Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.Br.Br.[CH2:4]([C:6]1[C:7]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([C:23]4[NH:32][C:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH2:31][C:25]=5[N:24]=4)=[N:19][NH:20]3)=[CH:16][CH:15]=2)=[CH:8][C:9]([F:13])=[C:10]([OH:12])[CH:11]=1)[CH3:5].[C:33]([C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][N:36]=1)#[N:34].CCN(C(C)C)C(C)C.C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:4]([C:6]1[CH:11]=[C:10]([OH:12])[C:9]([F:13])=[CH:8][C:7]=1[C:14]1[CH:22]=[C:21]2[C:17]([C:18]([C:23]3[NH:32][C:26]4[CH2:27][CH2:28][N:29]([C:39]([C:38]5[CH:42]=[CH:43][C:35]([C:33]#[N:34])=[N:36][CH:37]=5)=[O:40])[CH2:30][CH2:31][C:25]=4[N:24]=3)=[N:19][NH:20]2)=[CH:16][CH:15]=1)[CH3:5]
Reactant: N#Cc1ccc(C(=O)Cl)cn1
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNCC4)n[nH]c2c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3ccc(C#N)nc3)CC4)n[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.9 %

Procedure:
To a solution of 5-ethyl-2-fluoro-4-[3-(1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 32, 28 mg, 44 μmol) in DMF (1 mL), was added 6-cyano-nicotinoyl chloride (Preparation 46, 20.9 mg, 141 μmol), and DIPEA (31 μL, 176 μmol). The reaction mixture was stirred at room temperature for 18 hours and then saturated aqueous sodium hydrogen carbonate solution (5 mL) was added. The resulting solid was collected by filtration and washed with further saturated aqueous sodium hydrogen carbonate solution. The crude material was purified by HPLC Method A to afford 10.3 mg of the title compound.
Reaction SMILES: [Cl:1](O)(=O)(=O)=O.[CH2:6]([C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([C:30]([OH:32])=[O:31])=[CH:25][CH:24]=2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C(O)(=O)C.[Pd]>[ClH:1].[CH2:6]([CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:30]([OH:32])=[O:31])[CH:27]=2)[NH:22]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: [O-][Cl+3]([O-])([O-])O
Reactant: CCCCCCCCCCCCCCCc1cc2cc(C(=O)O)ccc2[nH]1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCC1Cc2cc(C(=O)O)ccc2N1
Product: Cl

Procedure:
Perchloric acid (3 ml) was added to a hot solution of 2-(n-pentadecyl)indole-5-carboxylic acid in glacial acetic acid (60 ml) and the mixture was hydrogenated at normal pressure using palladium on charcoal (5% w/w, 0.7 g) as catalyst. After 3.5 hours the hot mixture was filtered and the residue was washed with hot glacial acetic acid (30 ml). The pH of the combined filtrates was adjusted to 6 with 10% w/v sodium hydroxide solution. The mixture was extracted with diethyl ether (2×75 ml) and the ether solution was dried over magnesium sulphate. The solution was treated with a saturated solution of hydrogen chloride gas in ethanol to precipitate the hydrochloride. The solid was collected and recrystallised from isopropanol to give (RS)-2-(n-pentadecyl)indoline-5-carboxylic acid hydrochloride (5.6 g) as a white solid, m.p. 165°-170° C. with decomposition.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:10][CH3:11])[CH3:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH4+:15].[OH-].CCOC(C)=O.O>C1COCC1>[CH3:11][O:10][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([NH2:15])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1)[CH3:9]
Reactant: [NH4+]
Reactant: COC(C)c1ccc(F)c([N+](=O)[O-])c1
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(C)c1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.4 %

Procedure:
1-fluoro-4-(1-methoxyethyl)-2-nitrobenzene (664 g, 3.33 mmol) was stirred in THF (10 ml). NH4OH (0.39 ml, 10.0 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. Further 780 ul of NH4OH was added and the reaction mixture was heated at 120° C. for 10 minutes using microwave (Biotage Initiator) and then at 140° C. for 50 minutes. After cooling to room temperature, the reaction mixture was poured into EtOAc/water. The organic layer was washed with brine, dried over MgSO4 and evaporated. The resulting material was purified by flash chromatography on silica eluting with 0% to 50% EtOAc/Hexane to afford the title compound (290 mg, yield: 44%). 1H-NMR (400 MHz, CDCl3) δ 1.42 (d, 3H) 3.22 (s, 3H) 4.24 (q, 1H) 6.05 (br. s., 2H) 6.83 (d, 1H) 7.38 (dd, 2.01 Hz, 1H) 8.04 (d, 1H)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:15][C:16]1[C:17]([OH:26])=[N:18][O:19][C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CC(C)=O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:15][C:16]1[C:17]([O:26][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N:18][O:19][C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3].[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:15][C:16]1[C:17](=[O:26])[N:18]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:19][C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1onc(O)c1CC(NC(=O)OC(C)(C)C)C(=O)OCC
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1on(Cc2ccccc2)c(=O)c1CC(NC(=O)OC(C)(C)C)C(=O)OCC
Product: CCOC(=O)c1onc(OCc2ccccc2)c1CC(NC(=O)OC(C)(C)C)C(=O)OCC
Yield: 41 %
Yield: 18 %

Procedure:
A mixture of ethyl (RS)-2-tert-butoxycarbonylamino-3-(5-ethoxycarbonyl-3-hydroxyisoxazol-4-yl)propionate (3.2 g, 8.6 mmol), K2CO3 (2.4 g, 17.2 mmol) in acetone (40 mL) was heated to reflux temperature. Benzyl bromide (2.2 g, 12.9 mmol) was added, and the mixture was boiled under reflux for 1.5 h. Concentrated in vacuo and subjected to flash chromatography (SiO2, eluent: heptane/ethyl acetate (2:1)) to give ethyl (RS)-2-[(tert-butoxycarbonyl)amino]-3-[3-benzyloxy-5-(ethoxycarbonyl)isoxazol-4-yl]propionate (1.64 g, 41%) and ethyl (RS)-2-[(tert-butoxycarbonyl)amino]-3-(2-benzyl-5-ethoxycarbonyl-2,3-dihydro-3-oxoisoxazol-4-yl)propionate (0.7 g, 18%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[C:6](=[CH:11][CH:12]=1)[C:7]([O:9][CH3:10])=[O:8].[N+:14]([O-])([OH:16])=[O:15].O>C(O)(=O)C>[OH:13][C:5]1[C:4]([N+:14]([O-:16])=[O:15])=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(OC)cc1O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc(OC)c([N+](=O)[O-])c1O
Reaction time: 2 h

Procedure:
A solution of methyl 4-methoxysalicylate (50 g) in glacial acetic acid (700 ml) was treated dropwise with concentrated nitric acid (50 ml) over 15 minutes. After stirring for 2 hours, then standing at room temperature for 18 hours, the mixture was treated with a further aliquot of concentrated nitric acid (10 ml) then stirred for 6 hours. The reaction mixture was diluted with ice then poured into water (1000 ml), then filtered. The solid was dried then subjected to flash chromatography on silica eluting with a mixture of toluene and dichloromethane (2:1, v/v) to give the title compound as a while solid, m.p. 185-187° C.
Reaction SMILES: C(O[C@H:15]1[O:62][C@H:61]([CH2:63][O:64][C:65](=[O:77])[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH3:76])[C@H:46]([O:47][C:48](=[O:60])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[C@H:31]([O:32][C:33](=[O:45])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C@H:16]1[O:17][C:18](=[O:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=O)CCCCCCCCCCC.[C:78]([OH:81])(=[S:80])[CH3:79].FC(F)(F)S(O[Si](C)(C)C)(=O)=O>ClCCl>[C:78]([S:80][C@H:15]1[O:62][C@H:61]([CH2:63][O:64][C:65](=[O:77])[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH3:76])[C@H:46]([O:47][C:48](=[O:60])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[C@H:31]([O:32][C:33](=[O:45])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C@H:16]1[O:17][C:18](=[O:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:81])[CH3:79]
Reactant: CCCCCCCCCCCC(=O)OC[C@H]1O[C@H](OC(=O)CCCCCCCCCCC)[C@H](OC(=O)CCCCCCCCCCC)[C@@H](OC(=O)CCCCCCCCCCC)[C@H]1OC(=O)CCCCCCCCCCC
Reactant: CC(O)=S
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)OC[C@H]1O[C@H](SC(C)=O)[C@H](OC(=O)CCCCCCCCCCC)[C@@H](OC(=O)CCCCCCCCCCC)[C@H]1OC(=O)CCCCCCCCCCC
Reaction time: 20 h
Yield: 7.2 %

Procedure:
To compound 1 (25.0 g, 22.9 mmol) and thioacetic acid (8.5 mL, 114.5 mmol) in dry dichloromethane (100 mL) under argon, was added trimethylsilyl trifluoromethanesulfonate (5.6 mL, 45.8 mmol) at room temperature. After 20 h, the mixture was diluted with dichloromethane (600 mL), washed with saturated sodium hydrogen carbonate (250 mL) and water (2×200 mL), dried with Na2SO4 and concentrated. The residue was purified by column chromatography three times (SiO2, pentane/EtOAc 20:1, 30:1, 40:1) to give 1-S-acetyl-2,3,4,6-tetra-O-lauroyl-1-thio-α-D-galactopyranose (1.59 g, 7.2%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-])=O.C(=O)([O-])[O-].[K+].[K+].[C:26]1([CH2:32][CH2:33][NH2:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[H][H]>C(O)C.[C].[Pd].O>[C:26]1([CH2:32][CH2:33][NH:34][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[N:12]=3)=[CH:4][C:3]=2[NH2:17])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Reactant: NCCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Nc1cc(-c2nc3ccccc3o2)ccc1NCCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 37.4 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (300 mg, 1.16 mmol) in ethanol (5 mL) was added potassium carbonate (176 mg, 1.28 mmol) and 2-phenylethylamine (169 mg, 1.39 mmol), and this was heated to reflux for 4 hours. After the reaction was complete, this was cooled to room temperature, water was added, and the precipitated crystals were filtered, washed with water and then dried. To a tetrahydrofuran solution (5 mL) of the crystals obtained was added 10% palladium-carbon (50 mg). A hydrogen atmosphere was substituted in the flask, and this was stirred at room temperature for 14 hours. After the reaction was complete, this was filtered through Celite and the filtrate was concentrated. The residue obtained was purified by silica gel column chromatography to yield the title compound (143 mg, 37% yield).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][C:21]2[C:26]([Cl:27])=[CH:25][C:24]([NH:28][C:29]([N:31]3[CH2:35][CH2:34][N:33]([CH:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)[C:32]3=[O:42])=[O:30])=[C:23]([F:43])[CH:22]=2)[CH:17]=[CH:16][N:15]=1>C(Cl)Cl.CN(C=O)C.N1C=CC=CC=1>[Cl:27][C:26]1[C:21]([O:20][C:18]2[CH:17]=[CH:16][N:15]=[C:14]([NH:13][C:4](=[O:6])[CH2:3][C:1]#[N:2])[CH:19]=2)=[CH:22][C:23]([F:43])=[C:24]([NH:28][C:29]([N:31]2[CH2:35][CH2:34][N:33]([CH:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[C:32]2=[O:42])=[O:30])[CH:25]=1
Reactant: Nc1cc(Oc2cc(F)c(NC(=O)N3CCN(C4CCOCC4)C3=O)cc2Cl)ccn1
Reactant: N#CCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#CCC(=O)Nc1cc(Oc2cc(F)c(NC(=O)N3CCN(C4CCOCC4)C3=O)cc2Cl)ccn1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 49.7 %

Procedure:
A RT solution of cyanoacetic acid (0.500 g, 5.88 mmol) in DCM (20 mL) and DMF (0.1 mL) was treated drop-wise with oxalyl chloride (1.1 mL, 12.52 mmol), stirred at RT for 2.5 h, then concentrated to dryness. The residue was dissolved in DCM (5 mL), added drop-wise to a 0° C. solution of N-(4-((2-aminopyridin-4-yl)oxy)-5-chloro-2-fluorophenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (0.210 g, 0.467 mmol) in pyridine (10 mL), stirred for 0.5 h, then concentrated to dryness. The residue was dissolved in DCM, washed with satd. NaHCO3 and the aqueous layer extracted with EtOAc (3×). The combined organics were dried over Na2SO4, concentrated to dryness and purified twice via silica gel chromatography (MeOH/DCM, then MeOH/EtOAc). The material was further purified via silica gel chromatography (MeOH/DCM) to afford N-(5-chloro-4-((2-(2-cyanoacetamido)pyridin-4-yl)oxy)-2-fluorophenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (120 mg, 49%). MS (ESI) m/z: (M+H+): 516.8.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[C:19]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])=[O:10])[S:6][CH:7]=1.[CH3:26][N:27]([CH3:32])[CH2:28][C:29](O)=[O:30]>>[CH:21]1([C:19]([C:13]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:12]=2[NH:11][C:9](=[O:10])[NH:8][C:5]2[S:6][CH:7]=[C:3]([CH2:2][NH:1][C:29](=[O:30])[CH2:28][N:27]([CH3:32])[CH3:26])[N:4]=2)=[O:20])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CN(C)CC(=O)O
Reactant: Cc1ccc(NC(=O)Nc2nc(CN)cs2)c(C(=O)C2CCCC2)c1
Product: Cc1ccc(NC(=O)Nc2nc(CNC(=O)CN(C)C)cs2)c(C(=O)C2CCCC2)c1
Yield: 77.6 %

Procedure:
N-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-ylmethyl}-2-dimethylamino-acetamide (86 mg, 78%) was prepared from 1-(4-aminomethyl-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (90 mg, 0.25 mmol) and N,-N-dimethyl glycine (0.30 mg, 0.30 mmol) following the general procedure K.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)[NH:5][C:4](=[O:16])[CH:3]=1.N1C=CC=CC=1.[S-:23][C:24]#[N:25].[K+].BrBr>CN(C=O)C>[NH2:25][C:24]1[S:23][C:3]2[C:4](=[O:16])[NH:5][C:6]([S:8][CH2:9][C:10]3[N:11]=[C:12]([CH3:15])[S:13][CH:14]=3)=[N:7][C:2]=2[N:1]=1
Reactant: N#C[S-]
Reactant: Cc1nc(CSc2nc(N)cc(=O)[nH]2)cs1
Agent: BrBr
Agent: [K+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1nc(CSc2nc3nc(N)sc3c(=O)[nH]2)cs1
Yield: 29.2 %

Procedure:
The product from step (a) (24.3 g) was stirred in dry DMF (400 ml) with pyridine (13.1 ml) and potassium thiocyanate (37.1 g) at 0C. Bromine (4.5 ml) was added over 1 hr and the mixture kept at 0C for a further 2 hrs. The mixture was poured onto water to give a solution which was then evaporated to low volume. Water was added to give a precipitate which was collected. The solid was dissolved in dilute hydrochloric acid and reprecipitated by the addition of sodium bicarbonate solution. The solid was collected, washed with water and dried to afford the sub-title compound (8.7 g)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([NH:7][NH2:8])=[O:6].Br[CH2:14][CH2:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[C:19]([O:25][CH3:26])[CH:18]=1.[F:27][C:28]([F:38])([F:37])[C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1>>[CH3:26][O:25][C:19]1[CH:18]=[C:17]([O:16][CH2:15][CH2:14][NH:34][CH2:33][C:32]2[CH:31]=[CH:30][C:29]([C:28]([F:27])([F:37])[F:38])=[CH:36][CH:35]=2)[CH:24]=[CH:23][C:20]=1[CH:21]=[N:8][NH:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][C:11]([OH:12])=[C:2]([Cl:1])[CH:3]=1
Reactant: COc1cc(OCCBr)ccc1C=O
Reactant: NNC(=O)c1ccc(O)c(Cl)c1
Reactant: NCc1ccc(C(F)(F)F)cc1
Product: COc1cc(OCCNCc2ccc(C(F)(F)F)cc2)ccc1C=NNC(=O)c1ccc(O)c(Cl)c1

Procedure:
This compound was prepared analogously to the compound described in the previous example starting from resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (resin—[building block 1]) (2 g, ˜2 mmoles), 4-(2-bromoethoxy)-2-methoxybenzaldehyde ([building block 2]) (0.73 g, 1.5 equivs.), and 4-trifluoromethylbenzylamine ([building block 3]) (3.3 g, 10 equivs.). After cleavage with 50% trifluoroacetic acid, the residue (1 g) was purified by column chromatography on silica gel (20 g) eluting with a mixture of 25% aq. ammonia, ethanol and dichloromethane (1:9:115). This afforded 130 mg of the title compound.
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].Cl.[CH3:7][N:8]1[C:17]2[NH:16][C:15]3[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:14]=3[N:13]([C:23]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)=[C:27]([CH3:41])[CH:26]=3)=[O:24])[CH2:12][C:11]=2[CH:10]=[N:9]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CCN(C(C)C)C(C)C.CN(C=O)C>[CH3:7][N:8]1[C:17]2[NH:16][C:15]3[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:14]=3[N:13]([C:23]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH:35]4[CH2:36][CH2:37][N:38]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:39][CH2:40]4)=[C:27]([CH3:41])[CH:26]=3)=[O:24])[CH2:12][C:11]=2[CH:10]=[N:9]1
Reactant: CC(C)C=O
Reactant: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)c1ccc(OCCCC2CCNCC2)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)c1ccc(OCCCC2CCN(CC(C)C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of isobutyraldehyde (0.36 mg, 0.005 mmol) in 1,2-dichloroethane (0.05 ml) was added to a solution of (3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[3-methyl-4-(3-piperidin-4-yl-propoxy)-phenyl]-methanone hydrochloride (2.6 mg, 0.005 mmol) in 1,2-dichloroethane (0.05 ml) and DIEA (0.0026 ml). The mixture was stirred at room temperature for 1 h then a solution of sodium triacetoxyborohydride (1.59 mg, 0.0075 mmol) in DMF (0.05 ml) was added. The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=530.5
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[C:19]2[CH:20]([CH3:24])[NH:21][CH2:22][CH2:23][C:18]=2[S:17][CH:16]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:22][CH2:23][C:18]4[S:17][CH:16]=[C:15]([F:14])[C:19]=4[CH:20]3[CH3:24])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2scc(F)c21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1c2c(F)csc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 3-fluoro-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine to provide the title compound in moderate yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:35])[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:4][CH:3]=1.[N:36]1([C:42](=[O:50])[CH2:43][N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:35])[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:47]3[CH2:48][CH2:49][N:44]([CH2:43][C:42]([N:36]4[CH2:37][CH2:38][O:39][CH2:40][CH2:41]4)=[O:50])[CH2:45][CH2:46]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(C2=NC(C)(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)Cl)c(OC(C)C)c1
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Product: COc1ccc(C2=N[C@@](C)(c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)N2CCN(CC(=O)N3CCOCC3)CC2)c(OC(C)C)c1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4-methyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) to give the title compound. LC-MS: 708.3 [(M+H)+]
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:16])[C:12]([Cl:15])([Cl:14])[Cl:13])(=O)[CH3:2].[NH2:17][CH2:18][CH2:19][OH:20]>C(O)C>[Cl:13][C:12]([Cl:15])([Cl:14])[C:11]([NH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:1](=[N:17][CH2:18][CH2:19][OH:20])[CH3:2])=[O:16]
Reactant: CC(=O)c1ccccc1NC(=O)C(Cl)(Cl)Cl
Reactant: NCCO
Solvent: CCO
Product: CC(=NCCO)c1ccccc1NC(=O)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 59 %

Procedure:
A mixture of 60 parts of N-(2-acetylphenyl)-2,2,2-trichloroacetamide, 14 parts of 2-aminoethanol and 200 parts of ethanol is stirred first for 5.50 hours at reflux and further overnight while the temperature is allowed to cool to room temperature. The formed precipitate is filtered off. The product is washed with 2,2'-oxybispropane and dried in vacuo, yielding 40 parts (59%) of 2,2,2-trichloro-N-[2-[1-[(2-hydroxyethyl)imino]ethyl]phenyl]acetamide; mp. 182° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:30]=[CH:29][C:14]([C:15]([O:17]C3C([Cl:24])=C(Cl)C(Cl)=C(Cl)C=3Cl)=O)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([N:38]1[CH2:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][C:44]=2[F:47])[CH2:39]1)C1C=CC=CC=1>CC(O)C.[OH-].[OH-].[Pd+2]>[ClH:24].[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([N:38]3[CH2:46][C:45]4[C:40](=[CH:41][CH:42]=[CH:43][C:44]=4[F:47])[CH2:39]3)=[O:17])=[CH:29][CH:30]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Fc1cccc2c1CN(Cc1ccccc1)C2
Reactant: O=C(Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl)c1ccc(OCCCN2CCCCC2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(C)O
Product: Cl
Product: O=C(c1ccc(OCCCN2CCCCC2)cc1)N1Cc2cccc(F)c2C1
Reaction time: 8 h
Yield: 17.6 %

Procedure:
A mixture of pentachlorophenyl 4-(3-piperdin-1-ylpropoxy)benzoate (D10) (500 mg) and N-benzyl-4-fluoroisoindoline (D9) (200 mg) in IPA (10 ml) at rt was treated with poly(methylhydrosiloxane) (0.16 ml) and palladium hydroxide on carbon (30 mg, 20% Pd) and stirred overnight. The mixture was filtered and evaporated. The residue was redissolved in EtOAc (20 ml), washed with saturated sodium hydrogen carbonate solution (10 ml), water (2×10 ml), brine (10 ml), dried (MgSO4) and evaporated. The residue was chromatographed on a silica gel flash column [step gradient 2-8% MeOH (containing 10% 0.880 ammonia solution) in DCM]. The required fractions were evaporated, then redissolved in DCM and treated with excess 4M HCl in dioxan. The title compound (E55) (65 mg) was obtained by crystallisation from acetone. MS electrospray (+ion) 383 (MH+). 1H NMR δ (DMSO-d6): 10.15 (1H, m), 7.09-7.65 (7H, m),4.89 (4H, m), 4.13 (2H, t, J=6 Hz), 3.46 (2H, m), 3.16 (2H, m), 2.90 (2H, m), 2.22 (2H, m), 1.79 (5H, m), 1.42 (1H, m).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].C1(C)C=CC(S([CH2:18][N+:19]#[C-:20])(=O)=O)=CC=1.[H-].[Na+]>CCOCC.CS(C)=O.CCOCC.O>[CH3:4][C:3]1[C:2]([C:1]([O:6][CH2:7][CH3:8])=[O:5])=[CH:18][NH:19][CH:20]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: C/C=C/C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1c[nH]cc1C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
A solution of 11.86 g (0.1 moles) of ethyl crotonate and 19.50 g (0.1 moles) of p-toluenesulfonylmethylisocyanide in 500 mL of a 2:1 ether/dimethylsulfoxide was added dropwise into a suspension of 6.8 g of sodium hydride (60% mineral oil dispension, 0.17 moles) in ether at room temperature. Upon completion of addition the reaction mixture was stirred for 30 min and dilute with 400 mL of water. The aqueous layer was extracted with 3×100 mL of ether. The combined ether extracts were passed through a column of alumina eluting with dichloromethane. The organic solvent was evaporated and the resulting residue was solidified on standing. The solid was washed with hexane and dried at 40° C. in vacuum oven overnight to yield 12.38 g (80%) of the title compound.