Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[O:42])[CH2:3][C:4]1[C:5]([CH2:10][CH2:11][C:12]2[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:15]=[C:14]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH:29]4[CH2:34][CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30]4)=[CH:25][CH:24]=3)[N:13]=2)=[N:6][CH:7]=[CH:8][CH:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:31]1[CH2:32][CH2:33][CH2:34][CH:29]([C:26]2[CH:27]=[CH:28][C:23]([NH:22][C:14]3[N:13]=[C:12]([CH2:11][CH2:10][C:5]4[C:4]([CH2:3][C:2]([NH2:1])=[O:42])=[CH:9][CH:8]=[CH:7][N:6]=4)[C:17]([C:18]([F:20])([F:19])[F:21])=[CH:16][N:15]=3)=[CH:24][CH:25]=2)[CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ncccc4CC(N)=O)n3)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)Cc1cccnc1CCc1nc(Nc2ccc(C3CCCNC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 17 h
Yield: 95.3 %

Procedure:
To a solution of tert-butyl 3-(4-((4-(2-(3-(2-amino-2-oxoethyl)pyridin-2-yl)ethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I150) (23 mg, 0.039 mmol) in DCM (7 mL) was added TFA (1 mL). The resulting solution was stirred at room temperature for 17 hours then the volatiles were removed in vacuo. The residue was partitioned between ethyl acetate (50 mL) and a 2.0 M solution of NaOH (50 mL) then the organic layer was washed with water (50 mL), brine (50 mL) and dried over MgSO4 before being evaporated in vacuo to give the title compound (39) (18 mg, 94%) as a white solid; 1H NMR (400 MHz, d4-MeOH) δ 8.52 (s, 1H), 8.37 (dd, J=4.9, 1.6 Hz, 1H), 7.67 (dd, J=7.7, 1.6 Hz, 1H), 7.61 (d, J=8.6 Hz, 2H), 7.27-7.17 (m, 3H), 3.68 (s, 2H), 3.39-3.32 (m, 2H), 3.27 (d, J=8.7 Hz, 2H), 3.21-3.14 (m, 2H), 2.82-2.70 (m, 3H), 2.07-1.94 (m, 1H), 1.94-1.83 (m, 1H), 1.80-1.64 (m, 2H). LCMS Method C: rt 4.12 min, m/z=485.1 [M+H]+, 483.1 [M−H]−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=5)[CH:21]=4)=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[N:30]1[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=5)[CH:21]=4)=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cc2F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cccc(Cn2cc(-c3c[nH]c4ncc(-c5ccc(N6CCNCC6)c(F)c5)cc34)cn2)c1
Yield: 18.2 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(2-fluoro-4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (80 mg, 0.140 mmol) was deprotected in TFA/DCM (5/5 ml) to afford 12 mg (93% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 8.54 (s, 2H), 8.262-8.260 (d, 1H), 7.975-7.973 (d, 1H), 7.74 (s, 1H), 7.59-7.52 (m, 2H), 7.38-7.00 (m, 5H), 5.44 (s, 2H), 3.42-3.40 (m, 8H). MS: m/z=471.2 (M+1), HPLC: 97.06% in method B.
Reaction SMILES: [CH2:1]([C:15]1[C:16]([CH2:23][OH:24])=[C:17]([OH:22])[C:18]([CH3:21])=[N:19][CH:20]=1)[S:2][S:3][CH2:4][C:5]1[C:6]([CH2:13][OH:14])=[C:7]([OH:12])[C:8]([CH3:11])=[N:9][CH:10]=1.[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl>CCOCC>[CH2:4]([C:5]1[CH:10]=[N:9][C:8]([CH3:11])=[C:7]2[O:12][CH:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:14][CH2:13][C:6]=12)[S:3][S:2][CH2:1][C:15]1[CH:20]=[N:19][C:18]([CH3:21])=[C:17]2[O:22][CH:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:24][CH2:23][C:16]=12
Reactant: Cc1ncc(CSSCc2cnc(C)c(O)c2CO)c(CO)c1O
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: Cc1ncc(CSSCc2cnc(C)c3c2COC(c2ccccc2)O3)c2c1OC(c1ccccc1)OC2
Reaction time: 4 h

Procedure:
A mixture of 0.01 moles of 5,5'-(dithiodimethylene) bis[3-hydroxy-4-hydroxymethyl-2-methylpyridine] and 100 ml. of benzaldehyde was saturated with hydrogen chloride gas at 0°-5° and then stirred at this temperature for 4 hours. At this time 800 ml. of ether were added and the resulting precipitate was separated by filtration. This solid was then added to a well stirred mixture of 200 ml. chloroform and 200 ml. of water containing 20 gm. of sodium carbonate. After 15 minutes the chloroform layer was removed, dried, and concentrated to give an oil which gradually solidified. This solid was filtered with the aid of a small amount of ether to give 5,5'-(dithiodimethylene)bis[8-methyl-2-phenyl-4H-m-dioxino[4,5-c]pyridine].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]#[N:36])[CH:30]=2)[N:9]2[CH2:12][CH:11]([C@@H:13]([C:18]3[CH:19]=[C:20]([CH:25]=[C:26]([F:28])[CH:27]=3)[C:21]([NH:23][NH2:24])=[O:22])[C:14]([F:17])([CH3:16])[CH3:15])[CH2:10]2)=[CH:4][CH:3]=1.[C:37](Cl)(Cl)=[O:38]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([N:9]2[CH2:12][CH:11]([C@@H:13]([C:18]3[CH:19]=[C:20]([C:21]4[O:22][C:37](=[O:38])[NH:24][N:23]=4)[CH:25]=[C:26]([F:28])[CH:27]=3)[C:14]([F:17])([CH3:16])[CH3:15])[CH2:10]2)[C:29]2[CH:30]=[C:31]([CH:32]=[CH:33][CH:34]=2)[C:35]#[N:36])=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: CC(C)(F)[C@H](c1cc(F)cc(C(=O)NN)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Solvent: ClCCl
Product: CC(C)(F)[C@H](c1cc(F)cc(-c2n[nH]c(=O)o2)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 44 mg (0.86 mmol) of 3-((1S)-1-{1-[(S)-(4-chlorophenyl)(3-cyanophenyl) methyl]azetidin-3-yl}-2-fluoro-2-methylpropyl)-5-fluorobenzohydrazide (Preparation 19) in 2 mL CH2Cl2 was added 11.3 uL(0.215 mmol) of phosgene solution (20% in toluene) at 0° C., followed by stirring at rt. After 1.5 h, the solution was concentrated in vacuo to remove solvents and 2 mL of 2N NH3 in MeOH was added and the solution was concentrated again. The residue was purified by silica gel chromatography with CH2Cl2/acetone to afford the title compound as a white solid; 1H-NMR(CDCl3) δ 1.22(d, 3H, J=22 Hz), 1.28(d, 3H, J=22 Hz), 2.36 (t, 1H, J=8 Hz), 2.91 (t, 1H, J=8 Hz), 2.96 (m, 1H), 3.12 (t, 1H, J=7 Hz), 3.27 (m, 1H), 3.64 (t, 1H, J=6 Hz), 4.30 (s, 1H), 7.06-7.71 (m, 12H); Mass Spectrum: m/e=535 (M+1, 35Cl), 537 (M+1, 37Cl).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][NH:14][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:15]>CO>[NH:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:15])[C:11]=2[N:12]=[CH:13]1
Reactant: N
Reactant: Clc1nc2ccccc2c2[nH]cnc12
Solvent: CO
Product: Nc1nc2ccccc2c2[nH]cnc12

Procedure:
Using the method of Example 6, the product of Example 18, 0.2 g (0.0010 mole) of 4-chloro-1H-imidazo[4,5-c]quinoline was aminated at 175° C. in 12% ammonia in methanol to provide 1H-imidazo[4,5-c]quinolin-4-amine. The structure was verified by comparison of infrared and nuclear magnetic resonance spectra of the product with spectra of the product from Example 23.
Reaction SMILES: [NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([C:16]([O:18]C)=O)[CH:15]=2)[N:9]=1)[NH2:3].[NH3:20]>O1CCCC1>[C:16]([C:14]1[CH:15]=[C:10]([C:8]2[N:9]=[C:5]([N:4]=[C:2]([NH2:3])[NH2:1])[S:6][CH:7]=2)[CH:11]=[N:12][CH:13]=1)(=[O:18])[NH2:20]
Reactant: COC(=O)c1cncc(-c2csc(N=C(N)N)n2)c1
Reactant: N
Solvent: C1CCOC1
Product: NC(=O)c1cncc(-c2csc(N=C(N)N)n2)c1
Temperature: 25 °C
Reaction time: 9.5 h

Procedure:
A suspension of 2-(diaminomethyleneamino)-4-(5-methoxycarbonylpyridin-3-yl)thiazole (500 mg) in 28% ammonia solution (15 ml) and tetrahydrofuran (15 ml) was stirred at room temperature for 9.5 hours. The solvent was removed under reduced pressure. The residue was washed with methanol to afford 4-(5-carbamoylpyridin-3-yl)-2-(diaminomethyleneamino)thiazole (350 mg).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[C:10](=[O:19])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(OC)(O[CH3:24])(=O)=O>[OH-].[Na+]>[CH:1]1([N:7]=[C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[C:10]([O:19][CH3:24])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COS(=O)(=O)OC
Reactant: O=C1C=C(NC2CCCCC2)c2ccccc2C1=O
Agent: [Na+]
Agent: [OH-]
Product: COC1=CC(=NC2CCCCC2)c2ccccc2C1=O
Reaction time: 6 h

Procedure:
A solution of 9.0 g of 4-(cyclohexylamino)-1,2-naphthoquinone in 200 ml of dimethyl sulfate and 460 ml of 30% aqueous sodium hydroxide is heated slowly to reflux. The reaction mixture is stirred for 6 hours, washed with 300 ml of water and dried at 80° C. under vacuo to yield 4-cyclohexylimino-1-oxo-2-methoxy-1,4-dihydronaphthalene, m.p. 145°-147° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16](Br)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:22]1[CH2:27][CH:26]=[C:25](B2OCC(C)(C)CO2)[CH2:24][CH2:23]1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>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][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([C:25]3[CH2:26][CH2:27][S:22][CH2:23][CH:24]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)COB(C2=CCSCC2)OC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(Br)c2)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: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(C3=CCSCC3)c2)CC1
Temperature: 80 °C
Reaction time: 7 h
Yield: 67 %

Procedure:
To a mixture of 4-(4-amino-3-bromo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (as prepared in Example 13, step (c), 200 mg, 0.563 mmol), 2-(3,6-dihydro-2H-thiopyran-4-yl)-5,5-dimethyl-[1,3,2]dioxaborinane (as prepared in the previous step, 131 mg, 0.619 mmol) and Pd(PPh3)4 (65 mg, 0.056 mmol) in 5 mL of 1,4-dioxane was added 2.0 M aq Na2CO3 solution (2.25 mL, 4.5 mmol). The resulting mixture was stirred at 80° C. for 7 h under Ar, and then cooled to RT. Treated with 50 mL of EtOAc, the mixture was washed with H2O (3×15 mL), brine (20 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (15-30% EtOAc/hexane) gave 141 mg (67%) of the title compound as a colorless oil. 1H-NMR (CDCl3; 400 MHz): δ 6.91 (dd, 1H, J=8.2, 2.2 Hz), 6.81 (d, 1H, J=2.2 Hz), 6.65 (d, 1H, J=8.2 Hz), 5.91 (m, 1H), 4.22 (br s, 2H), 3.66 (br s, 2H), 3.29-3.31 (m, 2H), 2.87 (dd, 2H, J=5.7, 5.7 Hz), 2.77 (m, 2H), 2.47-2.56 (m, 3H), 1.78 (d, 2H, J=12.6 Hz), 1.50-1.63 (m, 2H), 1.48 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C21H30N2O2S, 375.2 (M+H), found 375.2.
Reaction SMILES: N1C=N[C:3]([CH2:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)=N1.[NH:15]1[CH:19]=[N:18][CH:17]=[N:16]1>C(#N)C.C(Cl)(Cl)Cl>[CH:13]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]([CH:6]([N:15]2[N:16]=[CH:17][N:18]=[CH:19]2)[C:3]2[CH:8]=[CH:9][C:10]([C:11]#[N:12])=[CH:13][CH:14]=2)[CH:14]=1
Reactant: N#Cc1ccc(Cc2nc[nH]n2)cc1
Reactant: c1nc[nH]n1
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: N#Cc1ccc(C(c2ccc(C#N)cc2)n2cncn2)cc1

Procedure:
U.S. Pat. No. 5,473,078 (“the '078 patent”) describes a method for preparing 4-[1-(1,2,4-triazolyl)methyl]benzonitrile by refluxing a solution of c-bromo-4-tolunitrile with 1,2,4-triazole for 15 hours in a mixture of acetonitrile and chloroform. The intermediate is purified by chromatography on silica gel, eluting with chloroform and isopropanol, and then reacted with 4-fluorobenzonitrile and potassium tert-butoxide in DMF, to obtain letrozole. An exemplary process described in the '078 patent is generally depicted in Scheme 1.
Reaction SMILES: [CH:1]([N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[N:9][N+:10]([O-:12])=[O:11])=[CH:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].CS(C)=O.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30]Cl)=[CH:26][N:25]=1>O>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:6]2[CH2:7][CH2:8][N:4]([CH:1]=[CH:2][CH3:3])[C:5]2=[N:9][N+:10]([O-:12])=[O:11])=[CH:26][N:25]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: CC=CN1CCNC1=N[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC=CN1CCN(Cc2ccc(Cl)nc2)C1=N[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
A mixture comprising 6.0 g of 1-(1-propenyl)-2nitroiminoimidazolidine, 7.0 g of potassium carbonate, 70 ml of DMSO and 7.4 g of 2-chloro-5-chloromethylpyridine was stirred at 60° C. for one hour. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried (with anhydrous MgSO4) and concentrated to give an oily residue. This was purified by column chromatography (silica gel, eluent: ethyl acetate/hexane=2/1) to give 8.6 g of 1-(2-chloropyridin-5-ylmethyl)-2-nitroimino -3- (1propenyl)imidazolidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[NH2:10].CC1C=CC=CC=1.[Cl:18][CH2:19][C:20](Cl)=[O:21]>O>[Cl:18][CH2:19][C:20]([NH:10][C:4]1[CH:5]=[C:6]([CH3:9])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[O:21]
Reactant: COc1ccc(C)cc1N
Reactant: O=C(Cl)CCl
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C)cc1NC(=O)CCl
Reaction time: 1.5 h
Yield: 66 %

Procedure:
To a stirred solution of 49.2 parts of 2-methoxy-5-methylbenzenamine and 270 parts of methylbenzene were added dropwise 22.5 parts of 2-chloroacetyl chloride while cooling (ice-bath) at 10°-20° C. Upon completion, stirring was continued for 1.50 hours at room temperature. 200 Parts of water were added. The organic phase was separated, washed with water, dried, filtered and evaporated. The oily residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 28.2 parts (66%) of 2-chloro-N-(2-methoxy-5-methylphenyl)acetamide; mp. 83.9° C. (intermediate 66).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.O.[NH2:24][NH2:25]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:11]([C:12]([NH2:13])=[N:24][NH:25]3)=[CH:14][CH:15]=2)[CH:5]=[C:4]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1
Reactant: NN
Reactant: N#Cc1ccc(-c2cc(-c3ccccc3)nc(N)n2)cc1F
Solvent: O
Solvent: CCO
Product: Nc1nc(-c2ccccc2)cc(-c2ccc3c(N)n[nH]c3c2)n1
Temperature: 95 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
Into a 25 mL sealable tube under argon were added 4-(2-amino-6-phenyl-4-pyrimidinyl)-2-fluorobenzonitrile (0.052 g, 0.18 mmol) and EtOH (5 mL). Hydrazine monohydrate (0.35 mL, 7.17 mmol) was added, the vial was sealed, and the reaction mixture was stirred overnight at 95° C. The reaction was cooled to room temperature and concentrated. The resulting solid was sonicated in a mixture of EtOH (1 mL) and water (10 mL), filtered, washed with water, and dried under vacuum at 40° C. to afford the title compound as a yellow solid (44 mg, 77%). LC-MS (ES) m/z=303 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 5.43 (s, 2H), 6.74 (s, 2H), 7.46-7.59 (m, 3H), 7.69-7.84 (m, 3H), 8.12 (s, 1H), 8.23 (m, 2H), 11.63 (s, 1H).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[C:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:9]=[CH:8][C:7]=1[CH2:17][CH2:18][O:19][C:20]1[CH:33]=[CH:32][C:23]([CH:24]=[C:25]2[S:29][C:28](=[O:30])[NH:27][C:26]2=[O:31])=[CH:22][CH:21]=1)(=[O:4])=[O:3].C(O)(=O)C>C(OCC)(=O)C.[Pd]>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[C:10]([O:12][S:13]([CH3:16])(=[O:14])=[O:15])[CH:9]=[CH:8][C:7]=1[CH2:17][CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:24][CH:25]2[S:29][C:28](=[O:30])[NH:27][C:26]2=[O:31])=[CH:32][CH:33]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Oc1ccc(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)c(OS(C)(=O)=O)c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Oc1ccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)c(OS(C)(=O)=O)c1
Yield: 76.2 %

Procedure:
0.718 g (1.4 mmole) 5-(4-[2-(2,4-dimethanesulfonyloxyphenyl)ethoxy]benzylidene)thiazolidine-2,4-dione was hydrogenated over night in 100 ml ethyl acetate and 1 ml acetic acid with 1.4 g Pd/C (10%) as catalyst. The catalyst was filtered off and the filtrate was washed with water, dried with magnesium sulfate and evaporated in vacuo to give 0.55 g (yield 76%) of the desired product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[S:12][C:11]([C:13]#[N:14])=[N:10][N:9]=2)[CH2:3][CH2:2]1.[F:15][C:16]([F:26])([F:25])[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O.C(OCC)(=O)C>[F:15][C:16]([F:25])([F:26])[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]2[S:12][C:11]([C:13]#[N:14])=[N:10][N:9]=2)[CH2:5][CH2:6]1
Reactant: N#Cc1nnc(NC2CCNCC2)s1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1nnc(NC2CCN(Cc3cccc(C(F)(F)F)c3)CC2)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 9 %

Procedure:
A mixture of 5-(piperidin-4-ylamino)-[1,3,4]thiadiazole-2-carbonitrile (D6) (0.16 g, 0.76 mmol), 3-(trifluoromethyl)benzaldehyde (0.152 ml, 1.14 mmol) and sodium triacetoxyborohydride (0.24 g, 0.95 mmol) in N,N-dimethylformamide (3 ml) was stirred at room temperature for 16 h. After this period, the reaction mixture was diluted with ethyl acetate and extracted with a saturated solution of sodium carbonate (25 ml). The organic layer was separated, dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; 1-4% ammonia in methanol (7M)/dichloromethane) to yield E17 (0.025 g, 9%) as a white solid. C16H16F3N5S requires 367. Found 368 (MH+).
Reaction SMILES: CN(C)C1N=CC([C:9]2[N:10]=[C:11]([CH2:36][CH3:37])[C:12]([NH:17][C@H:18]3[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][N:20]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])[CH2:19]3)=[N:13][C:14]=2[CH2:15][CH3:16])=C(C)C=1.[Cl:40][C:41]1[CH:46]=[C:45]([O:47][CH3:48])[CH:44]=[CH:43][C:42]=1B(O)O>>[Cl:40][C:41]1[CH:46]=[C:45]([O:47][CH3:48])[CH:44]=[CH:43][C:42]=1[C:9]1[N:10]=[C:11]([CH2:36][CH3:37])[C:12]([NH:17][C@H:18]2[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][N:20]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:27])[CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: COc1ccc(B(O)O)c(Cl)c1
Reactant: CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1nc(CC)c(-c2cnc(N(C)C)cc2C)nc1CC
Product: CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of benzyl (3R,4S)-3-({5-[6-(dimethylamino)-4-methylpyridin-3-yl]-3,6-diethylpyrazin-2-yl}amino)-4-ethoxypyrrolidine-1-carboxylate but substituting 2-chloro-4-methoxy phenyl boronic acid and making non-critical variations provided the title compound as a oil: 1H NMR (DMSO-d6) δ) 1.04, 1.16, 2.38, 2.68, 3.34, 3.40, 3.54, 3.70, 3.82, 4.18, 4.62, 5.10, 5.95, 6.98, 7.10, 7.26, 7.38; IR (diffuse reflectance) 2971, 2934, 2350 (w), 2338 (w), 2063 (w), 1949 (w), 1710 (s), 1568, 1482 (s), 1419 (s), 1397 (s), 1348, 1287, 1228, 1096, cm−1 HRMS (FAB) calcd for C29H35ClN4O4+H 539.2425. found 539.2436. Anal. Calcd for C29H35ClN4O4: C, 64.61; H, 6.54; N, 10.39; Cl, 6.58. Found: C, 64.30; H, 6.56; N, 10.26.
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][CH:8]=[C:9]([I:10])[N:4]2[N:3]=1.[CH3:11][S:12]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)(=[O:14])=[O:13].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[I:10][C:9]1[N:4]2[C:5]([S:6][C:2]([C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([S:12]([CH3:11])(=[O:14])=[O:13])[CH:20]=3)=[N:3]2)=[N:7][CH:8]=1
Reactant: Brc1nn2c(I)cnc2s1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CS(=O)(=O)c1cccc(-c2nn3c(I)cnc3s2)c1
Temperature: 110 °C
Yield: 37.1 %

Procedure:
A mixture of 2-bromo-5-iodoimidazo[2,1-b][1,3,4]thiadiazole (0.20 g, 0.606 mmol, 1 eq), 3-(methylsulfonyl)phenylboronic acid (0.182 g, 0.909 mmol, 1.5 eq), PdCl2(PPh3)2 (0.085 g, 0.121 mmol, 0.2 eq) and 2M Na2CO3 (1.0 mL) in dioxane (5 mL) was heated at 110° C. for 24 h. More PdCl2(PPh3)2 (0.1 eq) was added and the reaction mixture was heated at 110° C. for 4 h. The solvent was removed, water was added and the mixture was extracted with DCM. The organic layer was dried (MgSO4), filtered and evaporated. The residue was triturated from MeOH and filtered to give the desired product (91 mg, 37%) as an orange solid. It was used in the next step of the synthesis with no further treatment. HPLC-MS (10-95% B in 4 min at 0.5 mL+2 min 100% B, flow 0.8 mL/min, 50° C.): tR=3.98 min, [M+H]+ m/z 405.9.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][CH:12]=1)[CH:9]1[CH2:13][CH2:14][CH:5]2[CH2:6][N:7]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:8]1.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[C:25]([Cl:40])=[CH:24][N:23]=1>>[Cl:40][C:25]1[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[N:27][C:22]([NH:1][C:2]2[CH:3]=[C:4]3[C:10](=[CH:11][CH:12]=2)[CH:9]2[CH2:13][CH2:14][CH:5]3[CH2:6][N:7]([C:15](=[O:20])[C:16]([F:19])([F:17])[F:18])[CH2:8]2)=[N:23][CH:24]=1
Reactant: CS(=O)(=O)Nc1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)C1CCC2CN(C(=O)C(F)(F)F)C1
Product: CS(=O)(=O)Nc1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CN(C(=O)C(F)(F)F)C2)ncc1Cl

Procedure:
N-(2-{5-Chloro-2-[10-(2,2,2-trifluoro-acetyl)-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino]-pyrimidin-4-ylamino}-phenyl)-methanesulfonamide was prepared from 1-(4-amino-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-10-yl)-2,2,2-trifluoro-ethanone and N-[2-(2,5-dichloro-pyrimidin-4-ylamino)-phenyl]-methanesulfonamide in an analogous manner to Example 290. Product isolated as a pale yellow foam (263 mg, 64%). LCMS (m/e) 581 (M+1); 1H-NMR (CDCl3, 400 MHz) major rotomer δ 7.96 (s, 1H), 7.70-62 (m, 1H), 7.55-7.45 (m, 2H), 7.40-7.31 (m, 2H), 7.25-7.05 (m, 3H), 7.00-6.90 (m, 1H), 4.30-4.10 (m, 1H), 3.90-3.79 (m, 1H), 3.50-3.39 (m, 1H), 3.37-3.27 (m, 1H), 3.20-3.10 (m, 1H), 2.96 (s, 1H), 2.96-2.90 (m, 1H), 2.10-1.95 (m, 2H), 1.80-1.70 (m, 2H).
Reaction SMILES: Cl[CH2:2][C@H:3]([OH:20])[C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.CCO>[OH-].[Na+].O>[CH:6]1([CH2:5][C@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@@H:3]2[CH2:2][O:20]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H]1CO1
Reaction time: 1 h
Yield: 93.9 %

Procedure:
tert-Butyl (2S,3R)-4-chloro-1-cyclohexyl-3-hydroxybutan-2-ylcarbamate (1 g, 3.28 mmol) was dissolved in a solution of 0.7 N NaOH in EtOH (5.6 mL, 3.95 mmol, 1.2 eq). After stirring for 1 h, the mixture was concentrated to give the residue, which was dissolved in water, extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give tert-butyl (S)-2-cyclohexyl-1-((R)-oxiran-2-yl)ethylcarbamate (0.83 g, 95%). 1H NMR: 0.85 (m, 1H), 0.99 (m, 1H), 1.12-1.32 (m, 3H), 1.41 (m, 3H), 1.45 (s, 9H), 1.58 (m, 4H), 1.88 (m, 1H), 2.59 (m, 1H), 2.73 (m, 1H), 2.98 (m, 1H), 4.04 (m, 1H), 4.32 (m, 1H). MS (E/Z): 270 (M+H+).