Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:39])[C@@H:24]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:18][C@:14]2([OH:40])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([OH:58])[C:5]([C@@:7]1([CH3:57])[C@H:12]([C@@H:13]2[O:41][C:42]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[O:43])[C@:11]2([O:52][C:53]([CH3:55])=[O:54])[CH2:50][O:51][C@@H:10]2[CH2:9][C@@H:8]1[OH:56])=[O:6].C1CCCCC1.[OH2:65].C(OCC)(=[O:68])C>C(O)C>[CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:39])[C@@H:24]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:18][C@@:14]2([OH:40])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([OH:58])[C:5]([C@@:7]1([CH3:57])[C@H:12]([C@@H:13]2[O:41][C:42]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[O:43])[C@:11]2([O:52][C:53]([CH3:55])=[O:54])[CH2:50][O:51][C@@H:10]2[CH2:9][C@@H:8]1[OH:56])=[O:6].[OH2:68].[OH2:65].[OH2:6]
Reactant: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)c4ccccc4)C[C@@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C
Reactant: CCOC(C)=O
Solvent: O
Solvent: CCO
Solvent: C1CCCCC1
Product: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)c4ccccc4)C[C@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C
Temperature: 7.5 °C
Reaction time: 0.46 h
Yield: 70 %

Procedure:
Crude docetaxel (1.0 g,) was dissolved in a solution of ethanol:cyclohexane:demineralised water:ethyl acetate (20:2:10:0.8) at 25-30° C. under constant stirring. The clear biphasic reaction was then concentrated to 20 ml and cooled to 5-10° C. The precipitated solid was stirred for 25-30 min. at 5-10° C., then filtered, washed with DM water (1 ml) and dried under vacuum under humid atmosphere (until the moisture content was between 5-7% by Karl Fischer method) to afford Docetaxel trihydrate in 70-90% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2.[O:13]=[C:14]1[C:19]2=[CH:20][NH:21][C:22]([CH:23]=O)=[C:18]2[CH2:17][CH2:16][NH:15]1.N1CCCCC1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[CH:23][C:22]1[NH:21][CH:20]=[C:19]2[C:18]=1[CH2:17][CH2:16][NH:15][C:14]2=[O:13]
Reactant: COc1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1[nH]cc2c1CCNC2=O
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc2c(c1)C(=Cc1[nH]cc3c1CCNC3=O)C(=O)N2
Temperature: 80 °C

Procedure:
A mixture of 5-methoxy-1,3-dihydro-indol-2-one (32.6 mg, 0.2 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (32.8 mg, 0.2 mmol) and 0.1 mL of piperidine in ethanol (1 mL) was heated in a sealed tube at 80° C. for 4 hours. The precipitate was collected by vacuum filtration, washed with cold ethanol and dried to give the title compound.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][C@@H:5]([CH:7]2[CH2:9][N@@:8]2[S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[O:4][C:3]1=[O:22].[CH3:23][C:24]1([CH3:38])[CH2:29][N:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[C:27](=[O:37])[CH2:26][NH:25]1>C1(C)C=CC=CC=1>[CH3:23][C:24]1([CH3:38])[CH2:29][N:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[C:27](=[O:37])[CH2:26][N:25]1[CH2:9][C@H:7]([NH:8][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[C@@H:5]1[CH2:6][C@@H:2]([CH3:1])[C:3](=[O:22])[O:4]1
Reactant: C[C@@H]1C[C@@H](C2C[N@@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Reactant: Cc1ccccc1N1CC(C)(C)NCC1=O
Agent: C[C@@H]1C[C@@H](C2C[N@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Solvent: Cc1ccccc1
Product: Cc1ccccc1N1CC(C)(C)N(C[C@H](NS(=O)(=O)c2ccccc2[N+](=O)[O-])[C@@H]2C[C@@H](C)C(=O)O2)CC1=O
Yield: 103 %

Procedure:
A solution of 590 mg of (3R,5S)-3-methyl-5-[(S)-1-(2-nitrobenzenesulfonyl)aziridin-2-yl]dihydrofuran-2-one obtained in Example (76g) (1.8 mmol) and 512 mg of 5,5-dimethyl-1-(2-methylphenyl)piperazin-2-one obtained in Example (51d) (2.35 mmol) in toluene (18 ml) was stirred at 110° C. for two hours. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: toluene/acetone=4/1-3/1) to obtain 1.01 g of the title compound (yield: quant.).
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)[CH2:3]1.C[O:20][C:21]([CH:23]1[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2[S:32](Cl)(=[O:34])=[O:33])[CH2:24]1)=[O:22]>>[CH3:1][C@H:2]1[CH2:3][N:4]([C:8]2[CH:9]=[CH:10][C:11]([O:14][C:15]([F:18])([F:16])[F:17])=[CH:12][CH:13]=2)[CH2:5][CH2:6][N:7]1[S:32]([C:29]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:30]=1[CH2:31][CH:23]([C:21]([OH:22])=[O:20])[CH2:24]2)(=[O:34])=[O:33]
Reactant: C[C@H]1CN(c2ccc(OC(F)(F)F)cc2)CCN1
Reactant: COC(=O)C1Cc2cccc(S(=O)(=O)Cl)c2C1
Product: C[C@H]1CN(c2ccc(OC(F)(F)F)cc2)CCN1S(=O)(=O)c1cccc2c1CC(C(=O)O)C2

Procedure:
The compound 4-[2-(S)-Methyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylic acid was prepared from 3-(S)-methyl-1-(4-trifluoromethoxy-phenyl)-piperazine and 4-chlorosulfonyl-indan-2-carboxylic acid methyl ester following the procedure outlined in Example 79. 1H NMR (400 MHz, DMSO-d6): 7.65 (d, 1H), 7.53 (d, 1H), 7.38 (t, 1H), 7.18 (d, 2H), 6.98-6.92 (m, 2H), 4.15-4.00 (m, 1H), 3.60-3.12 (m, 9H), 2.83-2.75 (m, 1H), 2.64-2.50 (m, 1H), 1.18 (d, 3H); MS (ESI): 485.3 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([C:10]([O:12]C)=[O:11])=[N:8][N:7]([CH3:14])[N:6]=1)=[O:4].[OH-].[K+]>CO>[CH3:1][O:2][C:3]([C:5]1[C:9]([C:10]([OH:12])=[O:11])=[N:8][N:7]([CH3:14])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nn(C)nc1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1nn(C)nc1C(=O)O
Yield: 72.3 %

Procedure:
To a solution of 2-methyl-2H-1,2,3-triazole-4,5-dicarboxylic acid dimethylester (1.2 g; 6 mmol) in 30 ml methanol was added 358 mg KOH (assay 86%; 5.5 mmol). The mixture was heated at reflux temperature for 48 hours. The solvent was evaporated and the residue was then taken into water and extracted with ethyl acetate (3 times). The combined organic phases contained non-reacted starting material. The aqueous phase was acidified with 2N HCl (pH2-3) and extracted with ethyl acetate (3 times). The extracts were combined, dried (anhydrous MgSO4) and evaporated to dryness to give 803 mg (72%) of the desired compound (m.p. 125-126° C.; 1H-NMR (300 MHz, DMSO-d6), δ(ppm): 13.7(br.s,1H, exchangable with D2O), 4.24(s,3H), 3.84(s,3H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19].CCCCCC>C(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH:4][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cc(F)ccc1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CC(C)(C)C(=O)Nc1cc(F)ccc1Br
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91.5 %

Procedure:
To an ice-cold solution of 2-bromo-5-fluoroaniline (50.0 g, 263.14 mmol) in DCM (400 mL) was added triethyl amine (48.0 mL, 342.10 mmol). The resulting mixture was stirred at 0° C. for 10 min followed by addition of pivaloyl chloride (36.0 mL, 289.50 mmol) then stirred at rt for 3 h. After completion of reaction (by TLC), the reaction mixture was diluted with DCM and washed with saturated solution of NaHCO3. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified over 100-200 M silica-gel by using 1.0% EtOAc:hexane to obtain the product as an off white solid (66.0 g, 92% yield).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[C:16]([CH3:21])[N:15]=1.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>O1CCCC1>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:4][CH:5]=2)=[N:15][C:16]=1[CH3:21]
Reactant: Cc1nc(N)ccc1Br
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: Cc1nc(NCc2ccc(C(F)(F)F)cc2)ccc1Br
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of p-trifluoromethylbenzaldehyde (16, 1.00 g, 5.74 mmol) in tetrahydrofuran (9 mL) was added 2-amino-5-bromo-6-methylpyridine (33, 1.08 g, 5.77 mmol), followed by dibutyltin dichloride (40 mg, 0.13 mmol). The mixture was stirred for 5 minutes at 25° C and phenylsilane (0.69 g, 6.4 mmol) was added. The reaction was heated at 50° C. overnight, then the solvent was removed at reduced pressure. Ethyl acetate was added to the resulting solid which was washed with saturated sodium carbonate, dried over magnesium sulfate and filtered. Concentration under reduced pressure afforded a light yellow solid (34, 1.7 g, 4.93 mmol). MS(ESI) [M+H+]+=345.1.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]2[O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])=O.COC1C=CC(/C=[C:38]2/[C:39]([NH:41][C:42]([S:44]/2)=[NH:43])=[O:40])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+].O>C(O)(=O)C>[NH2:43][C:42]1[S:44]/[C:38](=[CH:1]\[C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]3[O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])/[C:39](=[O:40])[N:41]=1
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Reactant: COCCOCCOc1c(C#N)cnc2ccc(C=O)cc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COCCOCCOc1c(C#N)cnc2ccc(/C=C3\SC(N)=NC3=O)cc12
Temperature: 130 °C
Reaction time: 12 h
Yield: 23.9 %

Procedure:
The suspension of 6-formyl-4-[2-(2-methoxy-ethoxy)-ethoxy]-quinoline-3-carbonitrile (example 28b, 50 mg, 0.17 mmol), pseudothiohydantoin (19.3 mg, 0.17 mmol), and sodium acetate (55 mg, 0.68 mmol) in acetic acid (180 uL) was stirred at 130° C. for 12 h. After cooling to room temperature, water was added. The solid was collected by filtration, washed with water and dried. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 0%-7% methanol in methylene chloride in 30 min) afforded 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-[2-(2-methoxy-ethoxy)-ethoxy]-quinoline-3-carbonitrile (16.2 mg, 24%) as a slight yellow solid. LC-MS m/e 399 (MH+).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[C:16]1([CH3:25])[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13]
Reactant: Cc1ccccc1B(O)O
Reactant: COC(=O)c1ccc(Br)c(C(F)(F)F)c1
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: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccccc2C)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 80.1 %

Procedure:
A mixture of methyl 4-bromo-3-(trifluoromethyl)benzoate (6 g; 21.2 mmol; 1 eq.), o-tolylboronic acid (3.17 g; 23.3 mmol; 1.1 eq.), potassium carbonate (14.65 g; 106 mmol; 5 eq.) and Pd(PPh3)4 (2.45 g; 2.12 mmol; 0.1 eq.) in toluene (30 mL) and water (30 mL) was refluxed for 3 hours. After cooling to room temperature, the reaction mixture was filtered through a pad of Celite® which was further washed with toluene (20 mL). The filtrate was concentrated in vacuo, the residue taken up in ethyl acetate (200 mL) and washed with sat. aq. NaHCO3 (100 mL), water (100 mL) and brine (100 mL), dried over magnesium sulphate and concentrated in vacuo to afford the title compound (5 g, 80%) as a brown oil
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:34]=[CH:33][C:29]3[O:30][CH2:31][O:32][C:28]=3[CH:27]=2)[S:7](=[O:24])(=[O:23])[C:8]2[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=2[C:10]=1OS(C(F)(F)F)(=O)=O)=[O:4].[CH3:35][O:36][C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][C:42]=1[O:43][CH3:44]>>[O:30]1[C:29]2[CH:33]=[CH:34][C:26]([CH2:25][N:6]3[C:5]([C:3]([OH:2])=[O:4])=[C:10]([C:40]4[CH:39]=[CH:38][C:37]([O:36][CH3:35])=[C:42]([O:43][CH3:44])[CH:41]=4)[C:9]4[CH:19]=[CH:20][CH:21]=[CH:22][C:8]=4[S:7]3(=[O:24])=[O:23])=[CH:27][C:28]=2[O:32][CH2:31]1
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)c2ccccc2S(=O)(=O)N1Cc1ccc2c(c1)OCO2
Reactant: COc1ccc(B(O)O)cc1OC
Product: COc1ccc(C2=C(C(=O)O)N(Cc3ccc4c(c3)OCO4)S(=O)(=O)c3ccccc32)cc1OC

Procedure:
Prepared according to the method of Example 23, from 2-(benzo[1,3]dioxol-5-ylmethyl)-1,1-dioxo-4-(trifluoro-methanesulfonyloxy)-1,2-dihydro-1λ6 -benzo[e][1,2]thiazine-3-carboxylic acid methyl ester with 3,4-dimethoxyphenyl boronic acid, and saponification according to the method of Example 24; MS (CI) m/e 495, mp 267°-268° C.
Reaction SMILES: CC1C(CSC)=[N+]([O-])C2C(=CC=CC=2)[N+]=1[O-].C[C:18]1[C:27]([CH2:28][S:29]([CH3:31])=[O:30])=[N+:26]([O-:32])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N+:19]=1[O-:33]>>[CH3:31][S:29]([CH2:28][C:27]1[CH:18]=[N+:19]([O-:33])[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[N+:26]=1[O-:32])=[O:30]
Reactant: Cc1c(CS(C)=O)[n+]([O-])c2ccccc2[n+]1[O-]
Agent: CSCc1c(C)[n+]([O-])c2ccccc2[n+]1[O-]
Product: CS(=O)Cc1c[n+]([O-])c2ccccc2[n+]1[O-]

Procedure:
In like manner, 2-methyl-3-methylthiomethylquinoxaline 1,4-dioxide is converted to 2-methyl-3-methylsulfinylmethylquinoxaline 1,4-dioxide, m.p. 135°-136°C., in 13.1 percent yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:16][O:17][CH3:18])([C:13]([OH:15])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClCCl.C(Cl)(=O)C(Cl)=O.[Cl-].[Cl-].[F:30][C:31]([F:43])([F:42])[C:32]1[CH:33]=[N:34][C:35]2[CH2:36][CH2:37][NH:38][CH2:39][C:40]=2[CH:41]=1.C(N(CC)CC)C>ClCCl.CN(C=O)C>[CH3:18][O:17][CH2:16][C:10]1([C:13]([N:38]2[CH2:37][CH2:36][C:35]3[N:34]=[CH:33][C:32]([C:31]([F:30])([F:42])[F:43])=[CH:41][C:40]=3[CH2:39]2)=[O:15])[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1
Reactant: COCC1(C(=O)O)CCN(C(=O)OC(C)(C)C)C1
Reactant: FC(F)(F)c1cnc2c(c1)CNCC2
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCC1(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound was prepared according to general procedure C described in connection with Scheme 2. To 1-(tert-butoxycarbonyl)-3-(methoxymethyl)pyrrolidine-3-carboxylic acid (3 g, 11.6 mmol) in dichloromethane (30 mL) was added 2M oxalyl chloride dichloromethane solution (17 mL, 34 mmole) and a few drops of DMF at room temperature. The mixture was stirred at RT for 2 hours and concentrated to dryness under the reduced pressure. 3-(Trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine dichloride (3.19 g, 11.6 mmole) in 30 dichloromethane and triethyl amine (3.1 g, 30 mmole) was added to the above residue at 0° C. The mixture was stirred at 0° C. for 1 h, diluted with dichloromethane (100 mL) and washed with sodium bicarbonate solution (2×50 mL) and water (3×100 mL), dried over sodium sulfate and purified by silica chromatography using 2.5% MeOH in CH2Cl2 as eluent to give product (1.7 g, 33% yield). 1H NMR (400 MHz, CD3OD): δ 8.70 (s, 1H), 7.68 (m, 1H), 4.80 (s, 2H), 4.10-2.95 (m, 13H), 2.40-2.15 (m, 2H), 1.48 (s, 9H); MS (ESI) m/z: Calculated for C21H28F3N3O4: 443.2. found: 466 (M+Na)+.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][CH:7]([NH2:8])[CH:3]([CH2:4]2)[CH2:2]1.Cl[C:10]1[N:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]>[OH-].[Na+]>[C@H:3]12[CH2:4][C@H:5]([CH2:1][CH2:2]1)[CH2:6][C@H:7]2[NH:8][C:10]1[N:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]
Reactant: NC1CC2CCC1C2
Reactant: O=C(O)c1cccnc1Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cccnc1N[C@@H]1C[C@H]2CC[C@@H]1C2
Temperature: 160 °C
Reaction time: 24 h

Procedure:
A mixture of exo-2-aminonorbornane and 2-chloronicotinic acid was stirred at 160° C. for 1 day and then spontaneously cooled. The reaction liquid was diluted with 1 M sodium hydroxide aqueous solution and then washed with diethyl ether. The water layer was neutralized with 1 M hydrochloric acid and then the precipitated crystals were collected by filtration to obtain rel-2-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-ylamino]nicotinic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[CH:12]=2)=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH3:22]>O1CCOCC1>[NH2:22][C:6]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[CH:12]=2)=[O:9])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: N
Reactant: COc1cc(NC(=O)c2c(Cl)ncnc2Cl)cc(OC)c1
Solvent: C1COCCO1
Product: COc1cc(NC(=O)c2c(N)ncnc2Cl)cc(OC)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
4,6-Dichloro-N-(3,5-dimethoxyphenyl)pyrimidine-5-carboxamide (684 mg, 1.21 mmol) was dissolved in dioxane (5 ml) and cooled in an ice bath. Ammonia solution (0.86 ml, 7N in MeOH) was added dropwise and the mixture was stirred at 0° C. for 6 h and overnight at room temperature. After dilution with ethyl acetate, this organic phase was washed with water and brine, dried over magnesium sulphate, filtered and the solvents evaporated under reduced pressure, to yield an oil as a residue (575 mg, 66% purity, 100% yield) which was used in the next synthetic step without further purification.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].CC([O-])(C)C.[K+].C(O)=O>C1COCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:21](=[O:22])[C:20]1[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=1[Cl:18]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Clc1ccc(Nc2nc3ccccc3s2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O=CO
Solvent: C1CCOC1
Product: O=C(c1ccccc1Cl)N(c1ccc(Cl)cc1)c1nc2ccccc2s1
Yield: 67 %

Procedure:
A mixture of 39.1 mg (0.15 mmol) Benzothiazol-2-yl-(4-chloro-phenyl)-amine in 0.5 ml THF, 45.2 mg (0.18 mmol) 2-chlorobenzoyl chloride in 0.18 ml THF and 0.17 ml of a 1 M solution of KOtBu in THF was heated to 50° C. for 16 h. After addition of 0.5 ml formic acid the mixtures are subjected to preparative HPLC separation on reversed phase eluting with an acetonitrile/water gradient. Evaporation of the product fractions yielded 40.1 mg (67%) of the title compound. MS (m/e): 399.3 (MH+, 100%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:20][CH3:21])[C:9]([C:11]([N:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]3[CH2:16][CH2:15]3)=[O:12])=[CH:10][C:5]2=[C:4]2[N:22]([CH3:25])[CH:23]=[N:24][C:3]=12.C([N:34]=[C:35]=[S:36])(=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].Br.Br[CH2:45][C:46]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=1)=O>CC(C)=O>[CH:14]1([N:13]([CH:17]2[CH2:19][CH2:18]2)[C:11]([C:9]2[N:8]([CH2:20][CH3:21])[C:6]3=[N:7][C:2]([NH:1][C:35]4[S:36][CH:45]=[C:46]([C:48]5[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=5)[N:34]=4)=[C:3]4[N:24]=[CH:23][N:22]([CH3:25])[C:4]4=[C:5]3[CH:10]=2)=[O:12])[CH2:16][CH2:15]1
Reactant: O=C(CBr)c1ccccn1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N)nc21
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3nc(-c4ccccn4)cs3)nc21
Temperature: 60 °C
Yield: 9.7 %

Procedure:
A solution of 4-amino-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 1J, 70 mg, 0.21 mmol) and benzoyl isothiocyanate (36 μl, 0.27 mmol) in acetone (1 ml) was stirred at room temperature for 1.5 h. The solvent was removed in vacuo, the residue was taken up in EtOH (1.5 ml), and K2CO3 (40 mg, 0.290 mmol) was added. The reaction was heated at 60° C. for 3 h. Upon cooling to room temperature, 2-bromo-1-(pyridin-2-yl)ethanone, hydrobromide (139.4 mg, 0.50 mmol) was added and the reaction heated at 80° C. for 24 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (0-7% MeOH/dichloromethane). Re-purification by preparative HPLC provided 10.2 mg (10% yield) of N,N-dicyclopropyl-6-ethyl-1-methyl-4-(4-(pyridin-2-yl)thiazol-2-ylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide as a brown solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH2:9][CH2:8][C:7]=2[CH:14]=1)#[N:2].[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:15][CH:8]1[C:7]2[CH:14]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[O:11][C:10]([CH3:12])([CH3:13])[CH2:9]1
Reactant: CC1(C)CCc2cc(C#N)ccc2O1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)CC(Br)c2cc(C#N)ccc2O1
Yield: 79 %

Procedure:
To a solution of 6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (6.40 g, 34.18 mmol), title A compound, in carbon tetrachloride (90 mL) was added N-bromosuccinimide (6.69 g, 37.6 mmol). The solution was purged with argon. A solution of Azobisisobutyronitrile (0.4 g, 3.42 mmol) in carbon tetrachloride (10 mL) was added; the reaction was heated at reflux for 30 minutes with irradiation (high intensity visible light). The reaction mixture was concentrated under vacuum and the residue was dissolved in 75 mL ethyl acetate. The solution was washed successively with distilled water (4×75 mL), saturated sodium bicarbonate solution (75 mL), saturated NaCl solution (75 mL), and dried over magnesium sulfate. The solvent was recovered under vacuum to obtain an orange waxy solid which was triturated with cold pentane to provide a beige solid (7.19 g). This was crystallized from ethyl acetate and hexanes (10:90) to yield the title compound (4.60 g) as off-white needles, m.p. 94°-95° C. The mother liquors were combined and chromatographed on silica gel during with hexane/ethyl acetate (19:1) to afford additional product (2.26 g) for a combined yield of 75.4%.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][N:8]1[C:12]([CH2:13]CN)=[CH:11][S:10][C:9]1=[N:16][C:17](=[O:28])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1[O:26][CH3:27])(=[O:3])[CH3:2].C([N:31](CC)CC)C.[C:36]1([CH3:46])[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][N:8]1[C:12]([CH2:13][NH:31][S:42]([C:39]2[CH:40]=[CH:41][C:36]([CH3:46])=[CH:37][CH:38]=2)(=[O:44])=[O:43])=[CH:11][S:10][C:9]1=[N:16][C:17](=[O:28])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1[O:26][CH3:27])(=[O:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN(CC)CC
Reactant: COc1ccc(C(=O)N=c2scc(CCN)n2CCCNC(C)=O)c(OC)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N=c2scc(CNS(=O)(=O)c3ccc(C)cc3)n2CCCNC(C)=O)c(OC)c1

Procedure:
The compound (200 mg) obtained in the above (4) and triethylamine (100 mg) were dissolved in tetrahydrofuran (5 ml), and thereto was added p-toluenesulfonyl chloride (117 mg) at room temperature under nitrogen atmosphere. Two hours thereafter, to the reaction mixture was added a 10% aqueous citric acid solution, and the mixture was extracted with chloroform. The organic layer was washed with a saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [chloroform:methanol (97:32)] to give the title compound (240 mg) as amorphous.