)cc21
Product: CCOC(=O)Cc1csc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCCC3)n1

Procedure:
1-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-8-carboxylic acid was converted to the title compound in analogy to example 8, steps 3 and 4. Step 3 was performed using (2-amino-thiazol-4-yl)-acetic acid ethyl ester and 1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-8-carboxylic acid and yielded (2-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-8-carbonyl]-amino}-thiazol-4-yl)-acetic acid ethyl ester, which was hydrolyzed to (2-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-8-carbonyl]-amino}-thiazol-4-yl)-acetic acid in step 4, MS (ISP): m/e=536.1 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]([CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH2:9]O)([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]([CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH2:9][Br:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)Cc1cccnc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CBr)Cc1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ((R)-2-hydroxy-1-pyridin-3-ylmethyl-ethyl)-carbamic acid tert-butyl ester (0.43, 1.70 mmol) in dichloromethane (10 ml) is added carbon tetrabromide (0.33 g), 2.04 mmol) and triphenylphosphine (0.23 g, 1.70 mmol). The reaction mixture is stirred at ambient temperature for 2 hours, filtered, and the filtrate partioned between ethylacetate and hydrochloric acid (1M). The aqueous phase is separated, neutralised with saturated sodium bicarbonate solution and extracted into dichloromethane. The dichloromethane is dried over magnesium sulphate and evaporated to afford ((R)-2-bromo-1-pyridin-3-ylmethyl-ethyl)-carbamic acid tert-butyl ester. 1H NMR (400 MHz, CDCl3) δ 1.29 (s 9H), 3.05 (dd J 14.3 9.8 1H), 3.18 (dd J 14.3 4.9 1H), 3.51 (d J 4.9 2H) 4.07-4.16 (m 1H) 7.84 (dd J 7.9 5.9 1H), 8.35 (d J 7.9 1H), 8.65 (d, J 5.4 1H), 8.86 (s, 1H).
Reaction SMILES: [ClH:1].CO[C:4]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][N:5]=1.[NH2:11][NH:12][C:13]([NH:15][NH2:16])=[S:14]>CO>[ClH:1].[NH2:11][N:12]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:4][NH2:5])=[N:16][N:15]=[C:13]1[SH:14]
Reactant: COC1=NCCCCC1
Reactant: NNC(=S)NN
Agent: Cl
Solvent: CO
Product: NCCCCCc1nnc(S)n1N
Temperature: 25 °C
Yield: 56.4 %

Procedure:
To 200 ml of methanol is added 3.6 g (0.1 mole) of gaseous HCl followed by 12.7 g (0.1 mole) of O-methylcaprolactam and then 10.6 g (0.1 mole) of thiocarbohydrazide. After heating at reflux for 2 hours, the mixture is allowed to cool to room temperature and is refrigerated. The solid product is recrystallized twice from methanol/ethyl acetate, affording 13.4 g of 4-amino-5-(5-aminopentyl)-4H-1,2,4-triazole-3-thiol hydrochloride. m.p. 192°-194° C.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[C:18](C(OCC)=O)=[C:17]([C:24]2[N:25]=[N:26][C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][CH:29]=2)[C:16]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:15]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)[N:14]=1)=O)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[CH2:33]([O:32][C:30]([C:27]1[N:26]=[N:25][C:24]([C:17]2[C:18]3[C:6](=[O:5])[N:8]4[CH:9]([C:13]=3[N:14]=[C:15]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=3)[C:16]=2[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:10][CH2:11][CH2:12]4)=[CH:29][CH:28]=1)=[O:31])[CH3:34]
Reactant: CCOC(=O)c1ccc(-c2c(C(=O)OCC)c(Cc3ccc(F)cc3)nc([C@@H]3CCCN3C(=O)OC(C)(C)C)c2C(=O)OCC)nn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ccc(-c2c(C(=O)OCC)c(Cc3ccc(F)cc3)nc3c2C(=O)N2CCCC32)nn1
Reaction time: 1 h
Yield: 71.9 %

Procedure:
Diethyl 2-[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]-4-[6-(ethoxycarbonyl)-3-pyridazinyl]-6-(4-fluorobenzyl)-3,5-pyridinedicarboxylate (E, 260 mg crude) was first dissolved in 15 ml mixture of trifluoroacetic acid and dichloromethane (2 to 1 ratio) and stirred for 1 hour followed by the removal of the solvent. To this residue, 15 ml of mixture of triethylamine and dichloromethane (1 to 2 ratio) was added and the mixture was stirred for 2 hours. Upon removal of the solvent, the residue was purified by flash chromatography. 145 mg solid was obtained. 1H NMR (400 MHz, CDCl3) δ 8.21 (d, 1H), 8.03 (d, 1H), 7.18 (t, 2H), 6.90 (t, 2H), 4.75 (m, 1H), 4.54 (q, 2H), 4.42 (m, 2H), 3.96 (q, 2H), 3.65 (m, 1H), 3.38 (m, 1H), 2.45 (m, 1H), 2.32 (m, 2H), 1.45 (t, 3H), 1.40 (m, 1H), 0.92 (t, 3H) ppm. ESI-MS m/z 505 (M+H)+.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:20]1[CH2:22][CH:21]1[CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[S:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1>CCO>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([CH2:22][CH:21]([OH:20])[CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[S:32][C:33]3[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=3[N:35]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: c1ccc(-c2nc3ccccc3s2)c(OCC2CO2)c1
Solvent: CCO
Product: OC(COc1ccccc1-c1nc2ccccc2s1)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Yield: 42.7 %

Procedure:
A solution of 1-benzhydryl-piperazine (891 mg, 3.53 mmol) and 2-[2-(oxiran-2-yl-methoxy)phenyl]benzothiazole (1000 mg, 3.53 mmol) in EtOH (7 mL) were refluxed under N2 (g) for about 16 hours. The mixture was concentrated in vacuo to a white foam and flash chromatographed on silica (35% EtOAc/hexanes) to afford 807 mg (42%) of the free base of the product as a white solid. mp 152-155° C.; LSIMS m/z 536 (MH+).
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[Br:17][C:18]1[O:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1>CN(C)C=O>[Br:17][C:18]1[O:22][C:21](/[CH:23]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:20][CH:19]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1ccc(Br)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(Br)o1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.8 %

Procedure:
To a solution (200 ml) of ethyl diethylphosphonoacetate (10.5 g) in N,N-dimethylformamide was added sodium hydride (60% in oil, 1.87 g), and the mixture was stirred under a nitrogen atmosphere at room temperature for 15 min. To this solution was added a solution of 5-bromo-2-furaldehyde (7.45 g) in N,N-dimethylformamide (40 ml), and the mixture was stirred under a nitrogen atmosphere at room temperature for 1 hr. The reaction was quenched with saturated ammonium chloride solution (50 ml) and the reaction solution was partitioned between ethyl acetate (900 mL) and water (900 mL). The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate 90:10-85:15) to give the title compound (10.0 g, yield 96%) as a pale-yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:23])[N:9]([CH:20]([CH3:22])[CH3:21])[C:10]=1C(C1C=CC(Cl)=CC=1)O)=[O:5])[CH3:2].[Cl:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][C:31]=1[F:32])[NH2:28]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:23])[N:9]([CH:20]([CH3:21])[CH3:22])[C:10]=1[N:28]([C:27]1[CH:29]=[CH:30][C:31]([F:32])=[C:25]([Cl:24])[CH:26]=1)[C:29]1[CH:27]=[CH:26][C:25]([Cl:24])=[CH:31][CH:30]=1)=[O:5])[CH3:2]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CCOC(=O)c1nc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Product: CCOC(=O)c1nc(Br)n(C(C)C)c1N(c1ccc(Cl)cc1)c1ccc(F)c(Cl)c1

Procedure:
The title compound was prepared in analogy to the procedure described for step E2 using 2-bromo-5-[(4-chlorophenyl)-hydroxy-methyl]-1-isopropyl-1H-imidazole-4-carboxylic acid ethyl ester (intermediate B) and 3-chloro-4-fluoro-aniline as starting materials. tR 1.38 min (LC-MS 2); ESI-MS: 530.1 [M+H]+ (LC-MS 2).
Reaction SMILES: O.[C:2]1([NH:8][C:9]2[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[CH:18]([O-])=O.[NH4+]>[Pd].CO>[CH3:18][NH:15][C:14]1[C:9]([NH:8][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C[O-]
Reactant: Nc1cccnc1Nc1ccccc1
Agent: [Pd]
Agent: C=O
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CNc1cccnc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
Pd/C (10%, 11.49 g) was added to a three-neck flask. A gentle nitrogen flow was applied to the flask. Water (40 mL) and methanol (800 mL) were added to the flask. Then, N2-phenylpyridine-2,3-diamine (20 g, 108 mmol), formaldehyde (8.76 g, 108 mmol), and ammonium formate (136 g, 2160 mmol) were added. The reaction was stirred at room temperature overnight. The solution was filtered through a Celite® plug. The filtrate was concentrated and water was added. The solution was extracted with dichloromethane. The combined organic layer was concentrated and purified by column chromatography (30% ethyl acetate in hexanes) to give N3-methyl-N2-phenylpyridine-2,3-diamine (12 g, 55.8% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:20])=[CH:4][C:5]([OH:19])=[C:6]([C:8](=[O:18])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(#N)C.O>[CH2:27]([O:19][C:5]1[CH:4]=[C:3]([O:20][CH2:8][C:6]2[CH:7]=[CH:2][CH:3]=[CH:4][CH:5]=2)[C:2]([Cl:1])=[CH:7][C:6]=1[C:8](=[O:18])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(CC(=O)c2cc(Cl)c(O)cc2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(CC(=O)c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
1-(5-Chloro-2,4-dihydroxy-phenyl)-2-(4-methoxy-phenyl)-ethanone (1 eq) was dissolved in acetonitrile and potassium carbonate (4 eq) was added portion wise. The suspension was stirred for five minutes, before the addition of benzyl bromide (2.4 eq), and after which, the reaction mixture was stirred under nitrogen at reflux for 3 hours. The reaction was allowed to cool to room temperature and diluted with water. This was extracted into ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give a syrup. This was triturated with 1:1 diethyl ether:hexane to give 1-(2,4-bis-benzyloxy-5-chloro-phenyl)-2-(4-methoxy-phenyl)-ethanone as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[CH:13][C:14]([C:17]([O:19]C)=O)=[N:15][CH:16]=2)[CH2:7][CH2:6]1.[NH3:26]>CO>[Br:1][C:2]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[CH:13][C:14]([C:17]([NH2:26])=[O:19])=[N:15][CH:16]=2)[CH2:7][CH2:6]1
Reactant: COC(=O)c1cnc(N2CCC(Oc3cc(F)ccc3Br)CC2)cn1
Reactant: N
Solvent: CO
Product: NC(=O)c1cnc(N2CCC(Oc3cc(F)ccc3Br)CC2)cn1
Temperature: 55 °C

Procedure:
A methanol (30 mL) suspension of methyl 5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]pyrazine-2-carboxylate from Step 3 (2.00 g, 4.87 mmol) in a sealed tube was saturated with ammonia gas at 0° C. The mixture was then heated in an oil bath at 55° C. for two days. The reaction mixture was cooled and evaporated. To the white solid residue was added ether followed by filtration to provide the title compound.
Reaction SMILES: [N+:1]([CH:4]([CH3:6])[CH3:5])([O-:3])=[O:2].[CH3:7][O:8][CH2:9][CH2:10][C:11]1[CH:20]=[CH:19][C:14]([O:15][CH2:16][CH:17]=[O:18])=[CH:13][CH:12]=1.[Na].Cl>CO>[CH3:7][O:8][CH2:9][CH2:10][C:11]1[CH:20]=[CH:19][C:14]([O:15][CH2:16][CH:17]([OH:18])[C:4]([N+:1]([O-:3])=[O:2])([CH3:6])[CH3:5])=[CH:13][CH:12]=1
Reactant: COCCc1ccc(OCC=O)cc1
Reactant: CC(C)[N+](=O)[O-]
Agent: Cl
Agent: [Na]
Solvent: CO
Product: COCCc1ccc(OCC(O)C(C)(C)[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
39.5 g of 2-nitropropane and 27 g of 4-(2-methoxyethyl)-phenoxy-acetaldehyde are successively added dropwise to a solution of 2 g of sodium in 150 ml of methanol. After the mixture has been stirred at room temperature for 15 hours, the solution is poured onto water and acidified with 2N HCl. Extraction with CHCl3 gives, after crystallisation from diisopropyl ether, 23.3 g of the nitro compound mentioned in the title.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[C-:12]#[N:13].[Na+].O>CN(C=O)C>[N+:9]([C:5]1[CH:4]=[C:3]([CH2:2][C:12]#[N:13])[CH:8]=[CH:7][CH:6]=1)([O-:11])=[O:10]
Reactant: [C-]#N
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1cccc([N+](=O)[O-])c1
Yield: 43.9 %

Procedure:
A solution of 1-(bromomethyl)-3-nitrobenzene (30 g, 0.139 mol) and NaCN (10.21 g, 0.208 mol) in DMF (150 mL) was stirred at 50° C. for 5 hrs. The mixture was poured into water and extracted with ethyl acetate. The combined organic layer were dried, concentrated and purified by silica-gel column chromatography (PE:EA 20:1˜6:1) to give compound 2-(3-nitrophenyl)acetonitrile (9.9 g, yield 44%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[N:7]1([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3([C:28]([N:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[O:29])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:1][O:2][CH2:3][C:4]([N:33]1[CH2:34][CH2:35][N:30]([C:28]([C:22]2([C:19]3[CH:20]=[CH:21][C:16]([O:15][CH2:14][CH2:13][CH2:12][N:7]4[CH2:8][CH2:9][CH2:10][CH2:11]4)=[CH:17][CH:18]=3)[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[O:29])[CH2:31][CH2:32]1)=[O:5]
Reactant: COCC(=O)Cl
Reactant: O=C(N1CCNCC1)C1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)N1CCN(C(=O)C2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
Methoxyacetyl chloride (55 μl, 0.6 mmol) was added dropwise at 0° C. to a solution of 1-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}carbonyl)piperazine of example 181 (200 mg, 0.5 mmol) and N,N-diisopropylethylamine (100 μl, 0.6 mmol) in dichloromethane (3 ml). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (20 ml) and washed with 2N sodium hydroxide (20 ml). The layers were separated and the aqueous layer was further extracted with dichloromethane (20 ml). The organics were combined, dried over sodium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (97:3:0.3 to 90:10:1 by volume) to provide the title compound (160 mg, 67%). HRMS ESI+ m/z 474.2952 [MH]+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([F:15])[CH:8]=2)[C:4](=[O:16])[CH2:3]1.C([O-])([O-])=O.[K+].[K+].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[F:15][C:9]1[CH:8]=[C:7]([N:5]2[C:4](=[O:16])[CH2:3][CH:2]([NH:1][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:6]2)[CH:12]=[CH:11][C:10]=1[O:13][CH3:14]
Reactant: COc1ccc(N2CC(N)CC2=O)cc1F
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccc(N2CC(NC(=O)c3ccccc3)CC2=O)cc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 4-amino-1-(3-fluoro-4-methoxyphenyl)-pyrrolidin-2-one (Step 2, 0.8 g, 3.57 mmol) and K2CO3 (0.99 g, 7.14 mmol) in 20 mL of CH2Cl2 was added benzoyl chloride (0.75 g, 5.35 mmol). The reaction was stirred at RT for 16 h. The solid in the reaction was removed by filtration and the filtrate was diluted with 20 mL of CH2Cl2. The resulted solution was washed with 20 mL of satd. NaHCO3 followed by 20 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (30% to 100% EtOAc/hexane) to provide the title compound as a white solid. MS (ESI pos. ion) m/z: 329.4 (M+H). Calc'd Exact Mass for C18H17FN2O3: 328.34.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]=[O:12].N1C2C(=CC=CC=2)C=[C:14]1C(OCC)=O>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:14])[CH:8]=[C:7]2[CH:11]=[O:12]
Reactant: O=Cc1c[nH]c2c(F)cccc12
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Product: Cn1cc(C=O)c2cccc(F)c21
Yield: 43 %

Procedure:
According to the procedure of Preparation 9 (a), except substituting 7-fluoro-1H-indole-3-carboxaldehyde (0.5 g, 3.1 mmole) for the ethyl indole-2-carboxylate, the title compound (0.23 g, 43%) was prepared as a viscous oil: MS (ES) m/e 178 (M+H)+.