Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[F:25][C:26]([F:49])([F:48])[CH2:27][NH:28][C:29]([C:31]1([CH2:44][CH2:45][CH2:46]Br)[C:43]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:37]2[C:32]1=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:30]>CN(C=O)C.C(OCC)(=O)C>[F:25][C:26]([F:48])([F:49])[CH2:27][NH:28][C:29]([C:31]1([CH2:44][CH2:45][CH2:46][N:16]2[CH2:15][CH2:14][N:13]([C:10]3[CH:11]=[CH:12][C:2]([CH3:1])=[C:3]([CH:9]=3)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:18][CH2:17]2)[C:43]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:37]2[C:32]1=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:30]
Reactant: CCOC(=O)c1cc(N2CCNCC2)ccc1C
Reactant: O=C(NCC(F)(F)F)C1(CCCBr)c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(N2CCN(CCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)ccc1C
Temperature: 75 °C
Reaction time: 7 h
Yield: 59.4 %

Procedure:
Ethyl 2-methyl-5-piperazinylbenzoate (1.8 g, 9.1 mmol) was dissolved in 20 ml of anhydrous DMF. Potassium carbonate (1.7 g) and 3-[9-(2,2,2-trifluoroethylcarbamoyl)-9H-fluoren-9-yl]propyl bromide (2.5 g, 6.1 mmol) were added to the solution, and the mixture was stirred at 75° C. for 7 hr. The temperature of the reaction solution was returned to room temperature, and the reaction solution was then diluted with ethyl acetate. The dilution was washed twice with water and was then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography (development system, n-hexane:ethyl acetate=2:1) to give 2.1 g (yield 59%) of ethyl 5-[4-[3-[9-(2,2,2-trifluoroethylcarbamoyl)-9H-fluoren-9-yl]propyl]piperazinyl]-2-methylbenzoate as a pale yellow foam.
Reaction SMILES: [S:1]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15](=[O:22])[CH2:14][CH2:13][CH2:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:33])(=O)=O)=CC=1.[Cl-].[NH4+]>O1CCCC1.C(NC(C)C)(C)C.C([Li])CCC>[F:33][CH:14]1[C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:11]([S:1]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=2)(=[O:2])=[O:3])[CH2:12][CH2:13]1
Reactant: Cc1ccc(S(=O)(=O)N2CCCC(=O)c3ccccc32)cc1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1ccc(S(=O)(=O)N2CCC(F)C(=O)c3ccccc32)cc1
Temperature: -78 °C
Yield: 78.6 %

Procedure:
In 150 ml of tetrahydrofuran was dissolved 3.55 ml of diisopropylamine, and 14.9 ml of n-butyllithium was added dropwise while stirring at -78° C. in an atmosphere of argon. After 30 minutes of stirring under ice-cooling, the reaction mixture was cooled to -78° C., 60 ml of tetrahydrofuran solution containing 6.39 g of 1-tosyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one was added dropwise thereto and the resulting mixture was stirred for 30 minutes. Then, 90 ml of tetrahydrofuran solution containing 8.94 g of N-fluorobenzenesulfonimide was added dropwise, and the mixture was stirred for 1 hour while gradually increasing the temperature to 0° C. After adding saturated ammonium chloride aqueous solution to the reaction solution, the mixture was concentrated under a reduced pressure. Ethyl acetate was added thereto to separate the water layer, and the organic layer was washed with saturated sodium thiosulfate aqueous solution, saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution in that order. The organic layer was then dried over anhydrous magnesium sulfate and concentrated under a reduced pressure. The resulting residue was applied to silica gel column chromatography, which was eluted with chloroform to obtain 5.31 g of 4-fluoro-1-tosyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:9]2)C=CC=CC=1.C(Cl)(Cl)Cl.[OH-].[NH4+]>CO>[C:12]1([CH:10]2[CH2:11][NH:8][CH2:9]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc(C2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: c1ccc(C2CNC2)cc1

Procedure:
Compound C43 was prepared according to the general procedure for the synthesis of C40 in Example 9, except that 1-(diphenylmethyl)-3-phenylazetidine (See M. C. Hillier & C-y. Chen, J. Organic Chem. 2006, 71, 7885-7887) was used instead of 1-(diphenylmethyl)-3-(4-fluorophenoxy)azetidine, and the silica gel chromatography was carried out with 100:5:1 chloroform:MeOH:concentrated aqueous ammonium hydroxide as eluant. Yield: 427 mg (contains some impurities), <3.21 mmol, <19%. LCMS m/z 134.0 (M+1). 1H NMR (400 MHz, CD3OD), product peaks only: δ 4.02 (m, 2H), 4.11 (m, 3H), 7.29 (m, 5H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH3:19][Si:20]([CH3:27])([CH3:26])[CH2:21][CH2:22][O:23][CH2:24]Cl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]([O:10][CH2:24][O:23][CH2:22][CH2:21][Si:20]([CH3:27])([CH3:26])[CH3:19])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: COc1cc(Br)cc(C=O)c1O
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(Br)cc(C=O)c1OCOCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2 g of 5-Bromo-2-hydroxy-3-methoxy-benzaldehyde is dissolved in 200 ml of DMF and 4.78 g of potassium carbonate and 2.3 g of 2-trimethylsilyl-ethoxymethyl chloride are added. The reaction is stirred at RT for 18 h. The solvents are removed under reduced pressure, the residue is dissolved in ethyl acetate and washed with water. After drying over magnesium sulfate, filtration and evaporation, the product is purified by silica gel chromatography eluting with a gradient of ethyl acetate in heptane. Yield 1.8 g.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][C:3]=1[C:8]1[C:13]([CH3:14])=[CH:12][C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[CH3:24].C(N(CC)CC)C.Cl.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1>C(Cl)Cl>[Br:1][C:2]1[S:6][C:5]([NH:7][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)=[N:4][C:3]=1[C:8]1[C:13]([CH3:14])=[CH:12][C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[CH3:24]
Reactant: COc1ccc(Oc2cc(C)c(-c3nc(N)sc3Br)c(C)c2)cc1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Oc2cc(C)c(-c3nc(NC(=O)c4ccncc4)sc3Br)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
To a solution of 5-bromo-4-(4-(4-methoxyphenoxy)-2,6-dimethylphenyl)thiazol-2-amine (2-4, 325 mg, 0.70 mmol) in CH2Cl2 (10 ml) was added triethylamine (0.50 mL, 1.7 mmol) followed by isonicotinoyl chloride hydrochloride (302.5 mg, 3.4 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added with hot water. The resultant precipitate was filtered, and dried under vacuum to give N-{5-bromo-4-(4-(4-methoxyphenoxy)-2,6-dimethylphenyl)thiazol-2-yl}isonicotinamide (2, 345 mg) as white solids in 99% yield: 1H NMR (500 MHz, DMSO-d6) δ 13.3 (s, 1 H), 8.82 (m, 2 H), 7.98 (m, 2 H), 7.05 (d, J=9.0 Hz, 2 H), 6.99 (d, J=9.0 Hz, 2 H), 6.70 (s, 2 H), 3.76 (s, 3 H), 1.99 (s, 6 H); ESI-MS: m/z 509.6, 511.1 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C:15]1[CH:16]=[N:17][C:18]2[C:23]([C:24]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[N:22][C:21]([O:33][CH3:34])=[CH:20][CH:19]=2)(C)(C)C>ClCCl>[CH2:26]([O:25][C:24]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:33][CH3:34])[N:22]=2)[N:17]=[CH:16][C:15]=1[NH2:14])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc2ncc(NC(=O)OC(C)(C)C)c(OCc3ccccc3)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2ncc(N)c(OCc3ccccc3)c2n1
Temperature: 0 °C
Reaction time: 20 h
Yield: 92.3 %

Procedure:
Trifluoroacetic acid (10.0 mL, 131.2 mmol, 20.0 eq) is added at 0° C. to a stirred solution of (4-benzyloxy-6-methoxy-[1,5]naphthyridin-3-yl)-carbamic acid tert-butyl ester (2.50 g, 6.55 mmol, 1.0 eq) in dichloromethane (50 mL). After 20 hours stirring at 0° C., the reaction mixture is extracted with dichloromethane (3×200 mL) and water (200 mL) and the pH is adjusted to 12 by the addition of a 1N sodium hydroxide aqueous solution. The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford 4-benzyloxy-6-methoxy-[1,5]naphthyridin-3-ylamine as a light yellow solid (1.70 g, 92% yield).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14]O)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)[Cl:18]>>[CH2:1]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][Cl:18])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(Cc2ccccc2)ccn1
Product: ClCc1cc(Cc2ccccc2)ccn1
Yield: 100.7 %

Procedure:
A solution of 4-benzyl-2-(hydroxymethyl) pyridine (2.85 g, 14.6 mmol) in SOCl2 (7.50 mL, 102 mmol) was stirred at 25° C. for 30 min. and was concentrated under reduced pressure. The crude compound was diluted with EtOAc (100 mL), washed with NaHCO3 (2×100 mL), dried over Na2SO4 and was concentrated under reduced pressure to afford the title compound as a dark oil (3.2 g, 98%): 1H NMR (CDCl3) δ4.00 (s, 2H), 4.66 (s, 2H), 7.08 (d, J=5.1 Hz, 1H), 7.18 (d, J=7.2 Hz, 2H), 7.20-7.40 (m, 4H), 8.46 (d, J=5.1 Hz, 1H).
Reaction SMILES: N1([CH2:6][CH2:7][OH:8])C=CN=C1.C(N(CC)CC)C.[S:16](Cl)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>C(Cl)Cl>[C:22]1([CH3:23])[CH:24]=[CH:25][C:19]([S:16]([O:8][CH2:7][CH3:6])(=[O:18])=[O:17])=[CH:20][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCn1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
A portion of the crude 2-(imidazol-1-yl)ethanol (10 g, 89 mmol) and triethylamine (10.1 g, 100 mmol) were dissolved in methylene chloride (250 ml), tosyl chloride (17.5 g, 92 mmol) was added over 5 minutes as a solid, giving an exotherm to reflux. The reaction was stirred for 30 minutes at ambient temperature then quenched into 250 ml of 1M hydrogen chloride and 250 ml of methylene chloride. The organic phase was washed with brine and dried by passing it through a phase separator paper. Removal of the solvent by evaporation and purification by flash chromatography using methylene chloride/methanol/ammonia (100/10/1) gave 2-(imidazo]-1-yl)ethyl paratoluene sulphonate (10.95 g, 46%, impure). 4-Hydroxy-5-methoxy-2-nitrobenzamide (3 g, 15.3 mmol), (prepared as described for the starting material in Example 23), and 2-(imidazol-1-yl)ethyl paratoluene sulphonate (7 g, impure) were mixed in the presence of potassium carbonate (5 g, 72 mmol) and anhydrous DMF (20 ml) and heated at 100° C. for 3 hours. The reaction mixture was allowed to cool to ambient temperature and the DMF was removed by evaporation. The residue was resuspended in methylene chloride/methanol/ammnonia (100/10/1) and silica (15 g) was added. The solvent was removed by evaporation and the resulting powder was placed on the top of a silica gel column and eluted using first methylene chloride and slowly increasing the solvent polarity up to methylene chloride/methanol/ammnonia (100/10/1). Removal of the solvent by evaporation gave 4-(2-(imidazol-1-yl)ethoxy)-5-methoxy-2-nitrobenzaride as a cream solid (2.53 g, 55%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.C([C@H]1CC[C@H](CC(Cl)=O)CC1)CCCC.CC1(C)CO[C:39]([CH:42]2[CH2:47][CH2:46][C:45](=O)[CH2:44][CH2:43]2)=[N:38]1>C1C=CC=CC=1>[C:39]([C@H:42]1[CH2:47][CH2:46][C@H:45]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C@H:10]3[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:12][CH2:11]3)=[CH:4][CH:3]=2)[CH2:44][CH2:43]1)#[N:38]
Reactant: CCCCC[C@H]1CC[C@H](CCc2ccc(Br)cc2)CC1
Reactant: CC1(C)COC(C2CCC(=O)CC2)=N1
Agent: CCCCC[C@H]1CC[C@H](CC(=O)Cl)CC1
Solvent: c1ccccc1
Product: CCCCC[C@H]1CC[C@H](CCc2ccc([C@H]3CC[C@H](C#N)CC3)cc2)CC1

Procedure:
1-(p-Bromophenyl)-2-(trans-4-n-pentylcyclohexyl)-ethane [obtainable by Friedel-Crafts acylation of benzene with trans-4-n-pentylcyclohexylacetyl chloride, Wolff-Kishner reduction of the carbonyl group and bromination of the aromatic in the p-position] is subjected to a Grignard reaction with 4-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-cyclohexanone. Detachment of water, with simultaneous removal of the oxazolyl protective group, by boiling with ethanolic H2SO4, hydrogenation of the double bond, conversion of the ethyl ester into the amide, dehydration analogously to Example 2 and customary working up gives 1-[p-(trans-4-cyanocyclohexyl)-phenyl]-2-(trans-4-n-pentylcyclohexyl)-ethane.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.CO.C[C:12](C)([O-:14])C.[K+]>CN(C)C=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:14][CH3:12])=[N:3][CH:4]=1
Reactant: CC(C)(C)[O-]
Reactant: Brc1ccc(Br)nc1
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2,5-dibromopyridine (6.95 g, 29 mmol) in N,N-dimethylformamide (5 ml) was added methanol (3.56 ml) and 1M potassium tert-butoxide (32.3 ml) and the resulting mixture was stirred at room temperature for 18 hours. The resulting slurry was quenched with saturated aqueous ammonium chloride solution and partitioned between ethyl acetate and water. The crude product from the organic phase was chromatographed on silica gel eluting with a 1:9 mixture of ether and hexane to afford the 5-Bromo-2-methoxypyridine compound as an oil.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[C:25]([CH2:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH2:35][C:36]([NH2:38])=[O:37])[C:24]([C:39]([F:42])([F:41])[F:40])=[CH:23][N:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[C:25]([CH2:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH2:35][C:36]([NH2:38])=[O:37])[C:24]([C:39]([F:40])([F:42])[F:41])=[CH:23][N:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(N3CCC(N)CC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl(1-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)carbamate (I79) (138 mg, 0.231 mmol) was dissolved in dry dichloromethane (10 mL) under an atmosphere of nitrogen. Trifluoroacetic acid (1.0 mL, 13 mmol) was added to the solution and the reaction was stirred at room temperature overnight. The volatiles were removed in vacuo, EtOAc (50 mL) and sat. aq. NaHCO3 (50 mL) were added to the residue and the layers were separated.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH3:22])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:29]([O-])([N+]([O-])=O)=[O:30]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:29]=[O:30])[C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH3:22])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@@H:9]1[OH:10])=[O:6]
Reactant: CCCCN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O
Yield: 78.6 %

Procedure:
3.4 g of 1-(2-chloroethyl)-3-n-butyl-3-D-mannopyranosylurea are dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 2.9 g of 1-(2-chloroethyl)-1-nitroso-3-n-butyl-3-D-mannopyranosylurea are thereby obtained as yellow caramel.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[OH:20])[CH2:5][C:6]1[N:10]2[CH:11]=[CH:12][C:13]([CH3:15])=[CH:14][C:9]2=[N:8][C:7]=1[CH3:16].[CH2:21]([N:23]=[C:24]=[O:25])[CH3:22]>C(O)C.O1CCCC1>[CH2:21]([NH:23][C:24](=[O:25])[NH:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[OH:20])[CH2:5][C:6]1[N:10]2[CH:11]=[CH:12][C:13]([CH3:15])=[CH:14][C:9]2=[N:8][C:7]=1[CH3:16])[CH3:22]
Reactant: Cc1ccn2c(Cc3ccc(O)c(N)c3)c(C)nc2c1
Reactant: CCN=C=O
Solvent: CCO
Solvent: C1CCOC1
Product: CCNC(=O)Nc1cc(Cc2c(C)nc3cc(C)ccn23)ccc1O
Yield: 94.3 %

Procedure:
A solution of 3-(3-amino-4-hydroxybenzyl)-2,7-dimethylimidazo[1,2-a]pyridine (3.1 g) and ethyl isocyanate (1.24 g) in ethanol (50 ml) and tetrahydrofuran (50 ml) was refluxed for 2.5 hours under stirring. The reaction mixture was concentrated in vacuo and the precipitate was collected by filtration to give 3-[3-(3-ethylureido)-4-hydroxybenzyl]-2,7-dimethylimidazo[1,2-a]pyridine (3.7 g).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[NH4+].[Cl-].C(OC([N:14]1[CH2:19][CH2:18][CH:17]([O:20][C:21]2[C:22]([C:31]#[N:32])=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[N:26][CH:25]=[CH:24]3)[CH2:16][CH2:15]1)=O)(C)(C)C.ClCCl>CN(C=O)C>[NH:14]1[CH2:19][CH2:18][CH:17]([O:20][C:21]2[C:22]([C:31]3[NH:32][N:3]=[N:2][N:1]=3)=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[N:26][CH:25]=[CH:24]3)[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cnccc3c2C#N)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: c1cc2c(-c3nnn[nH]3)c(OC3CCNCC3)ccc2cn1
Temperature: 160 °C
Reaction time: 3 h
Yield: 13.5 %

Procedure:
Under argon atmosphere 78 mg (1.2 mmol) of NaN3 and 64 mg (1.2 mmol) of NH4Cl were added to a solution of 35 mg (0.1 mmol) 4-(5-Cyano-isoquinolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (15) in 1 mL of DMF. The mixture was heated to approximately 160° C. and 7 bar pressure for 3 h in a microwave reactor (CEM Discovery). After cooling to room temperature aqueous NH4Cl-solution and dichloromethane was added. The mixture was filtered through a phase separation cartridge and the aqueous layer was washed twice with dichloromethane. The organic layers were combined and the solvents were distilled off. The remainder was subjected to preparative HPLC to yield 4 mg (8%) of compound 32 as trifluoroacetate. LCMS Method #3, retention time 0.90 min, detected mass 297.04 [M+H]+
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[N:3]=1.[NH:21]1[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[C:23]([NH2:30])=[N:22]1.O.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[CH:8]1([C:6]2[N:5]=[C:4]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]([F:20])([F:19])[F:18])[N:3]=[C:2]([NH:30][C:23]3[C:24]4[C:25](=[N:26][CH:27]=[CH:28][CH:29]=4)[NH:21][N:22]=3)[CH:7]=2)[CH2:10][CH2:9]1
Reactant: FC(F)(F)c1ccccc1-c1nc(Cl)cc(C2CC2)n1
Reactant: Nc1n[nH]c2ncccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: FC(F)(F)c1ccccc1-c1nc(Nc2n[nH]c3ncccc23)cc(C2CC2)n1
Temperature: 130 °C
Yield: 56.6 %

Procedure:
A mixture of 4-chloro-6-cyclopropyl-2-(2-trifluoromethylphenyl)-pyrimidine (7.00 g, 23.4 mmol, prepared as described above in example 8) and 1H-pyrazolo[3,4-b]pyridin-3-ylamine (9.43 g, 70.3 mmol) in N-methylpyrrolidinone (50 mL) was heated at 130° C. for 12 hours. The residue was cooled, dissolved in N-methylpyrrolidinone (2 mL), poured into water (500 mL) and sodium bicarbonate (15 mL) then filtered, washing with water. Purification by flash chromatography [SiO2, ethyl acetate:hexanes (35:65)] provided the title compound (5.25 g, 57% yield) as a white solid. 1H-NMR (500 MHz, DMSO-d6) δ 13.1 (br s, 1H), 10.5 (br s, 1H), 8.50 (m, 2H), 7.82 (d, J=7.8 Hz, 1H), 7.73 (m, 3H), 7.66 (t, J=7.7 Hz, 1H), 7.12 (m, 1H), 2.07 (m, 1H), 1.02 (m, 2H), 0.97 (m, 2H) ppm; LC-MS 397.22 (M+H); Rt (Method A) 3.412 minutes.
Reaction SMILES: CC[N:3](C(C)C)C(C)C.[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C@@H:25]([NH:31][C:32](=[O:45])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:26][CH2:27][C:28](O)=[O:29])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N>CN(C=O)C>[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C@@H:25]([NH:31][C:32](=[O:45])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:26][CH2:27][C:28](=[O:29])[NH2:3])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)CC[C@@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)CCCCCCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)CC[C@@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)CCCCCCc1ccccc1
Reaction time: 0.17 h
Yield: 99.4 %

Procedure:
DIPEA (0.12 mL, 0.68 mmol) was added dropwise to a stirred solution of (63) (300 mg, 0.62 mmol) and BOP (300 mg, 0.68 mmol) in DMF (4 mL). After 10 min, NH3 solution (25%, 0.75 mL) was added, and the mixture stirred for 1 h. The solvent was removed under reduced pressure, and the crude residue diluted with water and extracted into warm EtOAc. The combined extracts were then washed with HCl solution (1 M), water, saturated NaHCO3 solution, brine and dried over MgSO4. Evaporation of the solvent in vacuo gave (64) (300 mg, quantitative) as a white powder, ESMS 487 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:29])([O:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([C:26](O)=[O:27])[CH:21]=3)[CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].Cl.C(N=C=NCCCN(C)C)C.ON1C(=O)CCC1=O.[CH2:50]([CH2:52][NH2:53])[OH:51]>CN(C=O)C.C(OCC)(=O)C>[F:29][C:2]([F:1])([O:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([C:26]([NH:53][CH2:52][CH2:50][OH:51])=[O:27])[CH:21]=3)[CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4]
Reactant: NCCO
Reactant: O=C(O)c1cc(-c2ccnc(Nc3cccc(OC(F)(F)C(F)F)c3)n2)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NCCO)c1cc(-c2ccnc(Nc3cccc(OC(F)(F)C(F)F)c3)n2)ccn1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
100 mg (0.2 mmol) of N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-carboxy-4-pyridyl)-2-pyrimidineamine, 73 mg (0.38 mmol) of N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride and 44 mg (0.38 mmol) of N-hydroxysuccinimide are dissolved in 3 ml of dimethyflormamide and stirred for 2.5 h at RT. The reaction mixture is then added dropwise at 0° over a period of 30 minutes to a solution of 0.75 ml (12.3 mmol) of ethanolamine in 2 ml of DMF. After stirring for 14 h at RT, the reaction mixture is poured into 50 ml of ethyl acetate and extracted with aqueous sodium chloride solution (30 ml) and pH 7 buffer (30 ml), and the organic phase is dried (sodium sulfate) and concentrated. Crystallisation from THF/diethyl ether gives N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(2-hydroxy-ethyl-aminocarbonyl)-4-pyridyl]-2-pyrimidineamine; m.p. 159°, FAB-MS: 452 (M+ +H).