Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[CH3:5][N:6]([CH3:23])[C:7]1[CH:12]=[CH:11][C:10]([CH:13](O)[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=O)=[CH:9][CH:8]=1>C(O)(=O)C>[CH3:23][N:6]([CH3:5])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:1][C:2](=[O:3])[NH:4][C:14]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:9][CH:8]=1
Reactant: CN(C)c1ccc(C(O)C(=O)c2ccccc2)cc1
Reactant: NC(N)=O
Solvent: CC(=O)O
Product: CN(C)c1ccc(-c2[nH]c(=O)[nH]c2-c2ccccc2)cc1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To acetic acid (2 mL) was added urea (0.6 g, 10 mmol) and 2-(4-dimethylaminophenyl)-2-hydroxy-1-phenylethanone (2.6 g, 10 mmol). After stirring for 2 hours at 120° C., the reaction was cooled to ambient temperature. The resulting solid was filtered, washed with ether, and dried in vacuo to give 4-(4-dimethylaminophenyl)-2,3-dihydro-5-phenyl-1H-imidazol-2-one; NMR (CDCl3) 10.98 (s,2), 7.5 (m,4), 7.4 (m,5), 3.18 (s,6) ppm.
Reaction SMILES: Cl.C([N:4]([CH:36]1[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]1)[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:13]=[CH:14][C:15]3[S:20][C:19]([C:21]([NH2:23])=[O:22])=[C:18]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH3:31])[C:16]=3[N:17]=2)=[C:7]([O:32][CH:33]([CH3:35])[CH3:34])[CH:6]=1)=O.N>O>[CH:33]([O:32][C:7]1[CH:6]=[C:5]([NH:4][CH:36]2[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH2:41]2)[CH:10]=[CH:9][C:8]=1[NH:11][C:12]1[N:13]=[CH:14][C:15]2[S:20][C:19]([C:21]([NH2:23])=[O:22])=[C:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])[C:16]=2[N:17]=1)([CH3:35])[CH3:34]
Reactant: COc1ccccc1-c1c(C(N)=O)sc2cnc(Nc3ccc(N(C=O)C4CCN(C)CC4)cc3OC(C)C)nc12
Agent: Cl
Agent: N
Solvent: O
Product: COc1ccccc1-c1c(C(N)=O)sc2cnc(Nc3ccc(NC4CCN(C)CC4)cc3OC(C)C)nc12
Temperature: 25 °C
Reaction time: 40 h
Yield: 54.7 %

Procedure:
A 5N hydrochloric acid solution (6.25 ml) is added to a single-necked round-bottomed flask containing 0.25 g of 2-{4-[formyl-(1-methylpiperidin-4-yl)amino]-2-isopropoxyphenylamino}-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxamide. The reaction mixture is stirred at ambient temperature for 40 h, and then a further 2.0 ml of 5N hydrochloric acid solution are added and the stirring is continued for 20 h. The mixture is then poured into 25 ml of water and alkalinized by adding a solution of aqueous ammonia at 28% (8 ml). After extraction with ethyl acetate (3×30 ml), the organic extracts are combined, washed with water (3×20 ml) to neutral pH, dried over magnesium sulfate, and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on a 25 g cartridge of 15-40 μm silica, elution being carried out successively with 94/3/3 v/v/v then 90/5/5 v/v/v dichloromethane/methanol/acetonitrile mixtures, and then a dichloromethane/methanol/acetonitrile/28% aqueous ammonia mixture (93/3/3/1 v/v/v/v) at a flow rate of 20 ml/min. The pasty orange solid obtained is triturated from diisopropyl ether and reconcentrated to dryness under reduced pressure, and then triturated from petroleum ether and filtered. The solid obtained is stove-dried under reduced pressure (40° C., 10-3 mbar), so as to obtain 0.13 g of 2-[2-isopropoxy-4-(1-methylpiperidin-4-ylamino)phenylamino]-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxamide in the form of a dark orange solid.
Reaction SMILES: [CH2:1]([O:5][C@H:6]1[N:9]([C:10](=C(C)C)[C:11]([O:13][CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:8](=[O:30])[C@@H:7]1[NH:31][C:32](=[O:40])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:2]([CH3:4])=[O:3].[O:41]=O>C(Cl)Cl>[CH2:1]([O:5][C@H:6]1[N:9]([C:10](=[O:41])[C:11]([O:13][CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:8](=[O:30])[C@@H:7]1[NH:31][C:32](=[O:40])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:2]([CH3:4])=[O:3]
Reactant: O=O
Reactant: CC(=O)CO[C@@H]1[C@@H](NC(=O)Cc2ccccc2)C(=O)N1C(C(=O)OC(c1ccccc1)c1ccccc1)=C(C)C
Solvent: ClCCl
Product: CC(=O)CO[C@@H]1[C@@H](NC(=O)Cc2ccccc2)C(=O)N1C(=O)C(=O)OC(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of diphenylmethyl α-[4(R)-acetonyloxy-3(R)-phenylacetamido-2-oxo-azetidin-1-yl]-α-isopropylideneacetate (2.342 g; 4.33 mmoles) in methylene chloride (40 ml) is introduced ozonized oxygen for 25 minutes at -78° C. Excess ozone is purged with nigrogen gas, and the mixture is mixed with dimethyl sulfide (3 ml), and stirred at -78° C. for 30 minutes, and at room temperature for 30 minutes. The reaction mixture is mixed with three drops of acetic acid, washed with water, dried over sodium sulfate, and evaporated under reduced pressure to give the product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]#[N:12])=[C:4]([C:8]([OH:10])=O)[NH:5][C:6]=1[CH3:7].ClC1C=C(C([NH:22][C@H:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][C@H:24]2[O:34][CH2:35][CH2:36][CH3:37])=O)NC=1C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>ClCCl>[Cl:1][C:2]1[C:3]([C:11]#[N:12])=[C:4]([C:8]([NH:22][C@@H:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][C@@H:24]2[O:34][CH2:35][CH2:36][CH3:37])=[O:10])[NH:5][C:6]=1[CH3:7]
Reactant: CCCO[C@@H]1CN(C(=O)OCC)CC[C@@H]1NC(=O)c1cc(Cl)c(C)[nH]1
Reactant: Cc1[nH]c(C(=O)O)c(C#N)c1Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCO[C@H]1CN(C(=O)OCC)CC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
To a solution of 4-chloro-3-cyano-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 16, 2 g, 8.69 mmol) and ethyl (3S,4R)-4-amino-3-propoxypiperidine-1-carboxylate (see Intermediate 73, 1.59 g, 8.695 mmol) in dichloromethane (150 mL) was added N-Hydroxybenzotriazole (1.6 g, 10.43 mM) and N-methylmorpholine (2.63 g, 26.08 mmol). The reaction mixture was stirred for 1 h at room temperature and 1-Ethyl-3-(3-dimethyl amino propyl)carbodiimide hydrochloride (2.87 g, 15.6 mM) was added. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with 2N hydrochloric acid (50 mL) and the layers were separated. The organic layer was washed with sodium bicarbonate (40 mL), water (60 mL) and finally with brine successively and dried over anhydrous sodium sulphate, filtered, concentrated under vacuum to afford ethyl (3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidine-1-carboxylate 2.6 g (76%) as solid.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][CH2:6]P(=O)(OCC)OCC)#[N:4].[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1C=O.O>O1CCCC1>[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:6]=[CH:5][C:3]#[N:4]
Reactant: O=Cc1ccccn1
Reactant: CCOP(=O)(CCC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC=Cc1ccccn1
Reaction time: 1 h
Yield: 15.4 %

Procedure:
Sodium hydride (ca. 60%, 1.0 g, 28.1 mmol) was suspended in tetrahydrofuran (12 ml), and a solution of diethyl cyanoethylphosphonate (4.7 g, 26.8 mmol) in tetrahydrofuran (12 ml) was added thereto under ice cooling condition. The reaction mixture was stirred for 1 hr. A solution of 2-pyridinecarbaldehyde (2.7 g, 25.0 mmol) in tetrahydrofuran (10 ml) was added to the mixture, and the mixture was stirred at 0° C. to room temperature for 6 hrs. The reaction mixture was combined with water under ice cooling condition, concentrated to the half amount and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel (100 g) column chromatography. The fractions eluted with hexane-ethyl acetate (2:1, v/v) were collected and concentrated to give Z-form of the titled compound (0.50 g, 15%). And simultaneously, the fractions eluted with hexane-ethyl acetate (3:2, v/v) were collected and concentrated to give E-form of the titled compound.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([CH3:8])[N:7]=1.[CH:10]1([O:16][C:17]2[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.O.O.O.O.O.O.O.O.O.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:17]1([O:16][C:10]2[CH:15]=[CH:14][C:13]([C:2]3[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([CH3:8])[N:7]=3)=[CH:12][CH:11]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Cc1cnc(N)c(Br)n1
Reactant: OB(O)c1ccc(OC2CCCCC2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cnc(N)c(-c2ccc(OC3CCCCC3)cc2)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.922 g) was added to a suspension of 3-bromo-5-methylpyrazin-2-amine (5 g), 4-(cyclohexyloxy)phenylboronic acid (7.61 g) and sodium carbonate decahydrate (15.2 g) in DME (200 mL) and water (40 mL) and the mixture was stirred at 80° C. under nitrogen overnight. The insoluble material was removed by filtration (eluted with EtOAc), and silica-gel was added and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (7.5 g) as a pale orange solid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:21][CH2:20][C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[CH2:13]1>CO>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:21][CH2:20][CH:19]2[CH:14]([CH2:15][CH2:16][CH2:17][CH2:18]2)[CH2:13]1
Reactant: c1ccc2c(c1)OCC(CN1CCC3=C(CCCC3)C1)O2
Solvent: CO
Product: c1ccc2c(c1)OCC(CN1CCC3CCCCC3C1)O2

Procedure:
The above described 2-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-1,2,3,4,5,6,7,8-octahydroiso-quinoline (195 mg, 0.68 mmol) was hydrogenated in MeOH (20 ml) under normal pressure (12 h, 50° C.) to give the crude title compound, which was purified by flash chromatography (heptane/EtOAc).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:10][CH:9]=1.I[CH:24]([CH3:26])[CH3:25]>>[CH:24]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[CH:10][CH:9]=1)([CH3:26])[CH3:25]
Reactant: CC(C)I
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2ccccc2O)cc1
Product: CC(C)Oc1ccccc1-c1ccc(CNC(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 20 using tert-butyl N-(2′-hydroxybiphenyl-4-ylmethyl)carbamate instead of tert-butyl N-(3′-hydroxybiphenyl-4-ylmethyl)carbamate and 2-iodopropane instead of 1-bromopropane.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[C:8](=[O:24])[N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:10]([CH3:13])=[CH:11][CH:12]=1)=[O:6])[C:2]#[CH:3].[OH:25][N:26]=[C:27](Cl)[CH3:28].O>CCOC(C)=O>[CH3:28][C:27]1[CH:3]=[C:2]([CH2:1][NH:4][C:5]([C:7]2[C:8](=[O:24])[N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=3)[C:10]([CH3:13])=[CH:11][CH:12]=2)=[O:6])[O:25][N:26]=1
Reactant: CC(Cl)=NO
Reactant: C#CCNC(=O)c1ccc(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(CNC(=O)c2ccc(C)n(-c3cccc(C(F)(F)F)c3)c2=O)on1
Reaction time: 48 h
Yield: 52.8 %

Procedure:
The compound obtained in step (a) (0.050 g, 0.15 mmol) was dissolved in EtOAc (15 ml) under magnetic stirring. To this solution was added N-hydroxyacetimidoyl chloride (0.15 g, 1.6 mmol), water (0.3 ml) and KHCO3 (0.16 g, 1.6 mmol). The mixture was stirred for 2 days at which time LC-MS showed 90% conversion. The reaction was stopped and the mixture was partitioned between EtOAc (25 ml) and water (25 ml). The organic phase was washed (water, brine) and dried. Filtration and evaporation gave a crude mixture which was purified by chromatography on silica. Freeze-drying the pure fractions afforded the subtitle compound (0.031 g, 53%) as a white powder.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[CH3:16][NH2:17]>O1CCOCC1>[CH3:15][O:14][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:17][CH3:16])[C:11]([CH:12]=[O:13])=[CH:10]2
Reactant: CN
Reactant: COc1ccc2nc(Cl)c(C=O)cc2c1
Solvent: C1COCCO1
Product: CNc1nc2ccc(OC)cc2cc1C=O
Temperature: 160 °C
Reaction time: 6 h
Yield: 98.4 %

Procedure:
To a stirred solution of 2-chloro-6-methoxyquinoline-3-carbaldehyde (1.50 g, 6.77 mmol) in 1,4-dioxan (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added methylamine (40 wt % solution in water, 2.10 mL, 24.3 mmol) and the reaction mixture was stirred for 6 h at 160° C. under microwave irradiation. After cooling to RT, the volatiles were removed at 40° C. under vacuum and the resulting yellow oil was taken up in a mixture of THF:1 N aq. HCl=1:1 (50 mL) and stirred for 1 h at RT. THF was removed at 40° C. under vacuum and the residue was then neutralised with a saturated NaHCO3 aqueous solution before to be extracted with CH2Cl2 (100 mL). The organic phase was washed with brine (20 mL), dried over MgSO4, filtered, and concentrated under vacuum, to give 6-methoxy-2-(methylamino)quinoline-3-carbaldehyde SLA 28150 as an orange oil (1.44 g, 98% yield).
Reaction SMILES: C([NH:3][C:4]([CH3:22])([CH3:21])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:20])=[CH:14][C:15]([O:17][CH2:18]C)=[O:16])=[CH:9][CH:8]=1)=O.[2H]C(Cl)(Cl)Cl.[2H]O[2H]>>[C:15]([CH:14]=[C:13]([C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][C:4]([CH3:22])([CH3:21])[NH2:3])=[CH:12][CH:11]=1)[CH3:20])([O:17][CH3:18])=[O:16]
Reactant: CCOC(=O)C=C(C)c1ccc(CCC(C)(C)NC=O)cc1
Agent: [2H]C(Cl)(Cl)Cl
Agent: [2H]O[2H]
Product: COC(=O)C=C(C)c1ccc(CCC(C)(C)N)cc1

Procedure:
This was prepared in an identical manner to the compound described in Description 6 using N-formyl-3-{4-(2-carboethoxy-1-methylethenyl)phenyl}-1, 1-dimethylpropanamine. τ(CDCl3 /D2O(8.8 (6H, s) 8.5-8.1 (2H, m), 7.48 (3H, d, J=1.5 Hz), 7.5-7.1 (2H, m), 6.3 (3H, s), {4.1 (broad) +3.88 (q, J=1.5 Hz), Total 1H}, 2.8 (2H, d, J=7 Hz), 2.55 (2H, d, J=7 Hz).
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[C:13]([F:25])=[C:14]([CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])[CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][C:5]=1[C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[F:34].[OH-].[Na+].Cl>CO>[CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[C:13]([F:25])=[C:14]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][C:5]=1[C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[F:34]
Reactant: CCOC(=O)CCc1cccc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(COc3cccc(CCC(=O)O)c3F)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 45 %

Procedure:
To a solution of ethyl 3-(3-((6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methoxy)-2-fluorophenyl)propanoate (400 mg) in methanol (4.0 mL) was added 1N aqueous sodium hydroxide solution (4.0 mL), and the mixture was stirred at room temperature for 15 hr. 1N Hydrochloric acid was added to the reaction mixture to adjust to pH<4, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (170 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1.[C:23]1([C:29]#[CH:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:30]#[C:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1
Reactant: C#Cc1ccccc1
Reactant: Cc1nnc2n1-c1sc(I)cc1C(c1ccccc1Cl)=NC2
Solvent: ClCCl
Solvent: CCO
Product: Cc1nnc2n1-c1sc(C#Cc3ccccc3)cc1C(c1ccccc1Cl)=NC2

Procedure:
The title compound was obtained by reacting 4-(2-chlorophenyl)-2-iodo-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine with phenylacetylene under the conditions described in EXAMPLE 37. The product was isolated by chromatography over the 50-fold amount of silica gel using 5% (v/v) of ethanol in methylene chloride for elution. The combined clean fractions were evaporated and the residue was crystallized from ethyl acetate to give colorless crystals of 4-(2-chlorophenyl)-9-methyl-2-(phenylethynyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]-diazepine with m.p. 215°-217°.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=3)[CH:9]=2)[C:4]=1[C:21]1[CH:22]=[C:23]([S:27]([NH:30][C:31]2[S:32][CH:33]=[CH:34][N:35]=2)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1.B(Br)(Br)Br>>[OH:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)[CH:9]=2)[C:4]=1[C:21]1[CH:22]=[C:23]([S:27]([NH:30][C:31]2[S:32][CH:33]=[CH:34][N:35]=2)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1
Reactant: COc1cccc(-c2ccc3c(-c4cccc(S(=O)(=O)Nc5nccs5)c4)c(OC)ccc3c2)c1
Agent: BrB(Br)Br
Product: O=S(=O)(Nc1nccs1)c1cccc(-c2c(O)ccc3cc(-c4cccc(O)c4)ccc23)c1
Yield: 27 %

Procedure:
The compound is prepared by the reaction of 3-(2-methoxy-6-(3-methoxyphenyl)naphthalene-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (75.3 mg, 0.15 mmol, 1 eq) with boron tribromide solution (14.1 ml, 14.1 mmol, 5 eq) according to method G. Purification by preparative thin-layer chromatography with dichloromethane/methanol 92.5/7.5 as the eluent yielded the desired compound in a yield of 27%, 19 mg.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([O-:19])=[O:18])=[CH:13][CH:12]=1.[Na+].C([O-])(=O)C.[K+]>C(O)CC>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH2:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: O=S([O-])c1ccc(Cl)cc1
Reactant: ClCc1ccncc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCCO
Product: O=S(=O)(Cc1ccncc1)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
Under heating, a 1-propanol (50 ml) solution of 4-chloromethylpyridine hydrochloride (1.26 g, 7.65 mmol), sodium 4-chlorobenzenesulfinate (1.52 g, 7.65 mmol) and potassium acetate (1.50 g, 15.3 mmol) was stirred at 70° C. for 8 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was filtered through a short column (silica gel, ethyl acetate) and the eluate was concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate (=2:3) eluate was concentrated under reduced pressure, whereby the title compound (1.26 g, 62%) was obtained as a white solid.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[C:16]2[C@@H:15]3[C@H:10]([CH2:11][NH:12][CH2:13][CH2:14]3)[CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1.Br[CH2:18][CH2:19][NH:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1>>[ClH:1].[F:28][C:25]1[CH:24]=[CH:23][C:22]([C:21]([NH:20][CH2:19][CH2:18][N:12]2[CH2:13][CH2:14][C@@H:15]3[C:16]4[C:4]([O:3][CH3:2])=[CH:5][CH:6]=[CH:7][C:8]=4[CH2:9][C@H:10]3[CH2:11]2)=[O:29])=[CH:27][CH:26]=1
Reactant: COc1cccc2c1[C@H]1CCNC[C@@H]1C2
Reactant: O=C(NCCBr)c1ccc(F)cc1
Agent: Cl
Product: COc1cccc2c1[C@H]1CCN(CCNC(=O)c3ccc(F)cc3)C[C@@H]1C2
Yield: 32.5 %

Procedure:
The product from Example 48 (0.310 g) was treated with 0.34 g 2-bromo-1-(4-fluorobenzamido)ethane as described as described in Example 7 to yield 0.170 g of the desired product as a white solid, mp: 242-4° C. NMR (d6DMSO) δ 1.95 (m, 2H), 2.29 (m, 2H), 2.45-2.75 (m, 2H), 2.82 (m, 2H), 3.05-3.45 (m, 4H), 3.60-3.90 (m, 2H), 3.77 (s, 3H), 6.80 (d, 1H), 6.87 (d, 1H), 7.13 (t, 1H), 7.31 (m, 2H), 8.00 (m, 2H), 8.98 (m, 1H).
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:12][CH:11]2[N:13]([C:14]([O:16]C(C)(C)C)=[O:15])[CH:8]([CH2:9][CH2:10]2)[CH2:7]1)=[O:5].[Br-].O.Cl>O1CCCC1>[C:6]([C@@:11]12[N:13]([C:14]([OH:16])=[O:15])[C@@H:8]([CH2:9][CH2:10]1)[CH2:7][CH:6]([C:4](=[O:5])[CH2:11][CH2:10][CH:9]=[CH2:8])[CH2:12]2)([CH3:12])([CH3:7])[CH3:4]
Reactant: CON(C)C(=O)C1CC2CCC(C1)N2C(=O)OC(C)(C)C
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCC(=O)C1C[C@@H]2CC[C@](C(C)(C)C)(C1)N2C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 173.4 %

Procedure:
While under a nitrogen atmosphere, a solution of tert-butyl 3-(methoxy(methyl)carbamoyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.7 g, 5.7 mmol), in tetrahydrofuran (25 mL) was cooled to 0° C. and treated with 3-butenylmagnesiun bromide (0.5 M in THF, 28.5 mL, 14.3 mmol) in a drop wise manner. The solution was stirred for 1 hour at 0° C. then allowed to warm to room temperature overnight. The resulting solution was poured into water, acidified to pH 3-4 with 1 N hydrochloric acid, and extracted with ethyl acetate (3×). The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (silica gel, 0-25% ethyl acetate in heptane) gave (1R,5S)-tert-Butyl-3-pent-4-enoyl-8-azabicyclo[3.2.1]-octane-8-carboxylic acid as a colorless oil (1.45 g, 87%); 1H NMR (CDCl3, 400 MHz) δ 5.81 (m, 1H), 5.01 (m, 2H), 4.29 (br s, 2H), 2.83 (m, 1H), 2.53 (t, J=7.5 Hz, 1H), 2.32 (q, J=7 Hz, 2H), 2.03 (m, 2H), 1.83 (t, J=12.5 Hz, 2H), 1.60-1.71 (m, 5H) and 1.48 (s, 9H); m/z for C17H27NO3 expected 293.2. found 316.3 (M+Na)+, 294.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:3]=1[C:4]([NH:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=2)[CH:8]=1)=[O:5].[Li+].[OH-]>C1COCC1>[Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:3]=1[C:4]([NH:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:24]=[CH:23][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)[CH:8]=1)=[O:5]
Reactant: CCOC(=O)c1ccc(Nc2cc(NC(=O)c3c(Cl)cccc3Cl)ncn2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Nc2cc(NC(=O)c3c(Cl)cccc3Cl)ncn2)cc1
Temperature: 60 °C
Yield: 92 %

Procedure:
To a solution of ethyl 4-(6-(2,6-dichlorobenzamido)pyrimidin-4-ylamino)benzoate (0.279 g, 0.647 mmol) in THF (5 mL) was added a solution of 3 N LiOH (2 mL). The mixture was heated at 60° C. for 12 hrs. THF was removed under reduced pressure. The residue was diluted with water, acidified with 1 N HCl to pH 3.0. The precipitated white solid was collected by filtration, washed with water, dried in high vacuum to give 4-(6-(2,6-dichlorobenzamido)pyrimidin-4-ylamino)benzoic acid (0.24 g, yield: 92%). 1H NMR (500 MHz, DMSO) δ 12.52 (s, 1H), 11.41 (s, 1H), 10.07 (s, 1H), 8.53 (s, 1H), 7.90 (d, J=8.9 Hz, 2H), 7.85 (d, J=8.9 Hz, 2H), 7.78 (d, J=0.8 Hz, 1H), 7.58-7.53 (m, 2H), 7.49 (dd, J=9.1, 6.9 Hz, 1H). LCMS (ESI) m/z: 403.0 [M+H+].