Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:34]([CH3:36])[CH3:35])[C:9]1[S:10][C:11]([C:14]2[CH:15]=[C:16]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:17]3[N:18]([CH:20]=[C:21]([C:23]([O:25]CC)=[O:24])[N:22]=3)[CH:19]=2)=[CH:12][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C:6]([N:8]([CH:34]([CH3:36])[CH3:35])[C:9]1[S:10][C:11]([C:14]2[CH:15]=[C:16]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:17]3[N:18]([CH:20]=[C:21]([C:23]([OH:25])=[O:24])[N:22]=3)[CH:19]=2)=[CH:12][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cn2cc(-c3cnc(N(C(=O)OC(C)(C)C)C(C)C)s3)cc(-c3ccccc3)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)N(C(=O)OC(C)(C)C)c1ncc(-c2cc(-c3ccccc3)c3nc(C(=O)O)cn3c2)s1
Yield: 98.2 %

Procedure:
A solution of ethyl 6-(2-(tert-butoxycarbonyl-(isopropyl)amino)thiazol-5-yl)-8-phenylimidazo[1,2-a]pyridine-2-carboxylate (1.00 g, 2.0 mmol) in THF/MeOH (2:1, 15 mL) was treated with 1 N NaOH (5 mL, 5 mmol) at room temperature for 5 hours. The organic solvents were removed under vacuum and the aqueous residue was acidified with 1 N HCl and the solids extracted into CH2Cl2. The extracts were washed with water and concentrated to give 940 mg of 6-(2-(tert-butoxycarbonyl(isopropyl)-amino)thiazol-5-yl)-8-phenylimidazo[1,2-a]pyridine-2-carboxylic acid as a yellow solid. LCMS (Conditions C): 3.98 min (RT); (M+H)+=479.43 (100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:26])[C:5]([CH3:25])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=O)[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]1[C:4](=[O:26])[C:5]([CH3:25])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][C:22]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:24])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: C1COCCN1
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(CCCC(=O)O)c2)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(Cc2cccc(CCCC(=O)N3CCOCC3)c2)=C(C)C1=O
Yield: 33 %

Procedure:
4-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]-n-butyric acid (73 mg, 0.20 mmol) obtained in Example 62 and morpholine (0.026 ml, 0.30 mmol) were used, and a method similar to that described in Example 46 was employed to obtain the title compound (28 mg, 0.066 mmol, yield 33%).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([NH2:9])[C:3]=1[N+:10]([O-:12])=[O:11].[Si:13]([O:20][C@@H:21]1[C@H:25]([CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:24][C@@H:23]([NH2:35])[CH2:22]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].CCN(C(C)C)C(C)C>C(O)C>[Si:13]([O:20][C@@H:21]1[C@H:25]([CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:29])[CH3:30])[CH2:24][C@@H:23]([NH:35][C:2]2[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([NH2:9])[C:3]=2[N+:10]([O-:12])=[O:11])[CH2:22]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](N)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Nc2c(Cl)cnc(N)c2[N+](=O)[O-])C[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 82.6 %

Procedure:
A solution of 4,5-dichloro-3-nitropyridin-2-amine (0.0365 g, 0.000175 mol) (Johansson, H; Lawitz, K; Nikitidis, G; Sjoe, P; Storm, P. PCT Int. Application WO2004/016611), (1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]-oxy}methyl)cyclopentanamine (0.0947 g, 0.000263 mol) and DIPEA (0.0907 g, 0.000702 mol) in ethanol (10.0 mL) was refluxed overnight. The reaction was concentrated and purified by flash chromatography (30% EtOAc/hexanes) to afford the title compound (0.0768 g, 82%) as a yellow solid.
Reaction SMILES: [CH3:1]C(C)(C)C#C/C=C/C/C(=C\CCCCOC1C=CC=C(C2C=CSC=2)C=1)/CO.C(I)C.[CH3:33][C:34]([CH3:61])([CH3:60])[C:35]#[C:36]/[CH:37]=[CH:38]/[CH2:39]/[C:40](=[CH:43]\[CH2:44][CH2:45][CH2:46]/[CH:47]=[CH:48]/[C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([C:55]2[CH:59]=[CH:58][S:57][CH:56]=2)[CH:50]=1)/[CH2:41][OH:42].CI>>[CH3:1][O:42][CH2:41]/[C:40](/[CH2:39]/[CH:38]=[CH:37]/[C:36]#[C:35][C:34]([CH3:61])([CH3:60])[CH3:33])=[CH:43]/[CH2:44][CH2:45][CH2:46]/[CH:47]=[CH:48]/[C:49]1[CH:50]=[C:51]([C:55]2[CH:59]=[CH:58][S:57][CH:56]=2)[CH:52]=[CH:53][CH:54]=1
Reactant: CC(C)(C)C#C/C=C/C/C(=C\CCC/C=C/c1cccc(-c2ccsc2)c1)CO
Reactant: CC(C)(C)C#C/C=C/C/C(=C\CCCCOc1cccc(-c2ccsc2)c1)CO
Solvent: CCI
Solvent: CI
Product: COC/C(=C/CCC/C=C/c1cccc(-c2ccsc2)c1)C/C=C/C#CC(C)(C)C

Procedure:
The compounds of Examples 30 and 31 are obtained by carrying out the same reaction as in Example 29 except that (E,E)-2-(6,6-dimethyl-2-hepten-4-ynyl)-7-[3-(3-thienyl)phenoxy]-2-hepten-1-ol and/or ethyl iodide are used in place of (E,E,E)-2-(6,6-dimethyl-2-hepten-4-ynyl)-8-[3-(3-thienyl)phenyl]-2,7-octadien-1-ol and/or methyl iodide which is the raw material compound used in the above reaction.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=O)[NH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[OH:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][C:33]=1[CH3:34])[NH2:30]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:30][C:29]3[CH:31]=[CH:32][C:33]([CH3:34])=[C:27]([OH:26])[CH:28]=3)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCc1ccccc1
Reactant: Cc1ccc(N)cc1O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COc1cc2c(Nc3ccc(C)c(O)c3)ncnc2cc1OCc1ccccc1
Yield: 65.9 %

Procedure:
A mixture of 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (5.18 g, 18.4 mmol), (prepared as described for the starting material in Example 4), DMF (1 ml) and thionyl chloride (70 ml) was heated at reflux under argon for 2 hours. The mixture was allowed to cool, excess thionyl chloride was removed by evaporation and the residue azeotroped to dryness with toluene. The resulting crude 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride was suspended in isopropanol (50 ml) and 3-hydroxy4-methylaniline (2.60 g, 21.1 mmol) added. The mixture was heated at reflux for 3 hours and then allowed to cool. The precipitated product was collected by filtration, washed with isopropanol and dried to give 7-benzyloxy-4-(3-hydroxy-4-methylanilino)-6-methoxyquinazoline (4.7 g, 60%).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1)#[N:2].CN([C:15]([O:19][N:20]1N=NC2C=CC=N[C:21]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN>C(Cl)Cl.O>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:20]([O:19][CH3:15])[CH3:21])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.9 %

Procedure:
To a stirred solution of 4-cyanobenzoic acid (5.0 g, 34.0 mmol) in DCM (75 mL) were added HATU (19.40 g, 51.0 mmol), N-methoxy, N-methylamine (4.90 g, 51.0 mmol) and TEA (14.30 mL, 102.0 mmol) at RT under a nitrogen atmosphere. The reaction mixture was then stirred at RT for 3 h, diluted with water and the aqueous layer was extracted with DCM (3×100 mL). The combined organic extracts were washed with water (60 mL) and brine (30 mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to afford 4-cyano-N-methoxy-N-methylbenzamide (6.2 g, 96%) as a yellow color oil.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([NH:9][CH2:10][CH:11]3[CH2:15][CH2:14][NH:13][CH2:12]3)[O:8][C:4]=2[CH:3]=1.Cl.[CH3:19][O:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[C:22]=1[C:23](Cl)=[O:24].CCN(CC)CC>C(Cl)Cl>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([NH:9][CH2:10][CH:11]3[CH2:15][CH2:14][N:13]([C:23]([C:22]4[C:26]([O:30][CH3:31])=[CH:27][CH:28]=[CH:29][C:21]=4[O:20][CH3:19])=[O:24])[CH2:12]3)[O:8][C:4]=2[CH:3]=1
Reactant: Clc1ccc2nc(NCC3CCNC3)oc2c1
Reactant: COc1cccc(OC)c1C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(OC)c1C(=O)N1CCC(CNc2nc3ccc(Cl)cc3o2)C1
Yield: 22.3 %

Procedure:
A mixture of 20 mg (0.07 mmol) (6-chloro-benzooxazol-2-yl)-pyrrolidin-3-ylmethyl-amine; hydrochloride, 15 mg (0.77 mmol) 2,6-dimethoxybenzoyl chloride and 10 mg (0.1 mmol) NEt3 in 2 mL DCM was shaken at room temperature over night. After evaporation the residue was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid. The product containing fractions were evaporated to yield 6.5 mg (22%) of the title compound. MS (m/e): 416.2 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([N:12]3[CH2:17][CH2:16][CH:15]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:14][CH2:13]3)[NH:9]2)=[CH:5][C:4]=1[C:25]([NH2:27])=[O:26].[H-].[Na+].Cl.[CH2:31]([N:33]([CH2:37][CH3:38])[CH2:34][CH2:35]Cl)[CH3:32].O>CN(C=O)C>[CH2:31]([N:33]([CH2:37][CH2:38][N:9]1[C:10]2[C:6](=[CH:5][C:4]([C:25]([NH2:27])=[O:26])=[C:3]([O:2][CH3:1])[CH:11]=2)[CH:7]=[C:8]1[N:12]1[CH2:13][CH2:14][CH:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:16][CH2:17]1)[CH2:34][CH3:35])[CH3:32]
Reactant: CCN(CC)CCCl
Reactant: COc1cc2[nH]c(N3CCC(Cc4ccccc4)CC3)cc2cc1C(N)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCn1c(N2CCC(Cc3ccccc3)CC2)cc2cc(C(N)=O)c(OC)cc21
Reaction time: 18 h
Yield: 55.2 %

Procedure:
0.3 g (0.862 mmol) of 6-methoxy-(4-benzylpiperidinyl)-indole-5-carboxamide was dissolved in 20 mL dry DMF. It was cooled in an ice-bath and reacted with 0.12 g NaH (3 mmol, 60% suspension). 0.172 mg (1 mmol) of 2-(diethylamino)-ethylchloride hydrochloride was added and the mixture was stirred for 18 h. The reaction mixture was poured in to water and extracted with dichloromethane (3×75 mL). The combined extract was washed again with water, dried over anhydrous MgSO4, evaporated and purified by silica gel chromatography on a chromatotron using CH2Cl2-Methanol (95:5) to yield 0.22 g of the desired product. It was converted to the HCl salt and lyophilized, M+ 448.
Reaction SMILES: [Br:1]Br.[CH2:3]([C:7]12[CH2:19][C:18](=[O:20])[CH:17]=[C:8]1[C:9]1[CH:10]=[CH:11][C:12]([OH:16])=[CH:13][C:14]=1[CH2:15]2)[CH2:4][CH2:5][CH3:6].C([O-])(O)=O.[Na+]>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:1][C:17]1[C:18](=[O:20])[CH2:19][C:7]2([CH2:3][CH2:4][CH2:5][CH3:6])[CH2:15][C:14]3[CH:13]=[C:12]([OH:16])[CH:11]=[CH:10][C:9]=3[C:8]=12
Reactant: CCCCC12CC(=O)C=C1c1ccc(O)cc1C2
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCCC12CC(=O)C(Br)=C1c1ccc(O)cc1C2
Temperature: 2.5 °C
Reaction time: 0.75 h

Procedure:
Bromine (0.005 mL, 0.095 mmol) was added to an ice-cold mixture of 8a-butyl-6-hydroxy-8,8a-dihydrocyclopenta[a]inden-2(1H)-one (23 mg, 0.095 mmol) and NaHCO3 (40 mg, 0.48 mmol) in CCl4 (0.3 mL). The resulting mixture was stirred at 0-5° C. for 45 minutes, then diluted with CH2Cl2 (30 mL) and washed with water (30 mL). The aqueous phase was back-extracted with CH2Cl2 (2×10 mL). The combined organics were washed with saturated aqueous Na2S2O3, dried over MgSO4, filtered, and evaporated under vacuum to provide an off-white solid. Recrystallization from hexane/CH2Cl2 afforded 3-bromo-8a-butyl-6-hydroxy-8,8a-dihydrocyclopenta[a]inden-2(1H)-one as small, white needles.
Reaction SMILES: [NH2:1][C:2]1[CH:37]=[CH:36][C:5]([C:6]([N:8]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>>[C:38]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27](=[O:35])[C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[CH2:23][CH2:22]2)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=2)=[O:7])=[CH:36][CH:37]=1)(=[O:40])[CH3:39]
Reactant: Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2cccc(C(F)(F)F)c2)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2cccc(C(F)(F)F)c2)cc1
Yield: 101.4 %

Procedure:
Using 4-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(3-trifluoromethylphenyl)benzamide (256.0 mg, 0.474 mmol) and acetic anhydride (0.13 ml, 1.40 mmol), the procedure of Inventive Example 94 was repeated to obtain 267.0 mg (96.2%) of the title compound in a colorless amorphous form.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[N:10]1([NH2:19])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1.O>CN1CCCC1=O>[Cl:9][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:19][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)[C:7]=1[NH2:8]
Reactant: Nn1ccc2ccccc21
Reactant: Nc1c(Cl)ncnc1Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: Nc1c(Cl)ncnc1Nn1ccc2ccccc21
Yield: 78.9 %

Procedure:
A solution of 8 g of 4,6-dichloro-5-pyrimidinamine, and 7 g of 1H-indol-1-amine, in 100 ml N-methyl-2-pyrrolidone was stirred at 130°-135° for seven hours, then cooled, stirred with water and extracted with ether. The organic extract was washed with water and saturated sodium chloride, dried (anhy. MgSO4), filtered and evaporated to 16 g of a residue. This was purified by flash chromatography (silica, 5% ethyl acetate/DCM) to give 10 g solid. This was combined with product obtained from other condensations and purified by HPLC (silica 5% ethyl acetate/DCM) to give 7 g oil. This oil was crystallized from ether-petroleum ether to give 2.2 g solid, 6-Chloro-N4 -(1H-indol-1-yl)-4,5-pyrimidinediamine, m.p. 175°-176°.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([C:22]1[S:23][C:24]([CH2:27][N:28]=[N+]=[N-])=[CH:25][CH:26]=1)#[N:21]>C1COCC1.O>[C:20]([C:22]1[S:23][C:24]([CH2:27][NH2:28])=[CH:25][CH:26]=1)#[N:21]
Reactant: N#Cc1ccc(CN=[N+]=[N-])s1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(CN)s1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Triphenylphosphine (Aldrich, 5.7 g) was added to a solution of 2-cyano-5-(azidomethyl)thiophene (compound 25, 2.5 g, 10 mmol) in THF (Aldrich, 40 ml) and water (10 ml) at 0° C. The resulting solution was allowed to warm to room temperature and stirred at ambient temperature for 10 hours. RP HPLC purification led to the title compound (2.3 g, 94%). MS (electrospray): 139 (M+1); 1HNMR (CDCl3): δ 4.01 (s, 2H), 4.75 (br s, 2H, NH2), 6.82 (d, 1H, J=3.5 Hz), 7.08 (d, 1H, J=3.5 Hz).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4](=[N:6][OH:7])Cl.[CH3:12][O:13][C:14](=[O:18])[C:15]#[C:16][CH3:17].CCN(CC)CC>CCOCC>[CH3:12][O:13][C:14]([C:15]1[C:4]([C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=2[F:1])=[N:6][O:7][C:16]=1[CH3:17])=[O:18]
Reactant: ON=C(Cl)c1ccccc1F
Reactant: CC#CC(=O)OC
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)c1c(-c2ccccc2F)noc1C
Temperature: 25 °C
Reaction time: 17 h
Yield: 57.2 %

Procedure:
To a solution (0° C., N2) of 2-fluorobenzoylchloride oxime (0.50 g, 2.9 mmol) and methyl-2-butynoate (0.57 g, 5.8 mmol) in Et2O (15 ml) was added a solution of Et3N (0.52 ml) in Et2O (2 ml) over a period of 1 h followed by warming to room temperature while stirring overnight (17 h). The reaction was diluted with Et2O, washed (H2O then brine), dried (MgSO4), filtered, and concentrated. Column chromatography (silica gel, hexanes/EtOAc gradient) gave the title compound (0.39 g, 58%).
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[CH:9]=[C:8]([Cl:12])[NH:7][C:6]1=[O:13])[CH2:2][CH2:3][CH3:4].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[N:32]([C:33]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:31]=[N:30][N:29]=2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([N:5]1[C:10](=[O:11])[CH:9]=[C:8]([Cl:12])[N:7]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:31]=[N:30][N:29]=3)=[CH:20][CH:21]=2)[C:6]1=[O:13])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)cc(Cl)[nH]c1=O
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCn1c(=O)cc(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 58.8 %

Procedure:
A mixture of 3-butyl-6-chloropyrimidine-2,4(1H,3H)-dione (1 g), 4-bromomethyl-2'-(N-trityltetrazol-5-yl)biphenyl (3.02 g) and potassium carbonate (0.82 g) in DMF (50 ml) was stirred at 60° C. for 4 hours. The reaction mixture was concentrated to dryness in vacuo and then the residue was dissolved in methylene chloride. The insoluble material was removed from the reaction mixture by filtration and the filtrate was concentrated to dryness. The resulting residue was purified by column chromatography on silica gel and recrystallized from ethyl acetate-hexane to give colorless prisms (1.97 g, 59%).
Reaction SMILES: [NH:1]=[C:2]([C:10]1[N:11]=[CH:12][N:13]2[C:18](=[O:19])[N:17]([CH3:20])[N:16]=[N:15][C:14]=12)[S:3][CH2:4][C:5](=O)[C:6]([OH:8])=O.ClC(OCC(C)C)=O.C(N(CC)CC)C.[CH:36]1([NH2:39])[CH2:38][CH2:37]1>C1COCC1>[CH:36]1([NH:39][C:6]([C:5]2[N:1]=[C:2]([C:10]3[N:11]=[CH:12][N:13]4[C:18](=[O:19])[N:17]([CH3:20])[N:16]=[N:15][C:14]=34)[S:3][CH:4]=2)=[O:8])[CH2:38][CH2:37]1
Reactant: Cn1nnc2c(C(=N)SCC(=O)C(=O)O)ncn2c1=O
Reactant: NC1CC1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1nnc2c(-c3nc(C(=O)NC4CC4)cs3)ncn2c1=O
Reaction time: 1 h
Yield: 48.7 %

Procedure:
To a solution of 3-(imino(3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazin-8-yl)methylthio)-2-oxopropanoic acid (0.500 g; 1.8 mmol) in dry THF (30 mL) under nitrogen was added isobutyl chloroformate (0.47 mL; 3.6 mmol), followed by triethylamine (0.51 mL; 3.6 mmol). The mixture was stirred for 1 hours, and then cyclopropylamine (0.206 g; 3.6 mmol) was added, and stirring continued for a further 3 hours. The precipitate was filtered, washed with water (5×20 mL) and diethyl ether (2×15 mL) to yield the title compound as a pale yellow solid (0.278 g; 49%). δH (DMSO-d6) 8.94 (1H, s), 8.41 (1H, s), 8.22 (1H, d, J=4.3), 3.89 (3H, s), 2.88 (1H, m), 0.66-0.76 (4H, m).
Reaction SMILES: [CH3:1][C@H:2]([CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=1[OH:15])[CH2:3][OH:4].[C:16](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:1][C@H:2]([CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=1[O:15][CH3:16])[CH2:3][OH:4]
Reactant: O=C([O-])[O-]
Reactant: COc1cccc(SC[C@@H](C)CO)c1O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cccc(SC[C@@H](C)CO)c1OC
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
0.43 g (0.0019 mol) of 2-(S)-methyl-3-(2-hydroxy-3-methoxyphenylthio)propan-1-ol (XXg), 10 ml of acetone and 0.26 g (0.0019 mol) of potassium carbonate are introduced into a round-bottomed flask kept under an inert atmosphere. After 15 minutes, 0.12 ml (0.0019 mol) of methyl iodide is introduced and the mixture is heated at 60° C. for 8 hours. The mixture is concentrated under reduced pressure. The residue is taken up in water and the aqueous phase is extracted with dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered and concentrated. The residue obtained is used without additional purification in the following stage.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12](/[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:22][CH:21]=3)\[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.Br[CH2:34][C:35]([O:37][CH3:38])=[O:36]>>[CH3:38][O:37][C:35]([CH2:34][NH:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12](/[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]4[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]4)=[CH:22][CH:21]=3)\[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1)=[O:36]
Reactant: Nc1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCCC2)cc1)c1ccccc1
Reactant: COC(=O)CBr
Product: COC(=O)CNc1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared from 6-amino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-2-indolinone and methyl bromoacetate
Reaction SMILES: NC[C@@H](C1C=CC(O)=C2C=1C=CC(=O)N2)O[Si](C(C)(C)C)(C)C.[N:24]([CH2:27][C@@H:28]([C:37]1[CH:38]=[CH:39][C:40]([O:48]CC2C=CC=CC=2)=[C:41]([NH:43][S:44]([CH3:47])(=[O:46])=[O:45])[CH:42]=1)[O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])=[N+]=[N-]>>[NH2:24][CH2:27][C@@H:28]([C:37]1[CH:38]=[CH:39][C:40]([OH:48])=[C:41]([NH:43][S:44]([CH3:47])(=[O:45])=[O:46])[CH:42]=1)[O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN=[N+]=[N-])c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Agent: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Product: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c(NS(C)(=O)=O)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 2, using Intermediate 16 in place of Intermediate 1. The compound was used with no further purification. ES/MS calcd. for C15H29N2O4SSi+ 361.2. found m/z=361 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1I)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].[C:15]([Cu])#[N:16]>CN(C=O)C.C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[C:15]#[N:16])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4]
Reactant: N#C[Cu]
Reactant: COC(=O)c1[nH]c2ccccc2c1I
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1[nH]c2ccccc2c1C#N
Temperature: 80 °C

Procedure:
To a solution of 2 g 3-Iodo-1H-indole-2-carboxylic acid methyl ester in 10 ml DMF and 20 ml THF, 1.5 g CuCN, 434 mg Et4NCN and 461 mg DPPF were added and the mixture was purged with argon for 15 min. Then, 254 mg Pd2(dba)3 were introduced and the reaction was heated to 80° C. for 5 h. Finally, 10 ml saturated NaHCO3 solution were added and the mixture was filtered through a chem elut® cartridge by elution with DCM. After subsequent removal of the solvent under reduced pressure the residue was purified by chromatography on silica gel with ethylacetate as eluent. The fractions containing the product were evaporated to yield a white solid. Yield: 1.2 g.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:18][CH2:17]1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([F:44])[C:30]=1[OH:45].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:28].[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:17][CH2:18][C@H:19]([CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:20][CH2:21]2)[CH:32]=[C:31]([F:44])[C:30]=1[OH:45]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CN2CCCC2)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1N[C@H]1CC[C@H](CN2CCCC2)CC1

Procedure:
Following general procedure II, 1-(6-chloro-4-{[trans-4-(pyrrolidin-1-ylmethyl)-cyclohexyl]amino}-1,5-naphthyridin-3-yl)ethanone (86 mg, 0.22 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (90 mg, 0.33 mmol) followed by formation of the dihydrochloride salt to afford the desired product (75 mg, 69%) as a light brown solid: 1H NMR (500 MHz, CD3OD) δ 9.14 (s, 1H), 8.45 (d, J=9.0 Hz, 1H), 8.34 (d, J=9.0 Hz, 1H), 8.02 (s, 1H), 7.88 (dd, J=11.5, 2.0 Hz, 1H), 5.74-5.64 (m, 1H), 3.74-3.68 (m, 2H), 3.18-3.10 (m, 4H), 2.76 (s, 3H), 2.47-2.41 (m, 2H), 2.22-1.98 (m, 7H), 1.74-1.62 (m, 2H), 1.47-1.34 (m, 2H); ESI MS m/z 497 [M+H]+; HPLC 96.6% (AUC), tR=9.90 min.