Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.Br[CH2:21][CH2:22][CH2:23][Cl:24].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:15]([O:14][C:13](=[O:19])[NH:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([O:1][CH2:21][CH2:22][CH2:23][Cl:24])=[CH:3][CH:4]=1)([CH3:16])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c2ccccc12
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1ccc(OCCCCl)c2ccccc12
Temperature: 25 °C

Procedure:
Tert-butyl (4-hydroxy-1-naphthyl)carbamate (3.93 g, 15.1 mmol), 1-bromo-3-chloropropane (5.5 g, 34.8 mmol), and K2CO3 (10.0 g, 75.8 mmol) in acetonitrile (50 ml) are heated to 80° C. with agitation for 8 h. After cooling to room temperature the mixture is filtered and concentrated under vacuum. The residue is purified by column chromatography on silica gel to yield [4-(3-chloropropoxy)-naphthalen-1-yl]-carbamic acid tert-butyl ester. 4 g, 78% is produced as an off-white solid. MS: 336.2 (M+1).
Reaction SMILES: [N:1]1[C:6]2[S:7][C:8]3[CH2:13][CH2:12][CH2:11]C[C:9]=3[C:5]=2[C:4](=O)[NH:3][CH:2]=1.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:4]1[C:5]2[C:9]3[CH2:11][CH2:12][CH2:13][C:8]=3[S:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: O=c1[nH]cnc2sc3c(c12)CCCC3
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Clc1ncnc2sc3c(c12)CCC3

Procedure:
To 10.56 g 5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4(3H)-one (0.51 mol) and 10 mL dimethylaniline was added, in one portion, 50 mL POCl3. The mixture was heated to reflux for 5 h under argon, cooled and the excess POCl3 was removed by concentration in vacuo. The residue was poured into 200 g ice and neutralized with satd Na2CO3. The resulting blue-gray gum was filtered, washed with water and crystallized from ethanol to give 7.03 g (0.031 mol) of product.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=1.N1C=CC=CC=1>ClCCl>[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][S:2]([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])=[C:17]([C:22]([F:23])([F:24])[F:25])[CH:16]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(F)cc1C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(O)c1ccc(S(=O)(=O)Nc2ccc(F)cc2C(F)(F)F)cc1
Temperature: -5 °C

Procedure:
2.21 g (10 mmol) of 4-chlorosulfonyl-benzoic acid is suspended in 30 ml of dichloromethane with exclusion of moisture, the suspension is cooled to -5° C and, at this temperature, a solution of 1.79 g (10 mmol) of 4-fluoro-2-(trifluoromethyl)-aniline and 1 ml of pyridine in 20 ml of dichloromethane is instilled. When the instillation is completed, it is allowed to come to room temperature and is stirred for 12 more hours. The resulting precipitate is suctioned off and extracted with ether. The ether extract and the filtrate are concentrated by evaporation together and the residue is dissolved in dichloroethane. The solution is extracted three times with 10 ml of saturated sodium bicarbonate solution each. The combined aqueous extracts are acidified with 2N hydrochloric acid and the product thus precipitating is filtered off. The filter residue is evaporated to dryness in a vacuum at 50° C. 3.3 g (9.08 mmol)=90.84% of the theoretical yield is obtained.
Reaction SMILES: [NH2:1][C:2]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4].[CH2:14](I)[CH3:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)P(=O)(N(C)C)N(C)C>[CH2:14]([NH:1][C:2]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4])[CH3:15]
Reactant: CCI
Reactant: CCC(N)(C(=O)OC)c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCNC(CC)(C(=O)OC)c1cccs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
Methyl 2-amino-2-(2-thienyl)butyrate (11.94 g) is dissolved in hexamethylphosphoric triamide (200 ml), and ethyl iodide (28.7 g) and potassium carbonate (37.3 g) is added thereto. The mixture is stirred at room temperature for 4 hours and further stirred at 70° C. for one hour. Water is added to the reaction mixture and the mixture is extracted with ether. The extract is washed with water, dried and concentrated to remove solvent. The residue is purified by silica gel column chromatography, whereby methyl 2-ethylamino-2-(2-thienyl)butyrate (8.99 g) is obtained.
Reaction SMILES: ClC1C=C(Cl)C=CC=1O[C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[CH:8]=[CH:7][C:6]=1[N+:20]([O-:22])=[O:21].[NH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[N+:20]([C:6]1[CH:7]=[CH:8][C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])=[CH:10][C:5]=1[NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2Cl)cc1Oc1ccc(Cl)cc1Cl
Reactant: NCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(O)CCNc1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
Amounts of 8.90 g of 2,4-bis(2,4-dichlorophenoxy)nitrobenzene, 5.35 g of β-alanine and 11.06 g of K2CO3 were added to 50 ml acetonitrile. The reaction mixture was refluxed for 5 days. After evaporating the solvent the residue was stirred with 150 ml of water and 100 ml of diethylether for 1 hour. The water phase was acidified with conc. hydrochloric acid and extracted with methylene chloride. After drying and evaporating the solvent the organic layer yielded the desired product as a yellow crystalline material; melting-point 115° C.; yield 2.64 g.
Reaction SMILES: C([Li])(C)(C)C.[C:6]([O:10][C:11](=[O:20])[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=1)([CH3:9])([CH3:8])[CH3:7].[I:21]I>C1COCC1>[C:6]([O:10][C:11](=[O:20])[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[C:14]=1[I:21])([CH3:9])([CH3:7])[CH3:8]
Reactant: II
Reactant: CC(C)(C)OC(=O)Nc1ccnc(Cl)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccnc(Cl)c1I
Temperature: -78 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
tert-Butyllithium (36.3 mL, 1.7M in pentane) is added dropwise to a solution of (2-chloro-pyridin-4-yl)-carbamic acid tert-butyl ester (6.00 g, 26.2 mmol) in THF (46 mL) at −78° C. under Ar. The yellow/orange mixture is stirred for 2 h at −78° C. then warmed to −40° C. for 1 h then cooled to −78° C. before dropwise addition of I2 (15.65 g, 61.7 mmol) in THF (49 mL). The reaction mixture is stirred for 1.5 h at −78° C. then at −10° C. for 30 minutes. The reaction is quenched with saturated NH4Cl solution then diluted with CH2Cl2 and washed with saturated NH4Cl, saturated sodium thiosulfate, water then brine. The organic layer is dried over MgSO4, filtered and concentrated to dryness. The crude product is chromatographed eluting with 1-2% MeOH/CH2Cl2 to yield the title product (7.96 g, 22.5 mmol) as a bright yellow solid. 1H NMR (CDCl3, 300 MHz) δ8.14 (d, 1H), 8.02 (d, 1H), 7.32 (bs, 1H), 1.60 (s, 9H). EI MS [M]+=354, 356, Cl pattern.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([N:10]2[CH:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:16]3[C:12](=[N:13][N:14](CC4C=CC(OC)=CC=4)[C:15]=3[CH3:25])[C:11]2=[O:35])[CH:3]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([N:10]2[CH:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:16]3[C:12](=[N:13][NH:14][C:15]=3[CH3:25])[C:11]2=[O:35])[CH:3]=1
Reactant: COc1ccc(Cn2nc3c(c2C)C(c2ccc(Cl)cc2)N(c2cc(Cl)c(=O)n(C)c2)C3=O)cc1
Solvent: CO
Solvent: ClCCl
Product: Cc1[nH]nc2c1C(c1ccc(Cl)cc1)N(c1cc(Cl)c(=O)n(C)c1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described in Example 2 using 5-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-(4-chlorophenyl)-2-(4-methoxybenzyl)-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(2H)-one (Step 5.5). tR: 3.55 min (HPLC 1); tR: 0.78 min (LC-MS 2); ESI-MS: 389/391 [M+H]+ (LC-MS 2); Rf=0.34 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.03 (s, 3H) 3.43 (s, 3H) 6.13 (s, 1H) 7.25 (d, J=8.2 Hz, 2H) 7.36 (d, J=8.2 Hz, 2H) 7.90 (d, J=2.4 Hz, 1H) 7.94 (d, J=2.7 Hz, 1H) 13.38 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([O:11][CH3:12])[CH:3]=1.Br[CH2:14][CH2:15][CH2:16][Cl:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(O)ccc1C(C)=O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(OCCCCl)ccc1C(C)=O
Yield: 47.4 %

Procedure:
A mixture of 10.6 g (0.637 mole) of 1-(4-hydroxy-2-methoxyphenyl)ethanone, 20 g (0.127 mole) of 1-bromo-3-chloropropane and 26.4 g (0.19 mole) of anhydrous potassium carbonate in 250 ml of acetone was heated at reflux for 20 hr. The mixture was cooled, filtered and the filtrate concentrated under vacuum pump pressure at 90° C. to give an oil which gradually crystallized. The solid was triturated with petroleum ether (30°-60° C.), collected by filtration and dried to yield 14.6 g (94%) of white solid, m.p. 47°-49° C. on recrystallizing from isopropyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([O:12]C)=[CH:7]2.B(Br)(Br)Br.ClC(Cl)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([OH:12])=[CH:7]2
Reactant: COc1cnc2c(Cl)ccnc2c1
Agent: BrB(Br)Br
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: Oc1cnc2c(Cl)ccnc2c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 56.2 %

Procedure:
A pressure-resistant vial was charged with 8-chloro-3-methoxy-1,5-naphthyridine (2.5 g, 12.8 mmol), boron tribromide (13.4 mL, 141.3 mmol) and dichloroethane (0.6M, 21.4 mL). Vessel sealed and mixture stirred at 60° C. for 16 hrs. Next day the reaction mixture was chilled in ice bath and diluted with dichloromethane (200 mL). This was allowed to sit under nitrogen system until all fuming ceased. The resulting yellow solid material was then filtered and dried under high vacuum. This was suspended in 40% (90:10:1 DCM/MeOH/NH4OH)/DCM and purified in this system by ISCO silica gel chromatography (80 g) afford 8-chloro-1,5-naphthyridin-3-ol (1.3 g, 56% yield). MS [M+H]=181.2. Calc'd for C8H5ClN2O=1180.59.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(O)(C)(C)C.[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[C:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:38]=[C:37]([CH:47]([CH3:49])[CH3:48])[C:36]=2[CH2:50][OH:51])=[CH:31][CH:30]=1>ClCl.C(Cl)Cl>[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[C:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:38]=[C:37]([CH:47]([CH3:49])[CH3:48])[C:36]=2[CH:50]=[O:51])=[CH:31][CH:30]=1
Reactant: CC(C)c1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: ClCl
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: CC(C)c1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1C=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.1 %

Procedure:
A solution of Dess-Martin periodinane (1.54 gm, 3.63 mmol) in dry CH2 Cl2 (17 ml) was treated with t-butanol (267 mg, 3.60 mmol) and stirred for 15 minutes at room temperature. A solution of 4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinemethanol (895 mg, 2.78 mmol) in CH2Cl2 (12 ml) was then added and stirring was continued 30 minutes, after which time the mixture was quenched by the addition of Et2O (70 ml) and 1N NaOH (35 ml). The biphasic mixture was stirred for 10 minutes and the layers were separated. The organic layer was washed with 1N NaOH, H2O and brine, then dried (Na2 SO4), filtered and stripped. The solid residue was chromatographed (Flash, Merck SiO2, 10% EtOAc in hexane) to afford pure 4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinecarboxaldehyde (782 mg, 88%) as a white solid. Analytically pure material was obtained by recrystallization of the solid from a minimum amount of hot hexane.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:18][CH2:19][C:20]#[N:21]>CN(C=O)C.[Cl-].[Na+].O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:18][CH2:19][C:20]#[N:21])[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:7]=1
Reactant: N#CCCBr
Reactant: Ic1ccc(Nc2ncccn2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCN(c1ccc(I)cc1)c1ncccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere, a solution of N-(4-iodophenyl)pyrimidin-2-amine (100 mg) in anhydrous DMF (1.0 ml) was added to a suspension of sodium hydride (16 mg) in anhydrous DMF (1.0 ml), and the resulting mixture was stirred at room temperature for 30 minutes. To the reaction solution, a solution of 3-bromopropionitrile (0.04 ml) in anhydrous DMF (0.5 ml) was added, and the resulting mixture was stirred at room temperature overnight. Saturated brine was added to the reaction solution and the resulting mixture was extracted with chloroform. Organic layer was dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: hexane/chloroform=1/10) to obtain 3-(N-(4-iodophenyl)-N-(pyrimidin-2-yl)amino)propanenitrile (94 mg). NMR (H1, CDCl3): δ 2.82(2H, t, J=6.8 Hz), 4.24 (2H, t, J=6.8 Hz), 6.68 (1H, t, J=4.9 Hz), 7.06-7.10 (2H, m), 7.74-7.78 (2H, m), 8.35 (2H, d, J=4.9 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:11]([F:30])=[CH:12][C:13]([F:29])=[C:14]([C@:16]4([CH3:28])[C:22]([F:24])([F:23])[C:21]([CH3:26])([CH3:25])[O:20][CH2:19][C:18](=O)[NH:17]4)[CH:15]=3)=[N:7][C:6]=2[CH:31]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:11]([F:30])=[CH:12][C:13]([F:29])=[C:14]([C@:16]4([CH3:28])[C:22]([F:24])([F:23])[C:21]([CH3:26])([CH3:25])[O:20][CH2:19][C:18](=[S:41])[NH:17]4)[CH:15]=3)=[N:7][C:6]=2[CH:31]=1
Reactant: CC1(C)OCC(=O)N[C@](C)(c2cc(-c3nc4cc(Cl)ccc4o3)c(F)cc2F)C1(F)F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: CC1(C)OCC(=S)N[C@](C)(c2cc(-c3nc4cc(Cl)ccc4o3)c(F)cc2F)C1(F)F

Procedure:
In a manner analogous to that described in Example 2b), the reaction of (R)-5-[5-(5-chloro-benzooxazol-2-yl)-2,4-difluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-one (35 mg, 77 μmol) with Lawesson's reagent (34 mg, 84 μmol) yielded the title compound in quantitative yield as a white powder. MS (ISP): m/z=473.0 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[C:11]([O:15][C:16]([N:18]1[CH:23]2[CH2:24][CH2:25][CH:19]1[C:20](=[O:26])[NH:21][CH2:22]2)=[O:17])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([O:15][C:16]([N:18]1[CH:23]2[CH2:24][CH2:25][CH:19]1[C:20](=[O:26])[N:21]([C:2]1[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[CH2:22]2)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1C2CCC1C(=O)NC2
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Product: CC(C)(C)OC(=O)N1C2CCC1C(=O)N(c1ccc([N+](=O)[O-])nc1)C2
Yield: 153.6 %

Procedure:
Following general N—C coupling procedure 1, 5-bromo-2-nitropyridine (110 mg, 0.542), was combined with 2-Oxo-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (135 mg, 0.596 mg), which after purification silica gel chromatography gave 3-(6-Nitro-pyridin-3-yl)-2-oxo-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (290 mg, 81%). MS m/z 349.0 (MH+), and was used directly as is without further characterization.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][NH:6][CH3:7].C(N(C(C)C)CC)(C)C.Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)=[O:23]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][N:6]([CH3:7])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)=[O:23]
Reactant: CNCc1cccc(Br)c1
Reactant: Cc1ccc(C(=O)CBr)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(C(=O)CN(C)Cc2cccc(Br)c2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 98.1 %

Procedure:
To a solution of (3-bromo-benzyl)-methyl-amine (3.0 g, 15.0 mmol) in methylene chloride (60 mL) was added diisopropylethylamine (5.2 mL, 30.0 mmol). The reaction mixture was cooled to 0° C. and treated with 2-bromo-1-p-tolyl-ethanone (3.19 g, 15.0 mmol) portionwise over a period of 10 minutes. The reaction mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was washed with water (3×), dried over sodium sulfate, filtered, and the solvent was evaporated to afford 2-((3-bromobenzyl)(methyl)amino)-1-p-tolylethanone (4.89 g, 98%) as a viscous, orange oil: 1H NMR (CDCl3, 500 MHz) δ 7.85 (d, J=8.2 Hz, 2H), 7.51 (br s, 1H), 7.38 (d, J=7.9 Hz, 1H), 7.28-7.23 (m, 3H), 7.17 (t, J=7.8 Hz, 1H), 3.78 (s, 2H), 3.63 (s, 2H), 2.41 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[N:27]=[CH:26][N:25]=[C:24]([C:28](O)=[O:29])[CH:23]=4)=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1.C(OP(C#N)(=O)OCC)C.[NH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CN(C=O)C.CCOC(C)=O.C([O-])(O)=O.[Na+]>[F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:23]=[C:24]([C:28](=[O:29])[NH:43][C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)[N:25]=[CH:26][N:27]=4)=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1cc(Oc2ccc3c(c2)CCN3C(=O)Nc2cccc(C(F)(F)F)c2)ncn1
Agent: CCOP(=O)(C#N)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1cc(Oc2ccc3c(c2)CCN3C(=O)Nc2cccc(C(F)(F)F)c2)ncn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an ice-cooled solution of 400 mg (0.90 mMol) 6-[1-(3-trifluoromethyl-phenylcarbamoyl)-2,3-dihydro-1H-indol-5-yloxy]-pyrimidine-4-carboxylic acid in 4 ml DMF, 402 μl (2.7 mMol) diethyl-cyanophosphonate and 248 μl (2.7 mMol) aniline are added. After stirring the solution for 3 h at rt, another 402 μl diethyl-cyanophosphonate are added and stirring continued for 16 h. Then the mixture is diluted with EtOAc and sat. NaHCO3, the aqueous layer separeted off and extracted twice with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and partially concentrated until crystals are formed. These are filtered and washed with EtOAC/DIPE, yielding the title compound: m.p.: 227-229° C.; MS: [M−1]=518; HPLC: AtRet=17.2.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](O)=O)=[CH:11][C:10]=1[CH2:18][O:19][CH3:20])[CH3:2].[NH2:21][C:22](=[N:40][OH:41])[C:23]1[CH:24]=[C:25]([CH:37]=[CH:38][CH:39]=1)[CH2:26][N:27]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH3:28]>>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:41][N:40]=[C:22]([C:23]3[CH:24]=[C:25]([CH:37]=[CH:38][CH:39]=3)[CH2:26][N:27]([CH3:28])[CH2:29][C:30]([O:32][C:33]([CH3:35])([CH3:36])[CH3:34])=[O:31])[N:21]=2)=[CH:11][C:10]=1[CH2:18][O:19][CH3:20])[CH3:2]
Reactant: CCc1ccccc1-c1ccc(C(=O)O)cc1COC
Reactant: CN(CC(=O)OC(C)(C)C)Cc1cccc(C(N)=NO)c1
Product: CCc1ccccc1-c1ccc(-c2nc(-c3cccc(CN(C)CC(=O)OC(C)(C)C)c3)no2)cc1COC

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 36 and Intermediate 51. The reaction mixture was filtered through a SPE NH2 column (10 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography (c-hex/(DCM/EtOAc 1:1) gradient from 1:0 to 1:1), affording the title compound as a pale yellow oil. 1H NMR (CDCl3) δ 8.43 (d, J=1.3 Hz, 1H), 8.19-8.16 (m, 2H), 8.11 (d, J=7.5 Hz, 1H), 7.61-7.47 (m, 2H), 7.41-7.34 (m, 3H), 7.29-7.23 (m, 1H), 7.13-7.10 (m, 1H), 4.27-4.18 (m, 2H), 3.80 (s, 2H), 3.33 (s, 3H), 3.24 (s, 2H), 2.48-2.29 (m, 5H), 1.50 (s, 9H), 1.05 (t, J=7.6 Hz, 3H). LC/MS (Method B): 528.3 (M+H)+. HPLC (Method A) Rt 5.05 min (Purity: 98.4%).
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:20].[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl>[O:9]=[C:8]1[N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3](=[O:20])[CH:2]1[NH:1][C:28]([NH:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:29]
Reactant: NC1C(=O)Nc2ccccc2N(c2ccccc2)C1=O
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1)NC1C(=O)Nc2ccccc2N(c2ccccc2)C1=O
Temperature: 25 °C
Yield: 71.9 %

Procedure:
To a slurry of 3-amino-1-phenyl-1,5-dihydro-benzo [b] [1,4]-diazepine-2,4-dione (0.398 g) in dichloromethane (5 ml) was added phenyl isocyanate (0.177 g) gradually with stirring at ambient temperature. The reaction mixture was stirred two hours at ambient temperature after which time a cream precipitate was separated by filtration to provide the title compound (0.413 g). 1H NMR (300 MHz, DMSO-d6): d 4.97 (d, J=7.5 Hz, 1H), 6.88-6.97 (m, 3H), 7.13-7.47 (m, 12H), 9.16 (s, 1H), 10.78 (br s, 1H); TLC (CH2Cl2 /CH3OH,19:1): Rf =0.21
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:12][C:13]3[CH:14]=[C:15]([C:19]4[N:24]=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]5)=[CH:21][N:20]=4)[CH:16]=[CH:17][CH:18]=3)[C:9](=[O:11])[O:10][C:5]2=[CH:4][CH:3]=1.Cl>C(#N)C.O1CCOCC1>[CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]4[N:24]=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)=[CH:21][N:20]=4)[CH:14]=3)[C:9](=[O:11])[O:10][C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc2oc(=O)n(Cc3cccc(-c4ncc(N5CCN(C(=O)OC(C)(C)C)CC5)cn4)c3)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: Cc1ccc2oc(=O)n(Cc3cccc(-c4ncc(N5CCNCC5)cn4)c3)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
80 mg (0.16 mmol) of tert-butyl 4-{2-[3-(5-methyl-2-oxooxazolo[4,5-b]pyridin-3-ylmethyl)phenyl]pyrimidin-5-yl}piperazine-1-carboxylate are dissolved in 6 ml of acetonitrile, and 6 ml of 4 M HCl in dioxane are added. The reaction mixture is stirred at room temperature for 1 h and evaporated. The residue is taken up in water and ethyl acetate, and the water phase is adjusted to pH 12 using NaOH and extracted with ethyl acetate and dichloromethane. The organic phases are combined, dried over sodium sulfate and purified by column chromatography.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[NH2:19][C:20]1[S:21][C:22]([C:26]2[CH:27]=[C:28]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:29]([Cl:32])=[N:30][CH:31]=2)=[C:23]([CH3:25])[N:24]=1>CC(N(C)C)=O>[Cl:32][C:29]1[N:30]=[CH:31][C:26]([C:22]2[S:21][C:20]([NH:19][C:1](=[O:9])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:24][C:23]=2[CH3:25])=[CH:27][C:28]=1[NH:33][S:34]([CH3:37])(=[O:36])=[O:35]
Reactant: Cc1nc(N)sc1-c1cnc(Cl)c(NS(C)(=O)=O)c1
Reactant: O=C(O)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1nc(NC(=O)c2ccccc2)sc1-c1cnc(Cl)c(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 40 %

Procedure:
A mixture of benzoic acid (27 mg), diisopropylethylamine (0.053 mL), 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(V) (84 mg) and DMA (0.5 mL) was stirred at room temperature under an atmosphere of nitrogen for 5 minutes. N-[5-(2-Amino-4-methyl-1,3-thiazol-5-yl)-2-chloropyridin-3-yl]methanesulfonamide (32 mg) was added and the mixture was stirred and heated to 80° C. for 30 minutes. The solvent was evaporated and the residue was triturated under water. The resultant gum was purified by HPLC using a Phenomenex ‘Luna’ preparative reversed-phase column (10 microns silica, 21 mm diameter, 150 mm length) using decreasingly polar mixtures of water (containing 0.2% trifluoroactic acid) and acetonitrile as eluent. There was thus obtained the title compound as a solid (17 mg); NMR Spectrum: (DMSOd6) 2.44 (s, 3H), 3.19 (s, 3H), 7.57 (t, 2H), 7.64-7.69 (m, 1H), 7.95 (s, 1H), 8.12 (d, 2H), 8.42 (s, 1H), 9.91 (s, 1H), 12.87 (s, 1H): Mass Spectrum: M−H− 421.