Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:12]=[CH:11][C:10]=1[CH:25]=[CH:26][C:27]1[S:31][C:30]([CH:32]=O)=[CH:29][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]([C:36]1[C:37](=[C:47]([C:50]#[N:51])[C:48]#[N:49])[O:38][C:39]([CH3:46])([C:42]([F:45])([F:44])[F:43])[C:40]=1[CH3:41])#[N:35]>C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:12]=[CH:11][C:10]=1[CH:25]=[CH:26][C:27]1[S:31][C:30]([CH:32]=[CH:41][C:40]2[C:39]([CH3:46])([C:42]([F:45])([F:43])[F:44])[O:38][C:37](=[C:47]([C:48]#[N:49])[C:50]#[N:51])[C:36]=2[C:34]#[N:35])=[CH:29][CH:28]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C(F)(F)F
Reactant: CCCCN(CCCCO)c1ccc(C=Cc2ccc(C=O)s2)c(OCc2ccccc2)c1
Solvent: CCO
Product: CCCCN(CCCCO)c1ccc(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C(F)(F)F)s2)c(OCc2ccccc2)c1
Temperature: 50 °C
Yield: 73.4 %

Procedure:
In 8 ml of ethanol were dissolved 180 mg (0.39 mmol) of 5-[2-[2-benzyloxy-4-[butyl(4-hydroxybutyl)amino]phenyl]vinyl]thiophene-2-carboaldehyde and 108 mg (0.43 mmol) of 2-(3-cyano-4,5-dimethyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. The mixture was stirred with heating at 50° C. for 3 hours. The precipitate was separated by filtration, purified by silica gel column chromatography and washed with methanol to give 200 mg of a dark brown crystal having a mp of 176-178° C. (yield: 73.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH2:16]Cl)[C:10]=3[OH:18])[N:8]=[C:4]2[CH:3]=1.[CH2:21]([OH:26])[CH2:22][CH:23]([CH3:25])[CH3:24].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH2:16][O:26][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:10]=3[OH:18])[N:8]=[C:4]2[CH:3]=1
Reactant: Cc1cc(CCl)c(O)c(-n2nc3ccc(Cl)cc3n2)c1
Reactant: CC(C)CCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1cc(COCCC(C)C)c(O)c(-n2nc3ccc(Cl)cc3n2)c1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 81.6 %

Procedure:
2-(5-Chloro-2H-benzotriazol-2-yl)-6-chloromethyl-4-methyl-phenol (5.0 g, 16 mmol) is suspended in a mixture of isoamyl alcohol (20.0 g, 227 mmol) and acetone (5 g) and stirred at 80° C. for 15 minutes. Sodium carbonate (2.1 g, 20 mmol) is added. The slightly yellow reaction mixture is stirred at 80° C. for 2 hours and evaporated to dryness. The residue is dissolved in ethyl acetate and extracted with aqueous citric acid (5%) and brine. The organic layer is dried over sodium sulphate, filtered and evaporated to dryness. The crude product is purified by column chromatography (ethyl acetate/heptane 1:12) to yield 4.7 g of 2-(5-Chloro-2H-benzotriazol-2-yl)-4-methyl-6-(3-methyl-butoxymethyl)-phenol.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[C:34]2[C:33]([NH:35][C:36]3[C:37]([O:42][CH:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[N:38][CH:39]=[CH:40][CH:41]=3)=[N:32][CH:31]=[N:30][C:29]=2[S:28][C:27]=1[C:49]([OH:51])=O.CCN(C(C)C)C(C)C.[CH3:61][N:62]([CH3:67])[CH2:63][CH2:64][CH2:65][NH2:66]>CN(C=O)C>[CH3:61][N:62]([CH3:67])[CH2:63][CH2:64][CH2:65][NH:66][C:49]([C:27]1[S:28][C:29]2[N:30]=[CH:31][N:32]=[C:33]([NH:35][C:36]3[C:37]([O:42][CH:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[N:38][CH:39]=[CH:40][CH:41]=3)[C:34]=2[C:26]=1[CH3:25])=[O:51]
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3OC3CCOCC3)c12
Reactant: CN(C)CCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(C(=O)NCCCN(C)C)sc2ncnc(Nc3cccnc3OC3CCOCC3)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 24.7 %

Procedure:
HATU (0.105 g, 0.28 mmol) was added into a mixture of 5-methyl-4-(2-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-ylamino)thieno[2,3-d]pyrimidine-6-carboxylic acid (0.097 g, 0.25 mmol) and Hünig's base (44 μL, 0.25 mmol) in DMF (2.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 hours. 3-Dimethylamino-1-propylamine (138 μL, 1.25 mmol) was added and the coolant removed. The reaction mixture was stirred at ambient temperature overnight. The solvent was concentrated in vacuo and the product purified by reverse phase preparative HPLC to yield off-white solid (0.029 g, 24%).
Reaction SMILES: C([N:9]1[C:56](=[O:57])[CH:55]=[CH:54][N:11]([C@@H:12]2[O:53][C@H:27]([CH2:28][O:29][C:30]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)([C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[C@@H:25]([OH:26])[C@H:13]2[O:14][CH2:15][CH2:16][C:17]([O:19]CC(F)(F)F)=O)[C:10]1=[O:58])(=O)C1C=CC=CC=1.[CH3:59][NH:60][CH3:61].O1CCCC1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([C:30]([O:29][CH2:28][C@H:27]2[O:53][C@@H:12]([N:11]3[CH:54]=[CH:55][C:56](=[O:57])[NH:9][C:10]3=[O:58])[C@H:13]([O:14][CH2:15][CH2:16][C:17](=[O:19])[N:60]([CH3:61])[CH3:59])[C@@H:25]2[OH:26])([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)n(C(=O)c4ccccc4)c3=O)[C@H](OCCC(=O)OCC(F)(F)F)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CNC
Solvent: C1CCOC1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](OCCC(=O)N(C)C)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To N3-benzoyl-5′-O-(4,4′-dimethoxytrityl)-2′-O-[2-(2,2,2-trifluoroethoxy)carbonylethyl]uridine (120 mg, 0.15 mmol) synthesized in Example 15 was added 2 M dimethylamine/tetrahydrofuran (4 mL), followed by stirring at room temperature for 15 hours. Then, the reaction was carried out at 40° C. for 2 hours. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography eluting with chloroform to give the title compound as a white foam-like material (80 mg, 83%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH:13]=[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:8][CH:7]=1.[Na+].[I-:25]>CC(C)=O>[I:25][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH:13]=[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:8][CH:7]=1
Reactant: [I-]
Reactant: O=C1Nc2ccccc2C1=CNc1ccc(OCCCCl)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C1Nc2ccccc2C1=CNc1ccc(OCCCI)cc1
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 3-{[4-(3-Chloro-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one (45 mg, 0.137 mmol) and NaI (103 mg, 5 equiv.) in 1 mL acetone is heated at 80° C. overnight. The reaction mixture is cooled to room temperature and evaporated to dryness. The residue is dissolved in EtOAc and H2O. The organic layer is collected and dried over anhydrous Na2SO4, filtered, and concentrated to give the named compound as yellow solid (100%).
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[P:8]([O:13]C)([O:11][CH3:12])[O:9][CH3:10]>>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][P:8]([O:11][CH3:12])([O:9][CH3:10])=[O:13])[CH3:7]
Reactant: CCOC(=O)CCl
Reactant: COP(OC)OC
Product: CCOC(=O)CP(=O)(OC)OC
Temperature: 130 °C
Reaction time: 10 h

Procedure:
An amount of 340.8 g of ethyl chloroacetate was mixed with 496 g of trimethyl phosphite in a reactor fitted with a thermometer, nitrogen inlet and a fractionation column (containing 5 mm Raschig rings as packing) topped with a variable reflux condenser. The reactor was heated to enable slow reflux in the column only followed by a slow increase in the temperature from 110 to 150 degrees C. over 10 hours and maintained at about this temperature. The pressure was reduced to 11 mm Hg and volatile material was removed on heating the reactor slowly from 50 to 140 degrees C. The yield of the pure product obtained was 85%.
Reaction SMILES: [OH-].[K+].[OH:3][CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5](=[CH2:10])[C:6]([O:8]C)=[O:7]>O.CO>[OH:3][C@H:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5](=[CH2:10])[C:6]([OH:8])=[O:7]
Reactant: C=C(C(=O)OC)C(O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=C(C(=O)O)[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of potassium hydroxide (2.65 g, 0.047 mol, 1.3 eq) in water (60 mL) was added drop wise to a solution of 1b (7 g, 0.036 mol, 1 eq) in methanol (20 mL) (see FIG. 5). The mixture was stirred at room temperature for 15 h. The solution was then concentrated under vacuum. The aqueous phase was washed with ether (2×100 mL), acidified with 6N aqueous HCl solution and extracted with ether (3×100 mL). The combined organic extracts were washed with brine (100 mL) and dried over sodium sulfate. Evaporation of the solvent afforded a colorless oil which crystallized upon standing. The desired product 9b was obtained as a solid (6.29 g, 97%). Rf 0.26 (hexane/EtOAc=6:4). 1H NMR δ (DMSO-d6) 5.41 (s, 1H), 5.61 (s, 1H), 5.93 (s, 1H), 6.15 (s, 1H), 7.22 (m, 5H), 12.45 (s, 1H). [M−H]− 177.1, tR=1.23 min; purity: 91%.
Reaction SMILES: C([O:3][C:4](=[O:52])[CH2:5][N:6]([CH2:46][C:47]([O:49]CC)=[O:48])[C:7](=[O:45])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH3:25])[C:9]=1[O:26][CH:27]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:28][CH2:29][CH2:30][CH3:31])C.[OH-].[Na+]>CO>[C:4]([CH2:5][N:6]([C:7](=[O:45])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH3:25])[C:9]=1[O:26][CH:27]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:46][C:47]([OH:49])=[O:48])([OH:52])=[O:3]
Reactant: CCCCCCCCCCCCCC(CCCC)Oc1c(OCCOCCOCCOCC)cccc1C(=O)N(CC(=O)OCC)CC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCC(CCCC)Oc1c(OCCOCCOCCOCC)cccc1C(=O)N(CC(=O)O)CC(=O)O
Yield: 71.2 %

Procedure:
A solution of 1.0 g (1.36 mmol) of N-(2-ethoxy-2-oxoethyl)-N-[3-[2-[2-(2-ethoxyethoxy)ethoxy]ethoxy]-(5-octadecyloxy)benzoyl]glycine ethyl ester and 1.1 ml (6.6 mmol) of 6N NaOH in 25 ml of methanol was stirred at room temperature for 4 hours. The solvent was removed at reduced pressure, the residue was acidified and the product was extracted with ethyl acetate. The dried extract was concentrated to an oil which was purified by chromatography on 30 g of silica gel (230-400 mesh) using 25% methanol-chloroform to give 0.66 g (71% yield) of N-(carboxymethyl)-N-[3-[2-[2-(2-ethoxyethoxy)ethoxy]ethoxy]-(5-octadecyloxy)benzoyl]glycine as an oil. The structure was confirmed by nmr and mass spectra.
Reaction SMILES: [CH:1]1([C@@H:7]([NH:9][C:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:13]=2[CH2:28][N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[O:11])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:35][N:36]=[C:37]=[S:38]>C(Cl)Cl>[CH:1]1([C@@H:7]([NH:9][C:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:13]=2[CH2:28][N:29]2[CH2:34][CH2:33][N:32]([C:37](=[S:38])[NH:36][CH3:35])[CH2:31][CH2:30]2)=[O:11])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN=C=S
Reactant: C[C@H](NC(=O)c1c(CN2CCNCC2)c(-c2ccccc2)nc2ccccc12)C1CCCCC1
Solvent: ClCCl
Product: CNC(=S)N1CCN(Cc2c(-c3ccccc3)nc3ccccc3c2C(=O)N[C@@H](C)C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.3 %

Procedure:
0.4 g (0.87 mmol) of 2-phenyl-3-piperazin-1-ylmethyl-quinoline-4carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide (compound of Example 34) were dissolved in 10 ml of methylene chloride and 0.09 g methylisothiocyanate were added. The mixture was stirred for 5 h at room temperature and the solvent was concentrated in vacuo and the residue was purified by flash chromatography on silicagel (EtOAc/heptane: 95/5) to afford 0.43 g (yield 92%) of the title compound as white crystals.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH2:12]([O:19][C:20]1[CH:29]=[CH:28][C:27]2[N:26]=[CH:25][C:24]3[N:30]=[C:31]([CH2:46][O:47][CH2:48][CH3:49])[N:32]([CH2:33][C:34]([NH:37][C:38]([CH:40]4[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]4)=[O:39])([CH3:36])[CH3:35])[C:23]=3[C:22]=2[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[CH2:12]([O:19][C:20]1[CH:29]=[CH:28][C:27]2[N+:26]([O-:9])=[CH:25][C:24]3[N:30]=[C:31]([CH2:46][O:47][CH2:48][CH3:49])[N:32]([CH2:33][C:34]([NH:37][C:38]([CH:40]4[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]4)=[O:39])([CH3:36])[CH3:35])[C:23]=3[C:22]=2[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOCc1nc2cnc3ccc(OCc4ccccc4)cc3c2n1CC(C)(C)NC(=O)C1CCCCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c[n+]([O-])c3ccc(OCc4ccccc4)cc3c2n1CC(C)(C)NC(=O)C1CCCCC1
Reaction time: 2 h
Yield: 111 %

Procedure:
mCPBA (60% pure, 1.34 g) was added to a solution of N-{2-[8-(benzyloxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}cyclohexanecarboxamide (2.34 g, 4.55 mmol) in chloroform (100 mL). The reaction was stirred for 2 hours and quenched by adding 50 mL of aqueous 2% sodium carbonate. The layers were separated and the aqueous fraction was extracted with two portions of chloroform. The combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated to give 2.68 g of crude N-{2-[8-(benzyloxy)-2-(ethoxymethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}cyclohexanecarboxamide as an orange foam.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[C:12]([Mg]Cl)#[CH:13]>C1COCC1>[OH:6][CH:5]([C:4]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:2]([OH:1])[CH:3]=1)[C:12]#[CH:13]
Reactant: C#C[Mg]Cl
Reactant: COc1ccc(C=O)cc1O
Solvent: C1CCOC1
Product: C#CC(O)c1ccc(OC)c(O)c1

Procedure:
3-Hydroxy-3-(3-hydroxy-4-methoxyphenyl)-1-propyne was prepared according to Method B above from 3-hydroxy-4-methoxybenzaldehyde (0.304 g, 2 mmol) (Aldrich) in THF (20 mL) and ethynylmagnesium chloride (5 mmol, 10 mL, 0.5M solution in tetrahydrofuran) (Aldrich). (Yield 273 mg, 77%).
Reaction SMILES: O=[C:2]1[NH:8][CH:7]([CH2:9][CH2:10][C:11]2[NH:36][C:14]3=[N:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[CH3:35])(=[O:27])=[O:26])=[CH:21][CH:20]=4)[CH:18]=[C:13]3[N:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:46])=CC=1>>[S:46]=[C:2]1[NH:8][CH:7]([CH2:9][CH2:10][C:11]2[NH:36][C:14]3=[N:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[CH3:35])(=[O:27])=[O:26])=[CH:21][CH:20]=4)[CH:18]=[C:13]3[N:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1ccccc1NS(=O)(=O)c1ccc(-c2cnc3[nH]c(CCC4CCCCC(=O)N4)nc3c2)cc1
Product: Cc1ccccc1NS(=O)(=O)c1ccc(-c2cnc3[nH]c(CCC4CCCCC(=S)N4)nc3c2)cc1
Yield: 85.9 %

Procedure:
The title compound is analogously synthesized as described for 7-[2-(6-{4-cyano-phen-1-yl}-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-thione (compound A2) from 88 mg of 4-{2-[2-(7-oxo-azepan-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-N-o-tolyl-benzenesulfonamide (compound B9) and 77 mg of Lawesson's reagent. Purification by chromatography on LiChroprep-NH2® (eluents: i. neat dichloromethane, ii. dichloromethane/ethanol 20:1 parts by volume) affords 78 mg of the title compound as a waxy solid. ESI-MS: 520.4 (MH+). TLC: Rf=0.44 (LiChroprep-NH2® HPTLC, dichloromethane/ethanol 10:1 parts by volume).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[N:5]=[CH:4][C:3]=1[C:19]1[NH:23]C2C=CC(F)=C(C)C=2N=1.[CH3:30][O-:31].[Na+]>CO>[CH3:30][O:31][C:2]1[C:3]([C:19]#[N:23])=[CH:4][N:5]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH:7]=1
Reactant: Cc1c(F)ccc2[nH]c(-c3cnc(OCCCC4CCN(C)CC4)cc3Cl)nc12
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(OCCCC2CCN(C)CC2)ncc1C#N
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 4-chloro-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-nicotinonitrile (Example 115) in methanol (0.2 M) was treated with sodium methoxide (4 equiv) at reflux temperature for 4 h. The mixture was cooled to rt, diluted with satd. aq. NaHCO3, and extracted with chloroform. The organic extract was dried (Na2SO4), filtered, and concentrated to yield 4-methoxy-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-nicotinonitrile (100%). This intermediate was converted to the title compound according to Example 115. MS (electrospray): mass calculated for C23H30ClN4O2, 394.24; m/z found, 395.4 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]1([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:53]1([S:58]([NH:61][C:62]([C@@:64]2([NH:69][C:70]([C@@H:72]3[CH2:83][C@:75]4([C:80]([CH3:82])([CH3:81])[C:76]54[CH2:79][CH2:78][CH2:77]5)[CH2:74][N:73]3[C:84](=[O:91])[C@@H:85]([NH2:90])[C:86]([CH3:89])([CH3:88])[CH3:87])=[O:71])[CH2:66][C@H:65]2[CH:67]=[CH2:68])=[O:63])(=[O:60])=[O:59])[CH2:57][CH2:56][CH2:55][CH2:54]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10](=[O:12])[NH:90][C@H:85]([C:84]([N:73]1[C@H:72]([C:70](=[O:71])[NH:69][C@:64]2([C:62]([NH:61][S:58]([N:53]3[CH2:54][CH2:55][CH2:56][CH2:57]3)(=[O:60])=[O:59])=[O:63])[CH2:66][C@H:65]2[CH:67]=[CH2:68])[CH2:83][C@:75]2([C:80]([CH3:82])([CH3:81])[C:76]32[CH2:79][CH2:78][CH2:77]3)[CH2:74]1)=[O:91])[C:86]([CH3:89])([CH3:88])[CH3:87])[C:13]1([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1(C)CCCCC1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@]2(CN1C(=O)[C@@H](N)C(C)(C)C)C(C)(C)C21CCC1)C(=O)NS(=O)(=O)N1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@]2(CN1C(=O)[C@@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C1(C)CCCCC1)C(C)(C)C)C(C)(C)C21CCC1)C(=O)NS(=O)(=O)N1CCCC1
Reaction time: 15 h

Procedure:
A solution of (S)-tert-Butoxycarbonylamino-(1-methyl-cyclohexyl)-acetic acid (0.217 g; 0.80 mmol) (prepared according to Tetrahedron Let. 2007, 48, 6343-6347) and HATU (0.38 g; 1.00 mmol) in DCM (10 mL) was stirred for 20 min at ambient temperature. After addition of DIPEA (0.698 mL; 4.00 mmol) and (5R,8S)-7-((S)-2-Amino-3,3-dimethyl-butyryl)-10,10-dimethyl-7-aza-dispiro[3.0.4.1]decane-8-carboxylic acid [(1R,2S)-1-(pyrrolidine-1-sulfonylaminocarbonyl)-2-vinyl-cyclopropyl]-amide (0.400 g; 0.67 mmol) in DCM (10 mL) the reaction mixture was stirred for 15 h, the solvent was removed in vacuo and the residue was purified by preparative HPLC (method L) to yield the title compound. LC-MS (method E): Rt=2.91 min; M/z=818 [M+H], HPLC (method A3) Rt=7.18 min
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:15][C:16]1[N:21]=[C:20]([C:22]2[N:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]3=[N:24][C:23]=2[C:31]2[CH:32]=[C:33]([CH:38]=[CH:39][CH:40]=2)[C:34]([O:36]C)=O)[CH:19]=[CH:18][N:17]=1.[F:41][C:42]1[CH:48]=[CH:47][CH:46]=[C:45]([F:49])[C:43]=1[NH2:44].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[F:41][C:42]1[CH:48]=[CH:47][CH:46]=[C:45]([F:49])[C:43]=1[NH:44][C:34](=[O:36])[C:33]1[CH:38]=[CH:39][CH:40]=[C:31]([C:23]2[N:24]=[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]3[C:22]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]([NH:15][C:4]3[CH:5]=[CH:6][C:7]([N:9]4[CH2:14][CH2:13][O:12][CH2:11][CH2:10]4)=[CH:8][C:3]=3[O:2][CH3:1])[N:21]=2)[CH:32]=1
Reactant: Nc1c(F)cccc1F
Reactant: COC(=O)c1cccc(-c2nc3ccccn3c2-c2ccnc(Nc3ccc(N4CCOCC4)cc3OC)n2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(N2CCOCC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Yield: 75 %

Procedure:
To a solution of methyl 3-[3-(2-{[2-(methyloxy)-4-(4-morpholinyl)phenyl]amino}-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]benzoate (65 mg, 0.12 mmol) in 2 mL THF was added 2,6-difluoroaniline (0.065 mL, 0.60 mmol) and a 1M solution of NaHMDS in THF (0.72 mL, 0.72 mmol). When LC/MS showed the reaction to be complete it was concentrated onto silica gel and purified by flash column chromatography to give 57 mg (75%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 9.38 (s, 1H), 8.45 (s, 1H), 8.27 (s, 1H), 8.18 (d, J=5.2 Hz, 1H), 8.01 (d, J=7.6 Hz, 1H), 7.78 (d, J=7.2 Hz, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.60-7.52 (m, 2H), 7.47-7.40 (m, 2H), 7.35-7.30 (m, 1H), 7.11-7.07 (m, 1H), 6.98-6.94 (m, 1H), 6.67 (s, 1H), 6.48-6.43 (m, 2H), 3.78 (s, 3H), 3.73-3.72 (m, 4H), 3.10-3.09 (m, 4H). MS (ESI) m/z=634 [M+H]+.
Reaction SMILES: [CH:1]1([N:4]([CH:26]2[CH2:28][CH2:27]2)[C:5]([C:7]2[N:23]([CH2:24][CH3:25])[C:10]3=[N:11][C:12]([NH:19][C:20]([NH2:22])=[S:21])=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.Br[CH2:30][C:31](=O)[CH2:32][F:33]>>[CH:26]1([N:4]([CH:1]2[CH2:2][CH2:3]2)[C:5]([C:7]2[N:23]([CH2:24][CH3:25])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][CH:30]=[C:31]([CH2:32][F:33])[N:22]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:27][CH2:28]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(NC(N)=S)nc21
Reactant: O=C(CF)CBr
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3nc(CF)cs3)nc21

Procedure:
Prepared from N,N-dicyclopropyl-6-ethyl-1-methyl-4-thioureido-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 2B) and 1-bromo-3-fluoropropan-2-one (example 3A) using the same procedure for 2.
Reaction SMILES: [CH3:1][C:2]1[C:16]([CH3:17])=[CH:15][C:5]2[NH:6][C:7]([C:9]3[C:13]([NH2:14])=[CH:12][NH:11][N:10]=3)=[N:8][C:4]=2[CH:3]=1.[CH3:18][N:19]=[C:20]=[O:21]>O1CCCC1>[CH3:17][C:16]1[C:2]([CH3:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]3[C:13]([NH:14][C:20]([NH:19][CH3:18])=[O:21])=[CH:12][NH:11][N:10]=3)=[N:6][C:5]=2[CH:15]=1
Reactant: Cc1cc2nc(-c3n[nH]cc3N)[nH]c2cc1C
Reactant: CN=C=O
Solvent: C1CCOC1
Product: CNC(=O)Nc1c[nH]nc1-c1nc2cc(C)c(C)cc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine [0.500 g, Example 233(c)] in tetrahydrofuran (5 ml) was treated with methyl isocyanate (0.502 ml) and the mixture stirred at ambient temperature for 16 hours. The mixture was then concentrated in vacuo and the residue was redissolved in 1N potassium hydroxide in a mixture of methanol and tetrahydrofuran (1:3, 5 ml). The mixture was stirred for a further 1 hour, then concentrated and then partitioned between ethyl acetate and water. The aqueous layer was extracted three times with ethyl acetate and the combined organic extracts were washed with brine, then dried over magnesium sulfate, and then evaporated. The residue was subjected to flash column chromatography on silica eluting initially with a mixture of ethyl acetate and hexane (1:1, v/v) and then with ethyl acetate to afford 1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-urea (230 mg) as a white solid. MS: 269 (M+H)+. HPLC (METHOD D1): RT=5.97 minutes. (b) 1-[3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-isopropyl-urea