Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[C:13]1[C:14]([C:20]#[N:21])=[CH:15][NH:16][C:17]=1[CH2:18][CH3:19])=O>[Ni].C(O)(=O)C>[Cl:12][C:10]1[CH:9]=[CH:8][C:7]2[C:13]3[C:14](=[CH:15][NH:16][C:17]=3[CH2:18][CH3:19])[CH2:20][N:21]=[C:4]([C:3]3[CH:22]=[CH:23][CH:24]=[CH:25][C:2]=3[Cl:1])[C:6]=2[CH:11]=1
Reactant: CCc1[nH]cc(C#N)c1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Agent: [Ni]
Solvent: CC(=O)O
Product: CCc1[nH]cc2c1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reaction time: 16 h

Procedure:
A mixture of 3.3 g (8.9 mmol) of 4-[2-(2-chlorobenzoyl)-4-chlorophenyl]-5-ethyl-1H-pyrrole-3-carbonitrile, 0.5 teaspoon of Raney nickel, and 100 ml of acetic acid was hydrogenated on a Parr apparatus at 50 psi for 16 hours. The Raney nickel was removed by filtration through a pad of Celite, and the filtrate was concentrated at reduced pressure to a dark residue. The residue was partitioned between ice water and ether and basified with concentrated ammonium hydroxide solution. The ether was removed at reduced pressure, and the aqueous residue was stirred for 1 hour. The resulting precipitate was collected by filtration and dissolved in tetrahydrofuran. The tetrahydrofuran solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to a residue which crystallized from ether to give 8-chloro-6-(2-chlorophenyl)-1-ethyl-2H,4H-pyrrolo[3,4-d][2]benzazepine as yellow prisms, mp 251°-253° C. Recrystallization from a mixture of ether and methylene chloride gave off-white prisms, mp 254° -255° C.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([O:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18](=O)[NH:19][CH:20]=[N:21]2)=[CH:16][C:15]=1[O:25][CH3:26])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(C(C)C)CC)(C)C.[OH-].[Na+]>>[CH2:6]([O:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([Cl:3])=[N:19][CH:20]=[N:21]2)=[CH:16][C:15]=1[O:25][CH3:26])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Temperature: 25 °C
Yield: 99 %

Procedure:
Phosphorus oxychloride (515 ml) was added to 7-(benzyloxy)-6-methoxy-3,4-dihydro-4-quinazolinone (400 mg) and diisopropylethylamine (0.3 ml), and the mixture was refluxed for 20 min. The reaction solution was cooled to room temperature. A 10% aqueous sodium hydroxide solution was then added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over sodium sulfate. The organic layer was filtered, and the solvent was then removed by distillation under the reduced pressure. The residue was dried through a vacuum pump to give 420 mg (yield 99%) of the title compound.
Reaction SMILES: [Br:1]Br.C([NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:21]([CH3:22])=[CH:20][S:19][C:18]=2[C:23]([O:25][CH3:26])=[O:24])=[CH:13][C:12]=1[CH3:27])(=[O:10])=[O:9])(C)(C)C>C(Cl)Cl>[Br:1][C:20]1[S:19][C:18]([C:23]([O:25][CH3:26])=[O:24])=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([S:8](=[O:10])(=[O:9])[NH2:7])=[C:12]([CH3:27])[CH:13]=2)[C:21]=1[CH3:22]
Reactant: COC(=O)c1scc(C)c1-c1ccc(S(=O)(=O)NC(C)(C)C)c(C)c1
Reactant: BrBr
Solvent: ClCCl
Product: COC(=O)c1sc(Br)c(C)c1-c1ccc(S(N)(=O)=O)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.2 %

Procedure:
Bromine (0.35 g, 0.11 ml, 2.2 mmol) was added drop wise to a stirred suspension of methyl 3-(4-(N-(tert-butyl)sulfamoyl)-3-methylphenyl)-4-methylthiophene-2-carboxylate (41a, 0.70 g, 1.83 mmol) in DCM (15 ml) at 0° C. The reaction mixture was then stirred at 25° C. for 3 hours. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated. DCM (50 ml) was added to the residue. The mixture so obtained was washed with water (2×20 ml), brine (lx 20 ml) and dried over sodium sulfate. The dried organic layer was then concentrated under reduced pressure to obtain a crude product as semi-solid (0.7 g), which was then purified by flash column chromatography using 40% ethyl acetate in hexanes as an eluent to obtain the title compound (0.63 g, 85.13%).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:27]=[C:28]([CH2:30][OH:31])[N:29]=2)[C:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:6][N:7]=1.[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][C:33]1=[O:38].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[OH:31][CH2:30][C:28]1[N:29]=[C:3]2[C:2]([N:35]3[CH2:36][CH2:37][NH:32][C:33](=[O:38])[CH2:34]3)=[N:7][CH:6]=[C:5]([C:8]3[CH:9]=[CH:10][C:11]([N:14]4[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]4)=[N:12][CH:13]=3)[N:4]2[CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(Cl)c4nc(CO)cn34)cn2)CC1
Reactant: O=C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(N4CCNC(=O)C4)c4nc(CO)cn34)cn2)CC1
Temperature: 130 °C
Reaction time: 6 h

Procedure:
A mixture of compound 87c (90.0 mg, 0.202 mmol), piperazin-2-one (40.5 mg, 0.405 mmol) and K2CO3 (55.9 mg, 0.405 mmol) in 2.5 mL of DMF was stirred at 130° C. for 6 h under an Argon atmosphere. After cooling to rt, the mixture was treated with 30 mL of EtOAc and washed with saturated NH4Cl (20 mL), water (20 mL), brine (10 mL) and then dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel (0-7 MeOH/DCM) to give compound 88a as an off white solid. 1H-NMR (CDCl3, 400 MHz): δ 8.34 (d, J=2.4 Hz, 1H), 7.67 (dd, J=8.8, 2.4 Hz, 1H), 7.54 (s, 1H), 7.30 (s, 1H), 6.76 (d, J=8.8 Hz, 1H), 6.23 (br. s., 1H), 4.89 (s, 2H), 4.80 (d, J=5.4 Hz, 2H), 4.55 (t, J=5.3 Hz, 2H), 3.55-3.69 (m, 10H), 1.50 (s, 9H). Mass spectrum (LCMS, ESI pos.): Calcd. for C25H32N8O4, 509.2 (M+H). found 509.2.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[OH:12])[CH:2]=[CH2:3].Cl.[NH2:14][OH:15].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([C:4]1[CH:9]=[C:8]([CH:7]=[CH:6][C:5]=1[OH:12])[C:10](=[N:14][OH:15])[NH2:11])[CH:2]=[CH2:3]
Reactant: NO
Reactant: C=CCc1cc(C#N)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C=CCc1cc(C(N)=NO)ccc1O
Temperature: 25 °C
Yield: 82.8 %

Procedure:
A solution of 2-allyl-4-cyanophenol (5.5 g), hydroxylamine hydrochloride (8.5 g) and sodium carbonate (6.1 g) in aqueous ethanol was heated at reflux for 3 hours. The solution was cooled to ambient temperature and the ethanol was removed by evaporation. The solid was collected by filtration, dissolved in ethanol and the solution was filtered. The filtrate was evaporated and the residual solid was triturated with hexane to give 3-allyl-4-hydroxybenzamidoxime as a solid (5.5 g), m.p. 144° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][C:13]([OH:15])=O)(=[O:11])=[O:10])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.Cl.C[O:22][C:23](=[O:31])[C@H:24]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[NH2:25].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH3:30][O:29][C:27](=[O:28])[CH2:26][CH:24]([NH:25][C:13](=[O:15])[CH2:12][S:9](=[O:10])(=[O:11])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:16]([F:19])([F:18])[F:17])[C:23]([OH:31])=[O:22]
Reactant: O=C(O)CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Reactant: COC(=O)C[C@H](N)C(=O)OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CC(NC(=O)CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F)C(=O)O

Procedure:
Under the conditions of Example 2(a), 3.012 g (10 mmol) of 2-[2-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]acetic acid, 1.836 g (10 mmol) of L-aspartic acid dimethyl ester hydrochoride, 1,531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is purified by column chromatography on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=3[F:43])([CH3:35])[N:26]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.[F:44][C:45]1[CH:46]=[C:47]([NH2:51])[CH:48]=[N:49][CH:50]=1>>[NH2:24][C:25]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]2[CH:41]=[C:40]([NH:51][C:47]3[CH:48]=[N:49][CH:50]=[C:45]([F:44])[CH:46]=3)[CH:39]=[CH:38][C:37]=2[F:43])([CH3:35])[N:26]=1
Reactant: Nc1cncc(F)c1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(C)(C)C(=O)N2C)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Nc3cncc(F)c3)ccc2F)N=C1N

Procedure:
The coupling of (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate K) and 5-fluoro-pyridin-3-ylamine according to procedure B followed by deprotection yielded the title compound as an off-white foam. MS (ESI): m/z=374.2 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:42])[C@H:5]([OH:41])[CH2:6][NH:7][C:8](=[O:40])[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:28][C:29]([NH:31][C:32]2[CH:37]=[C:36]([Cl:38])[CH:35]=[C:34]([Cl:39])[CH:33]=2)=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=3)=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)C.[OH-].[Na+].Cl>C(O)C.C1COCC1>[C:22]1([C:19]2[CH:18]=[CH:17][C:16]([CH:15]([NH:28][C:29]([NH:31][C:32]3[CH:33]=[C:34]([Cl:39])[CH:35]=[C:36]([Cl:38])[CH:37]=3)=[O:30])[C:12]3[CH:13]=[CH:14][C:9]([C:8]([NH:7][CH2:6][C@@H:5]([OH:41])[C:4]([OH:42])=[O:3])=[O:40])=[CH:10][CH:11]=3)=[CH:21][CH:20]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=1
Reactant: CCOC(=O)[C@H](O)CNC(=O)c1ccc(C(NC(=O)Nc2cc(Cl)cc(Cl)c2)c2ccc(C3=CCCCC3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(Nc1cc(Cl)cc(Cl)c1)NC(c1ccc(C(=O)NC[C@@H](O)C(=O)O)cc1)c1ccc(C2=CCCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.3 %

Procedure:
A solution of (R)-3-{4-[1-(4-cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]-benzoylamino}-2-hydroxypropionic acid ethyl ester (0.60 g, 0.98 mmol) in ethanol (5 mL) and THF (5 mL) was stirred and 4 N sodium hydroxide (0.76 mL, 2.94 mmol) was added. The solution was stirred for 3 hours at room temperature and then acidified with 1 N hydrochloric acid. Evaporation in vacuo afforded an oil, which was partitioned between ethyl acetate, water and brine. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were washed with water and brine. Drying (magnesium sulphate), filtration, and evaporation in vacuo afforded 0.43 g (73%) of the title compound as a solid.
Reaction SMILES: [CH:1]12[CH2:10]C3CC(CC(C3)[CH:2]1OCC1C(Cl)=CC(C(NS(C)(=O)=O)=O)=C(F)C=1)C2.Cl[C:29]1[C:30]([O:43][CH2:44][C:45]23[CH2:54][CH:49]4[CH2:50][CH:51]([CH2:53][CH:47]([C:48]4([F:56])[F:55])[CH2:46]2)[CH2:52]3)=[CH:31][C:32]([F:42])=[C:33]([CH:41]=1)[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[O:35]>>[CH:10]1([C:29]2[C:30]([O:43][CH2:44][C:45]34[CH2:46][CH:47]5[CH2:53][CH:51]([CH2:50][CH:49]([C:48]5([F:55])[F:56])[CH2:54]3)[CH2:52]4)=[CH:31][C:32]([F:42])=[C:33]([CH:41]=2)[C:34]([NH:36][S:37]([CH3:40])(=[O:38])=[O:39])=[O:35])[CH2:1][CH2:2]1
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(OCC23CC4CC(C2)C(F)(F)C(C4)C3)cc1F
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(COC2C3CC4CC(C3)CC2C4)cc1F
Product: CS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC23CC4CC(C2)C(F)(F)C(C4)C3)cc1F

Procedure:
Following the procedure as described in Example 49 and making variation as required to replace 4-((adamantan-2-yloxy)methyl)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamide with 5-chloro-4-((4,4-difluoroadamantan-1-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide, the title compound was obtained as a colorless solid (0.32 g, 86%): 1H NMR (300 MHz, CDCl3) δ 8.69 (br s, 1H), 7.59 (d, J=9.0 Hz, 1H), 6.53 (d, J=14.1 Hz, 1H), 3.59 (s, 2H), 3.39 (s, 3H), 2.28 (br s, 2H), 2.08-1.92 (m, 6H), 1.53-1.51 (m, 6H), 0.97-0.89 (m, 2H), 0.66-0.60 (m, 2H); MS (ES−) m/z: 456.2 (M−1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:8][C:7](=[O:17])[C:6]=2[CH:18]=1.Br[CH2:20][CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:8][C:7](=[O:17])[C:6]=2[CH:18]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCBr
Reactant: O=c1nc(-c2ccccn2)sc2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1ccc2sc(-c3ccccn3)nc(=O)c2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 86.2 %

Procedure:
A mixture of 6-hydroxy-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one (0.35 g, 1.3 mmol), 1-bromobutane (0.38 g, 2.7 mmol) and potassium carbonate (0.56 g, 4.0 mmol) and DMF (10 ml) was stirred at room temperature for 15 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated. The obtained crystals were recrystallized from tetrahydrofuran-hexane to give the titled compound (0.35 g, 83%).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[C:11]([O:13]CC)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>O.O1CCOCC1>[C:1]1([NH:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[C:11]([OH:13])=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cccc(Nc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cccc(Nc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 3-(phenylamino)benzoate (0.175 g; 0.725 mmol) was added to a mixture of NaOH in water (1 mL; 2M) and dioxane (1 mL) and stirred vigorously at room temperature overnight. The resulting mixture was concentrated in vacuo and extracted with dichloromethane. The aqueous layer was acidified with a 6N solution of hydrochloric acid in water. The precipitated product was collected by filtration to yield 0.155 g (quantitative) of the title compound as a grey solid which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:18])=O.CN(C=O)C>C(Cl)Cl>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([Cl:18])=[O:5]
Reactant: O=C(O)c1cc(C(F)(F)F)cnc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc(C(F)(F)F)cnc1Cl

Procedure:
To a suspension of 2-chloro-5-(trifluoromethyl)nicotinic acid (1.147 g, 4.83 mmol) in DCM (20 mL) was added oxalyl chloride (630 L, 7.35 mmol) dropwise with stirring. A single drop of DMF was added and the reaction mixture was stirred 40° C. for 1 hour. Concentration of the reaction mixture in vacuo resulted in the title compound as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[C@@H:10]([NH:12][C:13]2[N:21]=[CH:20][N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][N:17]3C2CCCCO2)[CH3:11])=[C:4]([NH:29][C:30]2[CH:35]=[CH:34][N:33]=[CH:32][N:31]=2)[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:45])=CC=1>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[S:45])[C@@H:10]([NH:12][C:13]2[N:21]=[CH:20][N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][NH:17]3)[CH3:11])=[C:4]([NH:29][C:30]2[CH:35]=[CH:34][N:33]=[CH:32][N:31]=2)[CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)C(=O)Nc1ccc(F)cc1Nc1ccncn1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H](Nc1ncnc2[nH]cnc12)C(=S)Nc1ccc(F)cc1Nc1ccncn1
Yield: 12.2 %

Procedure:
(S)—N-[4-Fluoro-2-(pyrimidin-4-ylamino)phenyl]-2-[9-(tetrahydro-pyran-2-yl)-9H-purin-6-ylamino]propionamide (88 mg, 0.18 mmol) and Lawesson's reagent (298 mg, 0.74 mmol) were heated at reflux in THF (4 mL) under nitrogen for 16 h. Further Lawesson's reagent (150 mg, 0.37 mmol) was added and the reaction refluxed for a further 24 h. The reaction mixture was cooled, diluted with EtOAc (30 mL) and extracted with 1M HCl (2×5 mL). The aqueous extracts were basified with Na2CO3 and extracted with EtOAc (2×20 mL). The combined organic extracts were dried (Na2SO4), concentrated in vacuo and purified by column chromatography (Si—PCC, gradient 0-10% (9:1 MeOH/0.880 NH3) in DCM to give the title compound as a colourless gum, (9 mg, 12%). LCMS (Method B): RT 1.88 min [M+H]+ 410.09
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:14]([C:15]3[N:23]=[C:22]([CH3:24])[N:21]=[C:20]4[C:16]=3[N:17]=[CH:18][N:19]4C3CCCCO3)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:31][C:32](=[O:34])[CH3:33].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:14]([C:15]3[N:23]=[C:22]([CH3:24])[N:21]=[C:20]4[C:16]=3[N:17]=[CH:18][NH:19]4)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:31][C:32](=[O:34])[CH3:33]
Reactant: CC(=O)Nc1ccc(Nc2ncccc2-c2nc(C)nc3c2ncn3C2CCCCO2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1ccc(Nc2ncccc2-c2nc(C)nc3[nH]cnc23)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
A mixture of N-(2-chloro-4-(3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)acetamide (100 mg, 0.209 mmol) in DCM (3 mL) was cooled to 0° C., treated with trifluoroacetic acid (3 mL, 40.4 mmol), and the yellow solution was stirred at 0° C. for 1 h. The mixture was concentrated in vacuo, the residue was treated with 2 M NH3 in MeOH and concentrated in vacuo. The crude product was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 2% to 10% 2M NH3-MeOH in DCM, to give N-(2-chloro-4-(3-(2-methyl-9H-purin-6-yl)pyridin-2-ylamino)phenyl)acetamide (70 mg, 0.178 mmol, 58.3% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 13.62 (s, 1H); 13.01 (s, 1H); 9.80 (s, 1H); 9.47 (s, 1H); 8.38-8.43 (m, 1H); 8.31 (d, J=1.57 Hz, 1H); 7.54-7.60 (m, 1H); 7.47-7.52 (m, 1H); 7.07 (dd, J=7.82, 4.69 Hz, 1H); 2.88 (s, 3H); 2.07 (s, 3H). m/z (ESI, +ve ion) 394 (M+H)+.
Reaction SMILES: C(=O)(O)[O-].[Na+].O.[S:7]1[C:11]2=[CH:12][N:13]=[C:14]([C:16](=[O:18])[CH3:17])[CH:15]=[C:10]2[CH:9]=[CH:8]1.[Br:19]Br>C(Cl)(Cl)(Cl)Cl>[Br:19][C:9]1[C:10]2[C:11](=[CH:12][N:13]=[C:14]([C:16](=[O:18])[CH3:17])[CH:15]=2)[S:7][CH:8]=1
Reactant: BrBr
Reactant: CC(=O)c1cc2ccsc2cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CC(=O)c1cc2c(Br)csc2cn1
Reaction time: 8 h
Yield: 35.9 %

Procedure:
An aqueous saturated sodium bicarbonate solution (10 ml) and water (10 ml) was added to a solution of 1-thieno[2,3-c]pyridin-5-yl-ethanone (600 mg, 3.39 mmol) in carbon tetrachloride (5 ml). Bromine (0.523 ml, 10.2 mmol) was added and the reaction was stirred overnight. The biphasic mixture was allowed to separate and the organic layer was diluted with dichloromethane (25 ml) and washed with 10% sodium sulfide (in ammonium hydroxide) (1×20 mL), and brine (1×20 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was then purified by chromatography (chromatotron, 4μ plate, 0-200% ethyl acetate in hexanes) to yield 1-(3-bromo-thieno[2,3-c]pyridin-5-yl)-ethanone as a white solid (311.3 mg, 36%). 1H NMR (250 MHz, CDCl3): δ 9.20 (s, 1H), 8.54 (s, 1H), 7.30 (s, 1H), 7.30 (s, 1H), 2.85 (s, 3H). MS [E+] 255 & 257 (M+H)+.
Reaction SMILES: Cl.[CH:2]1([N:9]2[CH2:14][CH2:13][C:12]3([O:19][C:18](=[O:20])[NH:17][C:16]4[CH:21]=[CH:22][CH:23]=[CH:24][C:15]3=4)[CH2:11][CH2:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[H-].[Na+].[CH3:27]I>CN(C)C=O.O>[CH:2]1([N:9]2[CH2:14][CH2:13][C:12]3([O:19][C:18](=[O:20])[N:17]([CH3:27])[C:16]4[CH:21]=[CH:22][CH:23]=[CH:24][C:15]3=4)[CH2:11][CH2:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C1Nc2ccccc2C2(CCN(C3CCCCCC3)CC2)O1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)OC2(CCN(C3CCCCCC3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1′-cycloheptylspiro[benzo[d][1,3]oxazine-4,4′-piperidin]-2(1H)-one hydrochloride (compound No. 5) (188 mg, 0.54 mmol) was suspended in anhydrous dimethylformamide (4.0 mL), treated with sodium hydride (48 mg, 60% dispersion in mineral oil, 1.2 mmol) and stirred at room temperature for 10 minutes under nitrogen. The reaction mixture was then treated with a solution of methyl iodide (92 mg, 0.65 mmol) in anhydrous dimethylformamide (1.0 mL) and stirred at room temperature for 1 hour. The reaction mixture was diluted with water (50 mL), and the product was extracted in dichloromethane (2×50 mL). The pooled extracts were washed with water (2×10 mL), saturated NaHCO3, (2×10 mL) and saturated brine (2×10 mL); then dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to afford crude 1′-cycloheptyl-1-methylspiro[benzo[d][1,3]oxazine-4,4′-piperidin]-2(1H)-one (compound no. 65) free base as a colorless oil.
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:12])[C:4](=[O:11])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[OH-].[Na+].O.[Cl:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=2)=[O:22])=[CH:19][N:18]=1>C(O)C.O>[Cl:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27][S:1][C:2]3[N:3]([CH3:12])[C:4](=[O:11])[C:5]4[S:10][CH:9]=[CH:8][C:6]=4[N:7]=3)=[CH:25][CH:24]=2)=[O:22])=[CH:19][N:18]=1
Reactant: Cn1c(S)nc2ccsc2c1=O
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(Cl)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1c(SCc2ccc(C(=O)c3ccc(Cl)nc3)cc2)nc2ccsc2c1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
To a solution of 2-mercapto-3-methylthieno[3,2-d]-pyrimidin-4(3H)-one (1.98 g) and 1N-sodium hydroxide/water (10.5 ml) in ethanol (30 ml) was added 4-(6-chloronicotinoyl)benzyl bromide (3.35 g) and the mixture was stirred at 60° C. fro 1 hour. This reaction mixture was poured in water and the resulting crystals were collected by filtration, rinsed with water, and recrystallized from ethyl acetate to provide the title compound as light-yellow solid (3.194 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]([OH:14])[C:11]([NH2:13])=[O:12])[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].Cl[C:16](OCC)=[O:17].O>[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C:11](=[O:12])[NH:13][C:16](=[O:17])[O:14]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: CCOC(=O)Cl
Reactant: NC(=O)N(O)c1cc(Cl)c(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]c(=O)n(-c2cc(Cl)c(Cl)c(Cl)c2)o1
Reaction time: 1 h

Procedure:
1-(3,4,5-Trichlorophenyl)-1-hydroxyurea (0.2 mole) dissolved in aqueous sodium hydroxide (200 ml; 2 N) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The solution is cooled to a temperature of about 10°C and ethyl chloroformate (0.21 mole) is slowly added with stirring. After the addition is completed stirring is continued for a period of about one hour. The reaction mixture is then poured into 2 liters of water. The resulting aqueous solution is then filtered and the filtrate is cooled and acidified with concentrated hydrochloric acid to form a precipitate. The precipitate is recovered by filtration and is dried. The dried product is then dissolved in a methylene chloride-tetrahydrofuran mixture and the resulting solution is dried over anhydrous magnesium sulfate, filtered and stripped of solvent to yield the desired product 2-(3,4,5-trichlorophenyl)-1,2,4-oxadiazolidin-3,5-dione.