Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.Cl.[CH3:37][NH:38][O:39][CH3:40]>C1COCC1>[CH3:40][O:39][N:38]([CH3:37])[C:14]([C@@H:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
To a stirred solution of (R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (233 g, 1.2 mol) in THF (1.2 L) was added carbonyldiimidazole (230 g, 1.42 mol). The mixture was stirred for 1 h in an ice-water bath. A suspension of triethylamine (207 mL, 1.41 mol) and N,O-dimethylhydroxylamine hydrochloride (138 g, 1.42 mol) in THF (900 mL) was added. The reaction mixture was allowed to warm to rt and stirred overnight. After tlc showed the reaction was complete, the solvent was evaporated. The residue was dissolved in CH2Cl2 (1.2 L) and washed successively with 0.5 N aq HCl, satd aq Na2CO3 and brine, dried over anhydrous sodium sulfate and evaporated to give (R)-tert-butyl 3-(methoxy(methyl)-carbamoyl)piperidine-1-carboxylate (250 g, 91%), which was used in the next step directly without purification. 1H NMR (400 MHz, CDCl3): 1.44 (s, 9H), 1.60-1.78 (m, 2H), 1.90 (m, 1H), 2.65 (m, 1H), 2.75-2.85 (m, 2H), 3.16 (s, 3H), 3.71 (s, 3H), 4.05-4.19 (m, 2H). MS (E/Z): 273 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:37][C:38]([O:40][CH3:41])=[O:39])[C:8]([O:35][CH3:36])=[C:9]([NH:11][C:12](=[O:34])[NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([O:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27](C(O)=O)[CH:26]=3)=[CH:16][CH:15]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.CNC.[CH3:64][N:65]([CH:67]=[O:68])[CH3:66]>O>[CH3:41][O:40][C:38](=[O:39])[NH:37][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=[C:9]([NH:11][C:12]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([O:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([C:67](=[O:68])[N:65]([CH3:66])[CH3:64])[CH:26]=3)=[CH:16][CH:15]=2)=[O:34])[C:8]=1[O:35][CH3:36]
Reactant: COC(=O)Nc1cc(C(C)(C)C)cc(NC(=O)Nc2ccc(Oc3ccnc(C(=O)O)c3)c3ccccc23)c1OC
Reactant: CN(C)C=O
Agent: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)Nc1cc(C(C)(C)C)cc(NC(=O)Nc2ccc(Oc3ccnc(C(=O)N(C)C)c3)c3ccccc23)c1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a cold solution (0° C.) of 4-{4-[3-(5-tert-butyl-2-methoxy-3-methoxycarbonylamino-phenyl)-ureido]-naphthalen-1-yloxy}-pyridine-2-carboxylic acid (Example 14) (56 mg, 0.1 mmol) in DMF (1 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (23 mg, 0.12 mmol) and triethyl amine (0.070 mL, 0.5 mmol). The solution was allowed to stir at 0° C. for 30 min, then dimethylamine (2M solution in THF, 0.25 mL, 0.5 mmol) was added in one portion. The resulting solution was allowed to stir at room temperature for 12 h. Water (4 mL) was added and the product was extracted with EtOAc, dried over magnesium sulfate and concentrated via rotary evaporation. The resulting crude solid was purified by column chromatography (CH2Cl2:MeOH, 95:5) to provide the title compound as a light tan solid (45 mg, 77% yield).
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][C@H:7]([C:15]([OH:17])=[O:16])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:14])[NH2:13].[CH3:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[OH:28])=O>O>[OH:28][C:22]1[CH:23]=[C:24]([OH:27])[CH:25]=[CH:26][C:21]=1[CH2:19][CH2:18][NH:6][C@H:7]([C:15]([OH:17])=[O:16])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:13])[NH2:14]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: N=C(N)NCCC[C@H](NCCc1ccc(O)cc1O)C(=O)O
Reaction time: 1 h

Procedure:
Ingredients. (1) Water 95.5 (2) Sodium Bicarbonate 0.9 (3) Arginine.2H2O 2.1 (4) Resacetophenone 1.5. Procedure. Mix (1) to (3). Heat to 70 to 80 C. Add (4). An instantaneous reaction occurs and a clear yellow solution is obtained. The mixing and heating is continued for 1 hour, and then hydrogenated over Pt catalyst. After filtration of catalyst, solution of N-[(2,4-dihydroxyphenyl)ethyl]arginine Sodium in water is thus obtained, pH 9.5. Water is evaporated to ⅓ in volume and the solution allowed to cool. The pH is adjusted to 6.5 with citric acid (2.0 grams of 50% solution). N-[(2,4-dihydroxyphenyl)ethyl]arginine is obtained as an off-white to pale, yellow crystalline solid, which is used directly in the preparation of cosmetic compositions.
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[C:21]([C:22]([OH:24])=O)=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[O:11])=[C:6]([O:25][CH2:26][CH3:27])[CH:5]=1)[CH3:2].[CH3:30][C:31]1[C:32]2[N:33]([CH:37]=[C:38]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:39]=2)[CH:34]=[CH:35][CH:36]=1.C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([N:3]([CH2:28][CH3:29])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:37]3[N:33]4[CH:34]=[CH:35][CH:36]=[C:31]([CH3:30])[C:32]4=[N:39][C:38]=3[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:12]3[C:21](=[N:20][C:19]4[C:14]([N:13]=3)=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:22](=[O:24])[O:11]2)=[C:6]([O:25][CH2:26][CH3:27])[CH:5]=1)[CH3:2]
Reactant: Cc1cccn2cc(-c3ccccc3)nc12
Reactant: CCOc1cc(N(CC)CC)ccc1C(=O)c1nc2ccccc2nc1C(=O)O
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CCOc1cc(N(CC)CC)ccc1C1(c2c(-c3ccccc3)nc3c(C)cccn23)OC(=O)c2nc3ccccc3nc21

Procedure:
A mixture of 3.9 grams of (4-diethylamino-2-ethoxyphenyl)(3-carboxyquinoxalin-2-yl)ketone, 2.1 grams of 8-methyl-2-phenylimidazo[1,2-a]pyridine and 15 ml. of acetic anhydride was heated at 80° C. for 1 hour and poured into a mixture of ice ammonia and toluene. The toluene portion was separated, washed with saturated sodium sulfate solution, filtered through phase separation paper and concentrated. Petroleum ether was added to the concentrate and 2.7 grams of crystalline material was filtered off. This material was recrystallized four times from a mixture of toluene and petroleum ether to yield a final product with a melting point of 135°-136° C. A solution of the product produced a blue color when applied to a record sheet material coated with a zinc-modified phenolic resin or silton clay.
Reaction SMILES: C(OC(=O)C)(=O)C.[C:8]([O:12][C:13]([C:15]1[CH:19]=[CH:18][N:17]([CH2:20][CH:21]([OH:38])[CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:26][CH:25]=2)[CH:16]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(=O)([O-])O.[Na+].[Na+].[Cl-]>CS(C)=O>[C:8]([O:12][C:13]([C:15]1[CH:19]=[CH:18][N:17]([CH2:20][C:21](=[O:38])[CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:26][CH:25]=2)[CH:16]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CCCCCCCCc1ccc(OCC(O)Cn2ccc(C(=O)OC(C)(C)C)c2)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCCc1ccc(OCC(=O)Cn2ccc(C(=O)OC(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.817 g (8.00 mmol) acetic anhydride is mixed with 10 ml absolute DMSO, stirred at room temperature for 10 min and added drop-wise to a solution of 0.086 g (0.200 mmol) tert-butyl-1-[2-hydroxy-3-(4-octylphenoxy)propyl]pyrrole-3-carboxylate in 10 ml absolute DMSO. Having stirred for 19 hours, the solution is poured into a mixture of 5% sodium hydrogen carbonate solution and saturated NaCl solution (1:1, v/v) and hydrolyzed for 10 min. Four extractions using diethyl ether, combination of the organic phases, concentration to half the volume on the rotary evaporator, three wash steps with saturated NaCl solution, drying on sodium sulfate, filtration and reconcentration on the rotary evaporator leave as a crude product a brown oil which is purified on silica gel by means of flash column chromatography (flow agent: petroleum ether/ethyl acetate 90:10) and yields the product as a yellowish oil.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH3:6][C:7]1[CH2:12][C:11](=O)[CH:10]=[C:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[N:8]=1.N12CCCN=C1CCCCC2>C(Cl)Cl>[Cl:3][C:11]1[CH:12]=[C:7]([CH3:6])[N:8]=[C:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[CH:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC1=NC(c2ccc(Oc3ccc(F)cc3)cc2)=CC(=O)C1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: Cc1cc(Cl)cc(-c2ccc(Oc3ccc(F)cc3)cc2)n1

Procedure:
To a flask containing 20 ml of POCl3 at 120° C. oil bath was carefully added a solution of 5 g (17 mmol) crude compound 4 and 2.6 ml of 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) (17 mmol) in 20 ml of methylene chloride. After the addition, the reaction mixture was refluxed for one hour. The resulting mixture was concentrated to dryness and diluted with ethyl acetate. Saturated aqueous NaHCO3 was carefully added to the solution to adjust pH to 5-6. The organic phase was separated and the aqueous phase was extracted with the same volume of EtOAc. The combined organic phases were then washed with brine and dried with magnisium sulfate, filtered and concentrated to dryness. The residue was purified with flash chromatography (silica gel, 5% EtOAc/hexane) to get 1.8 g of compound 5 and 850 mg of a mixture of compound 5 and unreacted compound 3. 1H NMR (CDCl3): δ 7.93 (d, 2H, J=6.7 Hz), 7.48 (d, 1H, J=1.36 Hz), 7.09 (d, 1H, J=1.5 Hz), 7.00 (m, 6H), 2.59 (s, 3H). MS: 314.1
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6]C)=O)#[C-:2].[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>>[N+:1]([CH2:3][C:4]([N:18]1[CH2:17][CH2:16][N:15]([C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14])[CH2:20][CH2:19]1)=[O:6])#[C-:2]
Reactant: [C-]#[N+]CC(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: [C-]#[N+]CC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Prepared in accordance with Method B with methyl isocyanoacetate (2.51 g, 25.29 mmol) and piperazine-1-carboxylic acid tert-butyl ester (6.28 g, 33.85 mmol. The reaction mixture was stirred 1 h at RT and then concentrated. The residue was dissolved in dichloromethane (50 mL) and the organic layer was washed with 10% aqueous citric acid (2×25 mL), dried over MgSO4, filtered and evaporated. tert-Butyl 4-(2-isocyanoacetyl)piperazine-1-carboxylate SLA 07116C was obtained as a colorless oil (0.41 g, 6.5% yield).
Reaction SMILES: [O:1]([C:9]1[C:10]([CH3:45])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C:14]([CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:31]([C:33]3[S:43][C:42]4[N:44]5[C:35](=[CH:36][N:37]=[C:38]5[CH:39]=[CH:40][CH:41]=4)[CH:34]=3)=[O:32])[CH2:26][CH2:25]1)([CH3:21])[CH2:13][CH2:12]2)[Si](C(C)(C)C)(C)C.[ClH:46].CO>C(O)C>[ClH:46].[ClH:46].[OH:1][C:9]1[C:10]([CH3:45])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C:14]([CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:31]([C:33]3[S:43][C:42]4[N:44]5[C:35](=[CH:36][N:37]=[C:38]5[CH:39]=[CH:40][CH:41]=4)[CH:34]=3)=[O:32])[CH2:26][CH2:25]1)([CH3:21])[CH2:13][CH2:12]2
Reactant: Cc1c(C)c2c(c(C)c1O[Si](C)(C)C(C)(C)C)CCC(C)(CCN1CCC(NC(=O)C3=Cc4cnc5cccc(n45)S3)CC1)O2
Agent: Cl
Solvent: CO
Solvent: CCO
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCN1CCC(NC(=O)C3=Cc4cnc5cccc(n45)S3)CC1)O2
Temperature: 25 °C
Reaction time: 90 h

Procedure:
To a solution of 1.17 g (1.78 mM) of N-[1-[2-(6-tert-butyldimethylsiloxy-2,5,7,8-tetramethylchroman-2-yl)ethyl]piperidin-4-yl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide in ethanol (5 ml) was added 5.0 ml (20 mM) of 4N—HCl/methanol and the mixture was stirred at room temperature for 90 hours. After the solvent was distilled off under reduced pressure, ethanol and diethyl ether were added and the resulting crystals were collected by filtration and rinsed with ethanol and diethyl ether to provide the title compound as orange-colored crystals.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]([CH3:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[N+](C1C=CC([O:27][C:28]([N:30]2[CH:34]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[C:37]([F:42])[CH:36]=3)[CH2:33][O:32][C:31]2=[O:43])=O)=CC=1)([O-])=O>C1COCC1>[CH3:17][C:8]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:28]([N:30]2[CH:34]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[C:37]([F:42])[CH:36]=3)[CH2:33][O:32][C:31]2=[O:43])=[O:27])[CH2:10][CH2:9]1
Reactant: O=C1OCC(c2ccc(F)c(F)c2)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC1(c2ccccc2)CCN(CCCN)CC1
Solvent: C1CCOC1
Product: CC1(c2ccccc2)CCN(CCCNC(=O)N2C(=O)OCC2c2ccc(F)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
To a solution of 1-(3-amino-propyl)-4-methyl-4-phenyl-piperidine (60 mg, 0.258 mmol) in 10 mL of THF, 4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid-4-nitro-phenyl ester (60 mg, 0.165 mmol) was added and the resulting yellow solution was stirred under argon atmosphere for 2 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 1:1 hexane/EtOAc followed by MeOH:EtOAc=1:19 (Rf =0.45, MeOH:EtOAc=1:3) to obtain 4-(3,4-difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic acid {3-[4-methyl-4-phenyl-piperidin-1-yl)-propyl}-amide (56 mg, 74%). The compound was dissolved in CH2Cl2 (3 mL) and was treated with 1N HCl in ether (1 mL). The solvent was removed in vacuo to give the corresponding hydrochloride salt as a pale yellow solid. M. P. 176-178° C.; [α]D =+76.9, (c=0.23, MeOH); Anal. Calcd. For C25H30N3O3F2Cl.0.60 CH2Cl2 : C, 56.32; H, 5.94; N, 7.70. Found: C, 56.30; H, 5.80; N, 7.35.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:3]=1[C:4]#[N:5].C(O)(=O)C.[CH:22]([NH2:24])=[NH:23]>CN(C)C(=O)C>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:24]=[CH:22][N:23]=1
Reactant: N#Cc1c(F)cccc1Oc1ccc(F)cc1
Reactant: N=CN
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Product: Nc1ncnc2cccc(Oc3ccc(F)cc3)c12
Temperature: 162 °C
Yield: 10.7 %

Procedure:
A mixture of 2-fluoro-6-(4-fluorophenoxy)benzonitrile (2.5 g, 11 mmol) and formamidine acetate (Aldrich) (2.3 g, 22 mmol) in 50 ml of N,N-dimethylacetamide was heated at 162° C. under nitrogen for 9 hours. After cooling to room temperature the reaction mixture was evaporated under reduced pressure. The product was suspended in 80 ml of cold water and the pH adjusted to 8.5 with concentrated ammonium hydroxide. After cooling the suspension overnight, the precipitate was isolated by filtration, washed with water (25 ml), dried and recrystallized from 30 ml of ethanol at 4° C. The precipitate was collected by filtration, washed with ethanol and dried at 50° C. in vacuo to give 4-amino-5-(4-fluorophenoxy)quinazoline (0.3 g, 10.7%, m.p. 188-190° C.):
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Br[CH2:34][CH:35]([CH3:37])[CH3:36]>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CC(C)CBr
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Product: CC(C)CN1CCN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CC1
Yield: 39.9 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.230 mmol) and 1-bromo-2-methyl propane (94 mg, 0.690 mmol) gave 7-cyclopentyl-2-[5-(4-isobutyl-piperazin-1-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (45 mg, 41%). MS (ESI) m/z 491.3 (M+H)+
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:5][CH2:4]1.Cl[CH2:7][C:8]1[N:13]=[C:12]([NH2:14])[CH:11]=[CH:10][N:9]=1.O>C1COCC1.[H-].[Na+]>[CH:3]1([CH2:2][O:1][CH2:7][C:8]2[N:13]=[C:12]([NH2:14])[CH:11]=[CH:10][N:9]=2)[CH2:5][CH2:4]1
Reactant: OCC1CC1
Reactant: Nc1ccnc(CCl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccnc(COCC2CC2)n1
Reaction time: 0.5 h
Yield: 21.6 %

Procedure:
Hydroxymethylcyclopropane (0.17 g) was dissolved in THF (2 mL) and at 0° C. sodium hydride dispersion (55% in oil, 0.1 g) was added. The mixture was allowed to stir for 30 minutes and subsequently, a solution of 2-chloromethyl-pyrimidin-4-ylamine (0.2 g, Eur. Pat. Appl. EP 61318 A2, 1982; Eur. Pat. Appl. 60094 A2, 1982) in THF (7 mL) was added dropwise. The resulting mixture was heated to reflux for 2 hours, cooled and water was added. The mixture was extracted with ethyl acetate and the organic layers were combined, dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (ethyl acetate/methanol 9:1) to give 2-cyclopropylmethoxymethyl-pyrimidin-4-ylamine as colorless solid (54 mg). 1H NMR (δ, CDCl3): 8.22 (d, 1H), 6.32 (d, 1H), 4.98 (br s, 2H), 4.58 (s, 2H), 3.46 (d, 2H), 1.21-1.12 (m, 1H), 0.59-0.53 (m, 2H), 0.27-0.24 (m, 2H). MS (ESI): 180.3 (MH+).
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[C:9]([Cl:26])=[CH:10][C:11]([F:25])=[C:12]([N:14]2[C:22](=[O:23])[C:17]3=[CH:18][CH2:19][CH2:20][CH2:21][N:16]3[C:15]2=[O:24])[CH:13]=1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.Cl>C(OCC)(=O)C>[Cl:26][C:9]1[C:8]([NH:7][S:33]([C:30]2[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=2)(=[O:35])=[O:34])=[CH:13][C:12]([N:14]2[C:22](=[O:23])[C:17]3=[CH:18][CH2:19][CH2:20][CH2:21][N:16]3[C:15]2=[O:24])=[C:11]([F:25])[CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cc(N2C(=O)C3=CCCCN3C2=O)c(F)cc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2cc(N3C(=O)C4=CCCCN4C3=O)c(F)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 59.3 %

Procedure:
To a pyridine (5 mL) solution of 2-(5-amino-4-chloro-2-fluorophenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1, 3[2H, 7H]-dione (0.35 g, 1.2 mmol) was dropwise added p-toluenesulfonyl chloride (0.25 g, 1.3 mmol) under cooling in an ice-water bath, and the mixture was stirred for 2.5 hours at the ambient temperature. 1N Hydrochloric acid (60 mL) and ethyl acetate (40 mL) were added to the resulting mixture and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (20 mL×2 times), and the organic layer combined was washed with a saturated sodium chloride solution (100 mL) and dried over anhydrous magnesium sulfate. After removal of magnesium sulfate by filtration, the filtrate was evaporated to give crude product, which was purified by silica gel column (Wakogel C-200, ethyl acetate/hexane =1/2) to obtain a white solid of 2-[4-chloro-2-fluoro-5-(p-toluenesulfonylamino)phenyl]-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.32 g, yield:59.3%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21](=[O:49])[C:22]1[CH:27]=[C:26]([CH3:28])[C:25](Br)=[C:24]([S:30]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=2[O:41][Si](C(C)(C)C)(C)C)(=[O:32])=[O:31])[CH:23]=1>O1CCCC1>[CH3:19][O:20][C:21]([C:22]1[CH:27]=[C:26]([CH3:28])[C:25]2[O:41][C:35]3[C:36]([Cl:40])=[CH:37][CH:38]=[CH:39][C:34]=3[CH2:33][S:30](=[O:32])(=[O:31])[C:24]=2[CH:23]=1)=[O:49]
Reactant: COC(=O)c1cc(C)c(Br)c(S(=O)(=O)Cc2cccc(Cl)c2O[Si](C)(C)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cccc(Cl)c1O2
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
A solution of tetrabutyl ammonium fluoride (90 g, 0.283 mol) in tetrahydrofuran (250 mL) was added dropwise to a solution of compound of Example 1h (72 g, 0.135 mol) in tetrahydrofuran (350 mL) over a period of 25 min under nitrogen, at 5° C. The reaction mixture was stirred at 5° C. for 30 min. Solvent was removed under reduced pressure and water (250 mL) was added. The solid was filtered and washed with water (2000 mL). The crude product was purified by column chromatography (silica gel, methanol in chloroform) to obtain the title compound. Yield: 37.0 g (87%); 1H NMR (CDCl3, 300 MHz): δ 2.71 (s, 3H, CH3), 3.91 (s, 3H, OCH3), 4.72 (s, 2H, CH2), 7.25 (d, 1H, Ar), 7.33 (d, 1H, Ar), 7.45 (d, 1H, Ar), 8.09 (s, 1H, Ar), 8.46 (s, 1H, Ar); MS: m/e (EI) 352 (M+).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]=1.Cl[C:18]1[N:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=1>>[CH3:1][C:2]1[N:3]([C:18]2[N:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=2)[CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]=1
Reactant: Cc1nc(C#Cc2cccc(C#N)c2)c[nH]1
Reactant: Cc1ccnc(Cl)n1
Product: Cc1ccnc(-n2cc(C#Cc3cccc(C#N)c3)nc2C)n1

Procedure:
The title compound, MS: m/e=300.4 (M+H+), was prepared in accordance with the general method of example 1 from 3-(2-methyl-1H-imidazol-4-ylethynyl)-benzonitrile and 2-chloro-4-methyl-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:16]1[N:17]=[C:18]([NH2:21])[S:19][CH:20]=1.[Br:22][C:23]1[C:28]([F:29])=[CH:27][C:26]([S:30](Cl)(=[O:32])=[O:31])=[C:25]([F:34])[CH:24]=1>>[Br:22][C:23]1[C:28]([F:29])=[CH:27][C:26]([S:30]([NH:21][C:18]2[S:19][CH:20]=[C:16]([C:3]3[CH:4]=[CH:5][C:6]([O:8][C:9]4[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=4)=[CH:7][C:2]=3[Cl:1])[N:17]=2)(=[O:31])=[O:32])=[C:25]([F:34])[CH:24]=1
Reactant: Nc1nc(-c2ccc(Oc3ccc(Cl)cc3)cc2Cl)cs1
Reactant: O=S(=O)(Cl)c1cc(F)c(Br)cc1F
Product: O=S(=O)(Nc1nc(-c2ccc(Oc3ccc(Cl)cc3)cc2Cl)cs1)c1cc(F)c(Br)cc1F

Procedure:
The title compound was prepared 4-[2-chloro-4-(4-chlorophenoxy)phenyl]-1,3-thiazol-2-amine (91 mg) and 4-bromo-2,5-difluorobenzenesulfonyl chloride (79 mg) as described in the synthetic METHOD B to give a white solid (46.9 mg) with purity >90%: MS (neg) m/z 589.5, 591.5, 593.5; HRMS m/z 589.8745 (calc. of monoisotopic mass for C21 H11 Br Cl2 F2N2 O3 S2 gives 589.8740).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[N:8]1([C:14]([C:16]2[CH:28]=[C:27]3[C:19]([C:20]4[CH:21]=[C:22](B5OC(C)(C)C(C)(C)O5)[CH:23]=[C:24]([C:29]([NH2:31])=[O:30])[C:25]=4[NH:26]3)=[CH:18][CH:17]=2)=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>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.CO>[N:8]1([C:14]([C:16]2[CH:28]=[C:27]3[C:19]([C:20]4[CH:21]=[C:22]([C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=5)[CH:23]=[C:24]([C:29]([NH2:31])=[O:30])[C:25]=4[NH:26]3)=[CH:18][CH:17]=2)=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: Brc1ccccn1
Reactant: CC1(C)OB(c2cc(C(N)=O)c3[nH]c4cc(C(=O)N5CCOCC5)ccc4c3c2)OC1(C)C
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: CO
Solvent: Cc1ccccc1
Product: NC(=O)c1cc(-c2ccccn2)cc2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Temperature: 100 °C

Procedure:
2-Bromopyridine (0.1 mL, 1.025 mmol), 7-(morpholine-4-carbonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazole-1-carboxamide 429A (140 mg, 0.125 mmol), Pd(Ph3P)4 (76 mg, 0.066 mmol) and Na2CO3 (2M) (0.8 mL, 1.600 mmol) were mixed with toluene (2 mL) and MeOH (1 mL) in a sealed microwave tube. The mixture was degassed and heated at 100° C. for 12 hrs. The mixture was concentrated and purified using preparative HPLC to give titled product. MS (ESI) m/z 401.16 (M+H)+. 1H NMR (DMSO-d6) δ ppm 11.66 (s, 1H), 9.13 (d, 1H, J=1.5), 8.73 (d, 1H, J=4.8), 8.71 (d, 1H, J=1.5), 8.40 (s, 1H), 8.33 (d, 1H, J=8.0), 8.21 (d, 1H, J=8.0), 7.95 (td, 1H, J=7.8, 1.8), 7.83 (s, 1H), 7.57 (s, 1H), 7.37 (m, 1H), 7.27(dd, 1H, J=8.1, 1.5), 3.7-3.5 (bm, 8 H).