Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[C:25](/[CH:26]=[CH:27]/[C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=4)=[N:24][N:23]([CH:35]4[CH2:40][CH2:39][CH2:38][CH2:37][O:36]4)[C:18]=3[N:19]=[C:20](Cl)[CH:21]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:41][C:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[C:25](/[CH:26]=[CH:27]/[C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=4)=[N:24][N:23]([CH:35]4[CH2:40][CH2:39][CH2:38][CH2:37][O:36]4)[C:18]=3[N:19]=[C:20]([C:45]3[CH:46]=[CH:47][C:42]([OH:41])=[CH:43][CH:44]=3)[CH:21]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(Cl)nc3c2c(/C=C/c2ccc(Cl)cc2)nn3C2CCCCO2)CC1
Reactant: OB(O)c1ccc(O)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: [Cs+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(-c3ccc(O)cc3)nc3c2c(/C=C/c2ccc(Cl)cc2)nn3C2CCCCO2)CC1
Yield: 80 %

Procedure:
To a solution of 4-[6-chloro-3-[(E)-2-(4-chloro-phenyl)-vinyl]-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (1.5 g, 2.56 mmol) in dioxane (38 ml) were added 4-hydroxyphenylboronic acid (0.39 g, 2.81 mmol) and an aqueous solution of cesium carbonate (0.3M, 4.6 mmol). The resulting solution was degassed using argon, tetrakis(triphenylphosphine)palladium (0.14 g, 0.13 mmol) was then added and the reaction mixture was refluxed for 3 hours. Solvents were removed under vacuum. The resulting crude mixture was submitted to a silica gel column chromatography using a gradient of ethyl acetate (0-45%) in cyclohexane to give the title compound (1.32 g, 80%) as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.N1C=CC=CC=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>O>[C:22]([O:1][CH2:2][C:3]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:4][CH2:5][C:6](=[O:9])[CH2:7][CH2:8]1)(=[O:24])[CH3:23]
Reactant: O=C1CCC(CO)(c2ccccc2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OCC1(c2ccccc2)CCC(=O)CC1
Reaction time: 20 h
Yield: 35.8 %

Procedure:
6.6 g. of 4-hydroxymethyl-4-phenylcyclohexanone is dissolved in 40 ml. of pyridine and 20 ml. acetic anhydride. After about 20 hours of standing at room temperature, the mixture is poured into ice and water. The gum that precipitates is extracted with ether. The organic layer is washed successively with water, 2.5 N hydrochloric acid, water, sodium bicarbonate solution, and brine, and then evaporated to dryness. The solid residue is recrystallized from Skellysolve B to give 6.74 g. (35.8% yield) of 4-acetoxymethyl-4-phenylcyclohexanone, having a melting point of 74° to 79°C.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([O:9][CH:10]2[CH2:13][CH:12]([NH2:14])[CH2:11]2)=[N:5][CH:6]=[CH:7][N:8]=1.Cl[C:16]1[S:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:2][C:3]1[C:4]([O:9][CH:10]2[CH2:11][CH:12]([NH:14][C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:13]2)=[N:5][CH:6]=[CH:7][N:8]=1
Reactant: Clc1nc2ccccc2s1
Reactant: NC1CC(Oc2nccnc2Cl)C1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nccnc1OC1CC(Nc2nc3ccccc3s2)C1
Temperature: 180 °C
Yield: 95.5 %

Procedure:
A mixture of 3-(3-chloro-pyrazin-2-yloxy)-cyclobutylamine hydrochloride (1.2 g, 6.28 mmol), 2-chloro-benzothiazole (purchased from ALDRICH™) (1.07 g, 6.28 mmol) and DIEA (1.8 g, 12.56 mmol) in NMP (12 mL) was heated to 180° C. for 2 hours in microwave. The reaction mixture was extracted with EtOAc (40 mL) and water, the organic phase was washed with brine and dried over Na2SO4. The organic layers were concentrated and purified by column chromatography on silica gel to give N-(3-((3-chloropyrazin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine (3.0 g, 6 mmol, 95.5%). ESI-MS (M+1): 333 calc. for C15H13ClN4OS 332.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].Cl.[CH3:12][NH:13][O:14][CH3:15].Cl.CN(C)CCCN=C=NCC>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([N:13]([O:14][CH3:15])[CH3:12])=[O:6]
Reactant: O=C(O)c1cccc(F)c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 75 h

Procedure:
To a suspension of 3-fluorobenzoic acid (140 mg, 1 mmol) and N,O-dimethylhydroxylamine hydrochloride (107 mg, 1.1 mmol) in dichloromethane (2.5 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC) (211 mg, 1.1 mmol) and the mixture stirred at room temperature for 75 h. The solvents were removed under reduced pressure and the residue chromatographed using ethyl acetate-hexane (4:6) to separate the pure product (130 mg, 71%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1.[Br:18]([O-])(=O)=O.[K+].[OH-].[Na+]>>[Br:18][C:9]1[CH:8]=[C:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:6]=[CH:5][C:4]=1[O:3][C:2]([F:1])([F:16])[F:17]
Reactant: FC(F)(F)Oc1ccc(-c2cccnc2)cc1
Reactant: [O-][Br+2]([O-])[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: FC(F)(F)Oc1ccc(-c2cccnc2)cc1Br
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 71.6 %

Procedure:
3-(4-Trifluoromethoxyphenyl)pyridine (Description 61) (1.26 g, 5.27 mmol) was suspended in aqueous sulfic acid (50%, 16 ml) and cooled to 0° C. Potassium bromate (0.88 g, 5.27 mmol) was added in portions over 2 hours and the mixture was stirred at room temperature for 40 min. The mixture was poured into ice/water and basified with aqueous sodium hydroxide (4M). The mixture was extracted with ethyl acetate (3×100 ml) and the combined organic fractions were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/ether (60:40) to give the title compound as an oil (1.2 g, 74%). 1H NMR (360 MHz, CDCl3) δ 8.82 (1H, s), 8.62 (1H, d), 7.84 (2H, m), 7.54 (1H, dd, J=8.5, 2.2 Hz), 7.41 (2H, m). m/z (ES+) 318, 320 (M+1).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)=[N+:2]=[N-:3].[BH4-].[Na+]>CO.C(OCC)(=O)C>[N:1]([CH2:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: [N-]=[N+]=NCc1ccc(CO)cc1
Reaction time: 1 h
Yield: 96.8 %

Procedure:
Azide 4 (2.0 g, 12.4 mmol) was dissolved in MeOH (50 ml) and cooled to 0° C. before NaBH4 was added slowly and the reaction mixture was stirred for 1 hour, after which the solvent was evaporated. The residue obtained was dissolved in ethyl acetate (50 ml) and water (50 ml), the phases were separated and the organic phase was washed with water (100 ml), dried over Na2SO4, and evaporated to yield 5 as a clear oil (1.96 g, 12.0 mmol, 97%). Rf=0.45 (DCM); νmax=cm−1; 1H NMR (300 MHz, CDCl3) δ=7.40 (d, 3J(H,H) 8.2 Hz, 2H, ArCH α to CH2OH), 7.33 (d, 3J(H,H)=8.2 Hz, 2H, ArCH α to CH2N3), 4.71 (s, 2H, CH2OH), 4.34 (s, 2H, CH2N3), 1.80 (bs, 1H, OH); 13C NMR (75 MHz, CDCl3) δ=141.0 (ArCCH2OH), 134.7 (ArCCH2N3), 128.5 (ArCH α to CH2N3), 127.4 (ArCH α to CH2OH), 64.9 (CH2OH), 54.5 (CH2N3).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[C:12]([Cu])#[N:13].O>CN(C)C=O.Cl.[Fe](Cl)Cl>[O:11]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: N#C[Cu]
Agent: Cl[Fe]Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2c(c1)CCC2=O

Procedure:
9.5 g of 5-bromo-1-indanone and 4.93 g of CuCN are suspended in 10 ml of dimethylformamide and boiled under reflux for 4 hours. A solution of 18 g of iron(II) chloride in 5 ml of concentrated hydrochloric acid with 30 ml of water are added dropwise to the cooled, dark-brown viscous suspension while stirring, and the mixture is then stirred at 70° C. for 30 minutes. The reaction mixture is extracted by shaking three times with 50 ml of toluene, and the combined organic phases are extracted by shaking with 50 ml of 2N hydrochloric acid and 50 ml of 2N sodium hydroxide solution and then washed with water until neutral. The toluene extract is dried over magnesium sulfate and concentrated in vacuo, and the residue is recrystallized from n-heptane. 1-oxoindane-5-carbonitrile is obtained with a melting point of 123-125° C.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].S(OOS([O-])(=O)=O)([O-])(=O)=[O:13].[K+].[K+].S(=O)(=O)(O)O>>[O:5]=[C:4]1[C:2](=[O:3])[NH:1][C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:13]1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: O=C1Nc2ccccc2C1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2ccccc2oc1=O
Reaction time: 0.25 h

Procedure:
103 parts of isatin are introduced slowly into a solution of 190 parts of potassium peroxydisulfate in 1,300 parts of 90% strength sulfuric acid at from 0° C. to 10° C. The mixture is then stirred for 10-20 minutes, after which it is poured onto ice. The product is filtered off and dried, giving 110 parts of 2,3-dioxo-1,4-benzoxazine, of melting point 285° C. (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][CH:39]=[CH:38][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=1[N:13]1[C:17]([CH3:18])=[N:16][N:15]=[C:14]1[CH2:19][NH:20][C:21]([C:23]1[N:24]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])=[O:5].[O-]S(C(F)(F)[F:47])(=O)=O.F[N+]1C(Cl)=CC=CC=1Cl>ClC(Cl)C>[Cl:1][C:2]1[CH:41]=[CH:40][CH:39]=[CH:38][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=1[N:13]1[C:17]([CH3:18])=[N:16][N:15]=[C:14]1[CH2:19][NH:20][C:21]([C:23]1[N:24]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:25]2[C:30]([C:31]=1[F:47])=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])=[O:5]
Reactant: CCOC(=O)Cn1c(C(=O)NCc2nnc(C)n2-c2sc(CC)cc2C(=O)c2ccccc2Cl)cc2ccccc21
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: F[n+]1c(Cl)cccc1Cl
Solvent: CC(Cl)Cl
Product: CCOC(=O)Cn1c(C(=O)NCc2nnc(C)n2-c2sc(CC)cc2C(=O)c2ccccc2Cl)c(F)c2ccccc21

Procedure:
Ethyl 2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethylcarbamoyl)indole-1-acetate is dissolved in dichloroethane, and reacted with 1-fluoro-2,6-dichloropyridiniumtriflate to give ethyl 2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethylcarbamoyl)-3-fluoroindole-1-acetate.
Reaction SMILES: ClC1C=CC2N(C(CNC3N=C([O:26][C@@H:27]4C[CH2:30][N:29](C)[CH2:28]4)C=CN=3)=C(C3C=CC(F)=CC=3)N=2)C=1.Cl[C:34]1[N:39]=[C:38]([NH:40][CH2:41][C:42]2[N:46]3[CH:47]=[CH:48][CH:49]=[CH:50][C:45]3=[N:44][C:43]=2[C:51]2[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][CH:52]=2)[CH:37]=[CH:36][N:35]=1.CNCCO>>[Cl:57][C:54]1[CH:55]=[CH:56][C:51]([C:43]2[N:44]=[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][N:46]3[C:42]=2[CH2:41][NH:40][C:38]2[CH:37]=[CH:36][N:35]=[C:34]([O:26][CH2:27][CH2:28][NH:29][CH3:30])[N:39]=2)=[CH:52][CH:53]=1
Reactant: CN1CC[C@@H](Oc2ccnc(NCc3c(-c4ccc(F)cc4)nc4ccc(Cl)cn34)n2)C1
Reactant: Clc1ccc(-c2nc3ccccn3c2CNc2ccnc(Cl)n2)cc1
Agent: CNCCO
Product: CNCCOc1nccc(NCc2c(-c3ccc(Cl)cc3)nc3ccccn23)n1

Procedure:
The title compound was prepared in the same fashion as that described for compound 183 from 2-chloro-N-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-4-amine and 2-(methylamino)ethanol. M/e+ 409 for C21H22ClN6O (M+H)+; 1H-NMR (400 MHz, CD3OD) δ 8.61 (s, 1H), 7.74 (d, J=8.4 Hz, 2H), 7.68 (d, J=6.2 Hz, 1H), 7.50 (t, J=7.3 Hz, 2H), 7.43 (d, J=7.3 Hz, 1H), 7.39 (m, 1H), 5.84 (d, J=6.2 Hz, 2H), 5.08 (d, J=8.8 Hz, 2H), 3.74 (m, 2H), 3.17 (s, 3H) ppm.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=2)[O:3]1.ClC1C=C(C=CC=1)C(OO)=[O:29].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][C:2]1([CH3:23])[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:22])=[O:29])=[CH:17][CH:16]=2)[O:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(C2=C(c3cccc(F)c3)C(=O)C(C)(C)O2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1ccc(C2=C(c3cccc(F)c3)C(=O)C(C)(C)O2)cc1
Yield: 62 %

Procedure:
To a stirred solution of 2,2-dimethyl-4-(3-fluorophenyl)-5-{4-(methylthio)phenyl}-3(2H)-furanone (2.0 g, Example 166) in 50 ml dichloromethane, was added 1.5 g of m-chloroperoxybenzoic acid at 0° C. The reaction solution was stirred at the same temperature for one and half hours, after which 30 ml 5% aqueous sodium bicarbonate was added and the solution was stirred for another 10 minutes. Then the reaction mixture was concentrated in vacuo, and the resulting residue was extracted with 50 ml water and dichloromethane (30 ml×3). The organic layer was concentrated in vacuo and was purified by column chromatography (hexane/ethylacetate=1:1) to give 1.3 g of 2,2-dimethyl-4-(3-fluorophenyl)-5-{4-(methylsulfinyl)phenyl}-3(2H)-furanone. mp: 143-144° C. NMR: δ1.58 (s, 6H), 2.76(s, 3H), 7.26-7.08 (m, 3H), 7.30-7.38 (m, 1H), 7.65 (d, J=8.2 Hz, 2H), 7.80 (d, J=8.2 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O>>[Cl:17][C:18]1[CH:19]=[C:20]([CH:21]2[C:8]3[NH:9][C:10]4[C:15]([C:7]=3[CH2:6][CH:4]([C:3]([O:2][CH3:1])=[O:16])[NH:5]2)=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:23]=[CH:24][CH:25]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Product: COC(=O)C1Cc2c([nH]c3ccccc23)C(c2cccc(Cl)c2)N1

Procedure:
The same method as employed in the preparation of intermediate 1 and 2 but starting from racemic tryptophan methyl ester and 3-chlorobenzaldehyde gave the title compound as white solid m.p.:150-160° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][OH:6].Cl.[NH2:12][CH2:13][C:14](=[O:20])[CH2:15][CH2:16][C:17](O)=[O:18]>>[ClH:1].[NH2:12][CH2:13][C:14](=[O:20])[CH2:15][CH2:16][C:17]([O:6][CH2:5][C:4]1[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=1)=[O:18]
Reactant: OCc1ccc(Cl)c(Cl)c1
Reactant: NCC(=O)CCC(=O)O
Agent: Cl
Product: NCC(=O)CCC(=O)OCc1ccc(Cl)c(Cl)c1
Reaction time: 45 h

Procedure:
From 3,4-dichlorobenzyl alcohol (5.0 g; 28 mmol) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol). The reaction was complete after 45 h at 100° C. The yield was 1.12 g (57%).
Reaction SMILES: CO[C:3]([C:5]1[CH:6]=[N:7][N:8]([C:10]2[N:11]=[C:12]([NH2:28])[C:13]3[N:14]=[CH:15][N:16]([C:26]=3[N:27]=2)[C@@H:17]2[O:25][C@H:22]([CH2:23][OH:24])[C@@H:20]([OH:21])[C@H:18]2[OH:19])[CH:9]=1)=[O:4].[CH3:29][NH2:30]>CO>[CH3:29][NH:30][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:10]2[N:11]=[C:12]([NH2:28])[C:13]3[N:14]=[CH:15][N:16]([C:26]=3[N:27]=2)[C@@H:17]2[O:25][C@H:22]([CH2:23][OH:24])[C@@H:20]([OH:21])[C@H:18]2[OH:19])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cnn(-c2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Reactant: CN
Solvent: CO
Product: CNC(=O)c1cnn(-c2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
A suspension of 1 g of 2-(4-methoxycarbonylpyrazol-1-yl)adenosine in 10 ml of 40% methylamine in methanol is stirred in a closed flask at 20° C. until formation of a solution (3 to 5 hours). The produced solution is left to stand at the given temperature for additional 15 hours. The solution is then filtered with active charcoal and the filtrate is concentrated in vacuo. The evaporation residue, which is the amorphous form of 2-[4-[(methylamino)carbonyl]-1H-pyrazol-1-yl]adenosine, is dissolved in 2 ml of dimethylsulfoxide and left to cool down freely to room temperature. The resulting turbid solution is added to 20 ml of methanol. The separated gel-like precipitate is stirred under the boil for 1.5-2.5 hours, wherein a powder-like suspension is formed. After cooling down, sucking off, and drying, 0.8 g of 2-[4-[(methylamino)carbonyl]-1H-pyrazol-1-yl]adenosine polymorph E is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:12]=[C:11]1[CH2:23][Cl:24])([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:38].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([NH2:38])[C:13]=2[N:12]=[C:11]1[CH2:23][Cl:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCn1c(CCl)nc2cnc3ccccc3c21
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCCn1c(CCl)nc2c(N)nc3ccccc3c21

Procedure:
Using the general method of Examples 43-68 Part B, a solution of tert-butyl[2-(2-chloromethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate (27.45 g, 76.1 mmol) in chloroform (500 mL) was treated with 3-chloroperoxybenzoic acid (25.6 g of 77% max, 114 mmol) and the resulting 5-oxide was aminated using ammonium hydroxide (150 mL) and para-toluenesulfonyl chloride (17.4 g, 91.3 mmol) to provide 41.83 g of crude tert-butyl[2-(4-amino-2-chloromethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate as a brown solid. A portion (˜32 g) of the crude material was dissolved in dichloromethane and then washed with 1 N hydrochloric acid (×3). The organic layer was allowed to stand for several days and a precipitate formed. This material was isolated by filtration to provide 7.0 g of tert-butyl[2-(4-amino-2-chloromethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate as an off white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH3:9].CC1(C)C(C)(C)OB([C:18]2[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])O1.C1(C)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:18]2[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=[CH:27][CH:28]=2)=[C:3]([CH3:9])[CH:4]=1
Reactant: Cc1cc(Cl)ccc1Br
Reactant: CCOC(=O)c1ccccc1B1OC(C)(C)C(C)(C)O1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccccc1-c1ccc(Cl)cc1C
Temperature: 25 °C
Yield: 99 %

Procedure:
Under an argon atmosphere, a mixture of 2-bromo-5-chloro-toluene (20.55 g), ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (55.23 g), toluene (200 ml), water (125 ml), tripotassium phosphate (53.07 g) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride-dichloromethane complex (1.633 g) was stirred with heating under reflux for 1 hr. The reaction mixture was cooled to room temperature, activated carbon (1 g) was added and the mixture was stirred for 10 min at room temperature. The insoluble material was filtered off, and the filtrate was partitioned in a separatory funnel. The organic layer was washed twice with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=98/2) to give the title compound (27.20 g, 99%).
Reaction SMILES: ClC1C=C(NC2N=C(N[C@@H]3C[C@H]4N(CCC4)C(C)(C)C3)C(F)=CN=2)C=CC=1OCCO.F[C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:34]=1[CH3:42].CC(C)([O-])C.[K+].[Si:49]([O:56][CH2:57][CH2:58][OH:59])([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50]>C1COCC1>[C:52]([Si:49]([CH3:51])([CH3:50])[O:56][CH2:57][CH2:58][O:59][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:34]=1[CH3:42])([CH3:55])([CH3:54])[CH3:53]
Reactant: CC(C)(C)[Si](C)(C)OCCO
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: CC(C)(C)[O-]
Agent: CC1(C)C[C@H](Nc2nc(Nc3ccc(OCCO)c(Cl)c3)ncc2F)C[C@@H]2CCCN21
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc([N+](=O)[O-])ccc1OCCO[Si](C)(C)C(C)(C)C

Procedure:
A similar procedure as detailed above for Compound 133 was used. 2-fluoro-5-nitrotoluene (310 mg, 2.0 mmol), potassium tert-butoxide (494 mg, 4.4 mmol) and 2-((tert-butyldimethylsilyl)oxy)ethan-1-ol (705 mg, 4.0 mmol) in THF (6 mL) was stirred for 3 hr at room temperature to give the product after workup (yield assumed quantitative=623 mg). The product was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][NH2:14])[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].C(N(CC)CC)C.[CH2:22]([O:24][C:25](Cl)=[O:26])[CH3:23].C([O-])(O)=O.[Na+]>ClCCl>[CH2:22]([O:24][C:25](=[O:26])[NH:14][CH2:13][CH2:12][C:4]1[CH:5]=[C:6]([O:10][CH3:11])[C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=1)[CH3:23]
Reactant: COc1cc(CCN)cc(F)c1OC
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NCCc1cc(F)c(OC)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(3-fluoro-4,5-dimethoxy-phenyl)-ethylamine (576 mg) and triethylamine (0.8 ml) in dichloromethane (20 ml) was added dropwise at 0° C. ethylchloroformate (300 μl). The mixture was stirred for 1 h, poured into ice water, neutralized with NaHCO3 and extracted with dichloromethane. The organic layers were separated, dried (MgSO4), filtered and concentrated in vacuo. The residue was passed through a short silica column (heptane/ethyl acetate as eluent).
Reaction SMILES: CS(O)(=O)=O.CS(O[CH2:11][CH2:12][CH2:13][O:14][CH2:15][C:16]#[CH:17])(=O)=O.[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([NH:22][CH2:11][CH2:12][CH2:13][O:14][CH2:15][C:16]#[CH:17])([CH3:21])([CH3:20])[CH3:19]
Reactant: C#CCOCCCOS(C)(=O)=O
Reactant: CC(C)(C)N
Agent: CS(=O)(=O)O
Product: C#CCOCCCNC(C)(C)C

Procedure:
A solution of 1 g of methane sulphonic acid and 1 g of 7d in 10 ml of tert-C4H9NH2 was heated at 60° C. for 24 hr in a closed vial. The reaction mixture was concentrated and the residue was diluted with 15 ml of 1M aq. K2CO3. Then, the product was extracted with ethyl acetate. The organic layer was washed once with sat. NaCl solution, dried and concentrated to provide 830 mg of 7e as a yellowish oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]=[C:12]=[S:13])=[O:10])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:43]=[CH:42][C:18]([O:19][C:20]2[CH:25]=[C:24]([NH:26][C:27]([N:29]3[CH2:34][CH2:33][N:32]([CH:35]4[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)=[O:28])[N:23]=[CH:22][N:21]=2)=[C:17]([F:44])[CH:16]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1.C(O)C>[F:44][C:17]1[CH:16]=[C:15]([NH:14][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[S:13])[CH:43]=[CH:42][C:18]=1[O:19][C:20]1[CH:25]=[C:24]([NH:26][C:27]([N:29]2[CH2:30][CH2:31][N:32]([CH:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)[CH2:33][CH2:34]2)=[O:28])[N:23]=[CH:22][N:21]=1
Reactant: CN1CCC(N2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4F)ncn3)CC2)CC1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN1CCC(N2CCN(C(=O)Nc3cc(Oc4ccc(NC(=S)NC(=O)Cc5ccc(F)cc5)cc4F)ncn3)CC2)CC1
Reaction time: 3.5 h
Yield: 31 %

Procedure:
After adding a solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (0.25 M, 2.5 ml) to a solution of 4-(4-amino-2-fluorophenoxy)-6-{[4-(1-methylpiperidin-4-yl)piperazin-1-yl]carbonylamino}pyrimidine (134 mg) and (+)-10-camphorsulfonic acid (109 mg) in ethanol (3.0 ml) at room temperature, the mixture was stirred for 3.5 hours. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine in that order and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=98:2). Fractions containing the target compound were concentrated to provide the title compound (60.7 mg, 31%) as white powder.