Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:37](=[O:43])OC(Cl)(Cl)Cl)Cl.[CH2:45]([N:52]1[CH2:57][CH2:56][CH:55]([NH2:58])[CH2:54][CH2:53]1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C(Cl)(Cl)Cl.O>[CH2:45]([N:52]1[CH2:57][CH2:56][CH:55]([NH:58][C:37]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:17][C:18]=2[N+:23]([O-:25])=[O:24])=[O:43])[CH2:54][CH2:53]1)[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: COc1cc2ncnc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)NC4CCN(Cc5ccccc5)CC4)c([N+](=O)[O-])c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-nitroaniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (131 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, 1-benzyl-4-piperidineamine (89 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (151 mg, yield 93%).
Reaction SMILES: [CH3:1][C:2]12[C:9](=[O:10])[O:8][C:6](=[O:7])[CH:3]1[CH2:4][CH2:5]2.[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[NH2:15]>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:13]=[C:14]([N:15]=[C:9]([C:2]2([CH3:1])[CH2:5][CH2:4][CH:3]2[C:6]([OH:8])=[O:7])[OH:10])[CH:16]=[C:17]([Cl:19])[CH:18]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: CC12CCC1C(=O)OC2=O
Solvent: Cc1ccccc1
Product: CC1(C(O)=Nc2cc(Cl)cc(Cl)c2)CCC1C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.9 %

Procedure:
10 g (0.07 mol) of 1-methyl-cyclobutane-1,2-dicarboxylic acid anhydride are dissolved in 50 ml of toluene, and 11.6 g (0.07 mol) of 3,5-dichloroaniline are added. After 24 hours' stirring at room temperature, the amide acid (m.p. 106°-108° C.) which has precipitated is separated. This amidocarboxylic acid is suspended in 40 ml of acetic anhydride, and the suspension is stirred for 24 hours at room temperature, in the course of which everything goes into solution. The acetic anhydride is evaporated off in a water-jet vacuum, and the pulverulent residue is recrystallised from dichloromethane/n-hexane to yield 15 g (73% of theory) of 1-methyl-cyclobutane-1,2-dicarboxylic acid-(3,5-dichlorophenyl)-imide, m.p. 110°-111° C. NMR Spectrum (100 MHz) δ in ppm: 1.55 (s, 3H, CH3), 2.0-3.2 (m, 5H, --CH2CH2 --CH--), 7.2-7.5 (m, 3H, aromat.). Compound No. 7.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([O:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C@@H:23]([NH:34][C:35](=[O:57])[NH:36][C@@H:37]([CH2:45][CH2:46][CH2:47][CH2:48][NH:49]C(OC(C)(C)C)=O)[C:38]([O:40]C(C)(C)C)=[O:39])[C:24](=[O:33])[NH:25][C@H:26]([C:30](=[O:32])[NH2:31])[CH:27]([CH3:29])[CH3:28])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:49][CH2:48][CH2:47][CH2:46][CH2:45][C@H:37]([NH:36][C:35]([NH:34][C@@H:23]([C:24](=[O:33])[NH:25][C@H:26]([C:30](=[O:32])[NH2:31])[CH:27]([CH3:28])[CH3:29])[CH2:22][CH2:21][CH2:20][CH2:19][NH:18][C:16]([O:15][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:17])=[O:57])[C:38]([OH:40])=[O:39]
Reactant: CC(C)[C@H](NC(=O)[C@@H](CCCCNC(=O)OCc1ccccc1)NC(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(N)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](NC(=O)[C@@H](CCCCNC(=O)OCc1ccccc1)NC(=O)N[C@@H](CCCCN)C(=O)O)C(N)=O
Yield: 70.2 %

Procedure:
tert-Butyl(S)-2-{3-[(R)-5-benzyloxycarbonylamino-1-((S)-1-carbamoyl-2-methyl-propylcarbamoyl)-pentyl]-ureido}-6-tert-butoxycarbonylaminohexanoate trifluoroacetate (37 mg, 0.045 mmol) was dissolved in 5 ml of CH2Cl2 and 1 ml of TFA and stirred at RT for 14 h. Preparative HPLC afforded 21 mg (70%) of (S)-6-amino-2-{3-[(R)-5-benzyloxycarbonylamino-1-((S)-1-carbamoyl-2-methyl-propylcarbamoyl)-pentyl]-ureido}-hexanoic acid trifluoroacetate.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:20][CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[NH:16][C:15]2=[O:25])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:26]>C(OCC)(=O)C>[ClH:26].[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:20][CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[NH:16][C:15]2=[O:25])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C1Nc2ccccc2CCN1C1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(1-t-butoxycarbonyl-4-piperidinyl)-1,3,4,5-tetrahydro-2H-1,3-benzodiazapin-2-one (4.80 g, 13.9 mmol) in ethyl acetate (300 mL) was saturated with hydrogen chloride gas at 0° C. The reaction was allowed to warm to room temperature and stirred overnight. The solid was filtered and washed with ethyl acetate. The ethyl acetate filtrate was concentrated for a second crop. The title compound was obtained as a solid (2.94 g). MS: m/z=246 (M+1). 1H NMR (500 MHz, CD3OD) δ 7.10 (m, 2H), 6.94 (d, J=8 Hz, 1H), 6.91 (t, J=8 Hz, 1H), 4.35 (tt, J=10, 1 Hz, 1H), 3.52 (m, 4H), 3.12 (t, J=12 Hz, 2H), 3.05 (m, 2H), 2.07 (qd, J=12, 4 Hz, 2H), 1.99 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[F:14][C:15]([F:39])([F:38])[CH2:16][NH:17][C:18]([C:20]1([CH2:33][CH2:34][CH2:35][CH2:36]Br)[C:32]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:19]>>[F:14][C:15]([F:38])([F:39])[CH2:16][NH:17][C:18]([C:20]1([CH2:33][CH2:34][CH2:35][CH2:36][N:11]2[CH2:12][CH2:13][N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[CH2:9][CH2:10]2)[C:32]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:19]
Reactant: Cc1ccccc1N1CCNCC1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: Cc1ccccc1N1CCN(CCCCC2(C(=O)NCC(F)(F)F)c3ccccc3-c3ccccc32)CC1

Procedure:
Prepared analogously to Example 2 b from 1-(2-methyl-phenyl)-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([NH2:19])[CH3:18]>>[CH2:17]([NH:19][C:8](=[O:9])[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:18]
Reactant: CCN
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: CCNC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, off-white solid, m.p. 87° C. and MS: m/e=239 (M+) was prepared in accordance with the general method of example 1 from diphenylacetyl chloride and ethylamine.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[C:13]([C:14](Cl)=[O:15])=[CH:12][S:11][N:10]=2)[CH:4]=1.[CH2:19]([OH:22])[CH2:20][CH3:21]>>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[C:13]([C:14]([O:22][CH2:19][CH2:20][CH3:21])=[O:15])=[CH:12][S:11][N:10]=2)[CH:4]=1
Reactant: CCCO
Reactant: O=C(Cl)c1csnc1-c1cccc(C(F)(F)F)c1
Product: CCCOC(=O)c1csnc1-c1cccc(C(F)(F)F)c1
Yield: 100.5 %

Procedure:
A solution of 2.92 g (0.010 mol) of 3-(α,α,α-trifluoro-m-tolyl)-4-isothiazolecarbonyl chloride and 4 g (0.0667 mol) of 1-propanol was heated on a steam bath for 1 hour and was concentrated under vacuum to 70° (0.5 torr) to give 3.17 g of clear oil, nD20.8 = 1.5261, infrared (film) 5.80 μ.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[S:12][C:11]([CH3:13])=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=2)[CH2:4][C@H:3]1[O:18][CH3:19].[Cl:20][C:21]1[N:22]=[C:23]([C:28](O)=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CC(N(C)C)=O.C(OCC)(=O)C>[Cl:20][C:21]1[N:22]=[C:23]([C:28]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[S:12][C:11]([CH3:13])=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=3)[CH2:4][C@H:3]2[O:18][CH3:19])=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27]
Reactant: COC(=O)c1cc(N2CC[C@H](N)[C@H](OC)C2)sc1C
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3cc(C(=O)OC)c(C)s3)C[C@H]2OC)nc1Cl
Temperature: 70 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
Methyl cis(±)-5-(4-amino-3-methoxypiperidin-1-yl)-2-methylthiophene-3-carboxylate obtained in Example (188d) (20 mg, 0.07 mmol) and 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (15 mg, 0.07 mmol) were dissolved in DMA (2 ml). WSC hydrochloride (40 mg, 0.21 mmol) and HOBt (10 mg, 0.07 mmol) were added, and the mixture was stirred at 70° C. for one hour and at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=0, 9, 17%) to obtain 16 mg of the title compound as a glassy solid. mass spectrum (ESI): m/z 441 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]=2[CH:20]=1.[Br:21]Br>C(O)(=O)C>[Br:21][C:5]1[C:4]([O:3][CH3:2])=[CH:20][C:8]2[CH:9]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10][NH:11][CH2:12][CH2:13][C:7]=2[CH:6]=1
Reactant: COc1ccc2c(c1)C(c1ccccc1)CNCC2
Reactant: BrBr
Agent: Cl
Solvent: CC(=O)O
Product: COc1cc2c(cc1Br)CCNCC2c1ccccc1

Procedure:
8-Methoxy-1-phenyl-2,3,4,5-tetrahydro-1H3-benzazepine hydrochloride (66 g, 0.23 m) was suspended in acetic acid (300 ml) and treated with bromine (43 g, 0.27 m). The mixture was heated to 95° for one hour, cooled and filtered. The filter cake was partitioned between ethyl acetate and ammonium hydroxide to afford 7-bromo-8-methoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[CH2:10]([OH:12])[CH3:11]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5](=[NH:6])[O:12][CH2:10][CH3:11]
Reactant: CCO
Reactant: N#Cc1cccc(Cl)c1
Product: CCOC(=N)c1cccc(Cl)c1
Product: Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 3-chlorobenzonitrile (50 g, 363 mmol) in anhydrous ethanol (500 mL), cooled to 0° C. in an ice bath, was bubbled HCl (g) through a gas dispersion tube for approximately 20 minutes until the solution was saturated. The resulting reaction mixture was stirred at room temperature for 16 h. Volatiles were removed in vacuo and the residue was triturated with anhydrous ether (˜200 mL). The white solid was collected by filtration and dried in vacuo overnight to afford ethyl 3-chlorobenzimidate hydrochloride (INTERMEDIATE II.1) (80 g, 363 mmol, 100%) which was used directly without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[C:6]([F:16])[C:5]([CH:17](Br)Br)=[CH:4][CH:3]=1.C([OH:23])(C)C.O>[N+]([O-])([O-])=O.[Ag+].ClCCl>[C:8]([C:7]1[C:6]([F:16])=[C:5]([CH:4]=[CH:3][C:2]=1[Cl:1])[CH:17]=[O:23])(=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)O
Reactant: O=C(c1ccccc1)c1c(Cl)ccc(C(Br)Br)c1F
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: ClCCl
Product: O=Cc1ccc(Cl)c(C(=O)c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
Step 4 A mixture of (6-chloro-3-dibromomethyl-2-fluoro-phenyl)-phenyl-methanone (582 mg, 1.38 mmol), silver nitrate (469 mg, 2.76 mmol), isopropanol (10 ml) and water (2 ml) was stirred at room temperature overnight. Dichloromethane was added and the mixture was filtered under suction washing with isopropanol. The organic liquors were concentrated then purified by silica chromatography eluting with 0-20% ethyl acetate/petroleum ether furnishing 3-benzoyl-4-chloro-2-fluoro-benzaldehyde (222 mg oil, 90% clean). Analytical data as above
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:25].[CH2:26]([NH:29][CH2:30][CH2:31][CH3:32])[CH2:27][CH3:28]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:29]([CH2:30][CH2:31][CH3:32])[CH2:26][CH2:27][CH3:28])[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:25]
Reactant: CCCNCCC
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccc(F)c(Cl)c2C1=O
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1nc(-c2ncn3c2CN(C)C(=O)c2c-3ccc(F)c2Cl)no1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.9 %

Procedure:
A suspension of 1.30 g (3.4 mmol) of 7-chloro-3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one in 13 ml of N,N-dimethylformamide was treated with 1.72 g (0.017 mol) of dipropylamine. After stirring at room temperature for 16 hrs. the solution obtained was completely freed from the solvents. The residue was chromatographed over silica gel with methylene chloride/methanol as the eluent. The product was recrystallized from ether/n-hexane. There were obtained 1.32 g (87%) of 7-chloro-3-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl) -8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as white crystals; m.p. 143°-146° (dec.).
Reaction SMILES: [OH-:1].[K+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[CH:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])CC#N.Cl.CCCCC.[CH2:28]([OH:31])[CH2:29]O>>[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[CH:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:29][C:28]([OH:31])=[O:1]
Reactant: CCCCCC(CC#N)c1ccc(OC)cc1OC
Reactant: OCCO
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CCCCC
Product: CCCCCC(CC(=O)O)c1ccc(OC)cc1OC
Temperature: 25 °C
Yield: 87 %

Procedure:
1.00 g (17.8 mmol) of potassium hydroxide was added to a solution of 1.27 g (4.86 mmol) of (-)-2-(2,4-dimethoxyphenyl)heptyl cyanide [prepared as described in step (ii) above] in 6 ml of ethylene glycol, and the resulting mixture was heated under reflux for 2.5 hours in an atmosphere of nitrogen. At the end of this time, the reaction mixture was cooled to room temperature, after which it was acidified with 1 N aqueous hydrochloric acid and then extracted with diethyl ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through 100 g of silica gel, using a 1:2 by volume mixture of ethyl acetate and hexane as the eluent, to give 1.19 g (yield 87%) of the title compound as crystals, melting at 51-52° C. (from pentane).
Reaction SMILES: [CH:1]1([N:4]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[C:9](B4OC(C)(C)C(C)(C)O4)[CH:10]=3)[C:5]2=[O:22])[CH2:3][CH2:2]1.Br[C:24]1[CH:38]=[CH:37][C:27]([CH2:28][N:29]2[CH2:33][C:32](=[O:34])[N:31]([CH3:35])[C:30]2=[O:36])=[CH:26][CH:25]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[CH:1]1([N:4]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:24]4[CH:38]=[CH:37][C:27]([CH2:28][N:29]5[CH2:33][C:32](=[O:34])[N:31]([CH3:35])[C:30]5=[O:36])=[CH:26][CH:25]=4)[CH:10]=3)[C:5]2=[O:22])[CH2:2][CH2:3]1
Reactant: CC1(C)OB(c2ccc3c(c2)CN(C2CC2)C3=O)OC1(C)C
Reactant: CN1C(=O)CN(Cc2ccc(Br)cc2)C1=O
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CN1C(=O)CN(Cc2ccc(-c3ccc4c(c3)CN(C3CC3)C4=O)cc2)C1=O
Temperature: 130 °C
Yield: 54.6 %

Procedure:
2-Cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (1A5) (3.34 mmol, 1.0 g), 1-(4-bromobenzyI)-3-methylimidazolidine-2,4-dione (1B6) (3.34 mmol, 0.946 g), tris(dibenzylidineacetone)dipalladium (0.167 mmol, 153 mg), tricyclohexylphosphine (0.401 mmol, 112 mg) and potassium phosphate (5.68 mmol, 1.2 mg) were suspended in a mixture of dioxane (10 ml) and water (5 ml) and heated at 130° C. in the microwave for 15 min. The reaction was quenched with sat. NaHCO3 and diluted with DCM and then passed through a hydrophobic fritted tube. The combined organic layers were concentrated and the residue purified on silica eluting with 75-100% EtOAc/Heptane to afford 1-(4-(2-cyclopropyl-1-oxoisoindolin-5-yl)benzyl)-3-methylimidazolidine-2,4-dione (Example 1a) (685 mg, 55%) 1H NMR (400 MHz, CDCl3) δ 7.99 (d, 1H) 7.65 (d, 1H) 7.62 (d, 2H) 7.59 (s, 1H) 7.36 (d, 2H) 4.63 (s, 2H) 4.38 (s, 2H) 3.79 (s, 2H) 3.08 (s, 3H) 2.95 (m, 1H) 0.98-0.87 (m, 4H) LCMS m/z (M+H) 376.2.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][CH2:14][CH:13]([CH3:17])[CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:3]=1.C(N(CC)CC)C.[CH3:35][C:36]1([CH3:43])[C:40]([CH3:42])([CH3:41])[O:39][BH:38][O:37]1>O1CCOCC1.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]>[CH3:27][C:24]1[CH:25]=[CH:26][C:21]([S:18]([N:4]2[C:5]3[N:6]=[CH:7][N:8]=[C:9]([N:11]4[CH2:16][CH2:15][CH2:14][CH:13]([CH3:17])[CH2:12]4)[C:10]=3[C:2]([B:38]3[O:39][C:40]([CH3:42])([CH3:41])[C:36]([CH3:43])([CH3:35])[O:37]3)=[CH:3]2)(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: CC1(C)OBOC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(Br)c3c(N4CCCC(C)C4)ncnc32)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3c(N4CCCC(C)C4)ncnc32)cc1
Temperature: 95 °C

Procedure:
5-Bromo-7-[(4-methylphenyl)sulfonyl]-4-(3-methylpiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine (racemic version of C15, see Example 7) (1.44 g, 3.20 mmol) was added to a solution of triethylamine (1.3 g, 13 mmol) in 1,4-dioxane (15 mL). 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (1.64 g, 12.8 mmol) was then slowly added, and the mixture was degassed by bubbling nitrogen through it for 5 minutes. 2-Dicyclohexylphosphino-2′,6′-triisopropylbiphenyl (XPhos, 137 mg, 0.287 mmol) and tris(dibenzylideneacetone)dipalladium(0) (146 mg, 0.160 mmol) were then introduced, and the reaction mixture was heated at 95° C. for 18 hours. After cooling, the mixture was filtered through cotton and the filtrate was concentrated in vacuo. Chromatography on silica gel (Gradient: 0% to 75% ethyl acetate in heptane) afforded the product as a solid. Yield: 1.25 g, 2.52 mmol, 79%. 1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 8.10 (br d, J=8.4 Hz, 2H), 7.95 (s, 1H), 7.30 (brd, J=8.6 Hz, 2H), 4.28 (brd, J=13 Hz, 1H), 4.18-4.24 (m, 1H), 2.99 (ddd, J=13, 11, 4 Hz, 1H), 2.70 (dd, J=12.9, 10.9 Hz, 1H), 2.40 (s, 3H), 1.77-1.85 (m, 1H), 1.56-1.70 (m, 4H), 1.35 (s, 12H), 0.88 (d, J=6.6 Hz, 3H).
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[H-].[Na+].C(OCCO)C.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19](Br)[N:18]=1>>[NH2:16][C:17]1[N:18]=[C:19]([S:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])[CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)CCCS
Reactant: Nc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCCO
Product: Nc1cccc(SCCCC(=O)O)n1
Yield: 62.9 %

Procedure:
A mixture of 4-mercaptobutyric acid (0.72 g.) a 50% w/w dispersion of sodium hydride in mineral oil (0.58 g.) and 2-ethoxyethanol (5 ml.) was treated with 2-amino-6-bromopyridine (0.35 g.) and the mixture was heated under reflux for 18 hours and then evaporated to dryness. The residue was partitioned between water and EtOAc and the aqueous phase was neutralised with HOAc. The precipitated yellow solid was collected to give 4-(6-aminopyrid-2-ylthio)butyric acid (0.27 g.) which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][NH2:12])=[O:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[Br:13][CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=O)=[CH:17][CH:16]=1.BrP(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCN(C(C)C)C(C)C>CC#N>[Br:8][C:5]1[N:4]=[C:3]([C:9]2[O:10][C:19]([C:18]3[CH:22]=[CH:23][C:15]([CH2:14][Br:13])=[CH:16][CH:17]=3)=[N:12][N:11]=2)[C:2]([NH2:1])=[N:7][CH:6]=1
Reactant: NNC(=O)c1nc(Br)cnc1N
Reactant: O=C(O)c1ccc(CBr)cc1
Agent: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Br)nc1-c1nnc(-c2ccc(CBr)cc2)o1
Reaction time: 1 h
Yield: 67.9 %

Procedure:
To a suspension of 3-amino-6-bromo-pyrazine-2-carbohydrazide (200 mg, 0.86 mmol) and 4-(bromomethyl)benzoic acid (185 mg, 0.86 mmol) in MeCN (4 mL) at room temperature was added dibromo(triphenyl)phosphorane (1.7 g, 4.14 mmol) and the resulting reaction mixture was stirred for 1 h. The reaction mixture was diluted with acetonitrile (2 mL) and DIPEA (668 mg, 900 μL, 5.2 mmol) was added dropwise and the suspension was allowed to stir overnight. The suspension was filtered, washed with CH3CN and hexane, and air dried to provide 5-bromo-3-(5-(4-(bromomethyl)phenyl)-1,3,4-oxadiazol-2-yl)pyrazin-2-amine (240 mg, 68%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 8.11 (d, J=8.1 Hz, 2H), 7.72 (d, J=8.2 Hz, 2H), 4.82 (s, 2H). LC/MS m/z 412.1 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[N:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](O)=[CH:6][C:7](=[O:15])[NH:8]2)[CH3:2].P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:5]1[C:4]2[C:9](=[CH:10][C:11]([CH2:13][CH3:14])=[N:12][C:3]=2[CH2:1][CH3:2])[NH:8][C:7](=[O:15])[CH:6]=1
Reactant: CCc1cc2[nH]c(=O)cc(O)c2c(CC)n1
Reactant: O=P(Cl)(Cl)Cl
Product: CCc1cc2[nH]c(=O)cc(Cl)c2c(CC)n1

Procedure:
Compound C (17.6 g) was dissolved in phosphorus oxychloride (100 ml) and the mixture was heated at reflux for 24 hours. Unreacted phosphorus oxychloride was removed by evaporation and the residue was dissolved in concentrated hydrochloric acid (100 ml) containing water (15 ml). The mixture was heated at reflux for 4 hour. The mixture was then diluted with water (500 ml) and basified with solid potassium carbonate. The resulting precipitate was collected by filtration and washed with water. The solid was purified by flash chromatography, eluting with ethyl acetate, to give 4-chloro-5,7-diethyl-1,6-naphthyridin-2(1H)-one (D) (8.9 g); m.p. 172°-174° C.; NMR (CDCl3): 1.35(dt, 6H), 2.86(q, 2H), 3.49(q, 2H), 6.83(s, 1H), 7.0(s, 1H), 12.4(broad, 1H); mass spectrum (CI, ammonia): 237 (M+H)+ ; microanalysis, found: C, 60.3; H, 5.5; N, 11.5%; C12H13ClN2O requires: C, 60.9; H, 5.5; N, 11.8%.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C1COCC1>[C:32]([NH:1][CH2:2][CH:3]1[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CN)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCC1CN(C(=O)OC(C)(C)C)CCOC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 110.5 %

Procedure:
To a solution of tert-butyl (6RS,7RS)-6-(aminomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (144 mg) in THF (1.5 ml) were added triethylamine (0.08 mL) and acetyl chloride (45 mg), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (177 mg).