Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[O:6][CH:5]1[CH2:4][N:3]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:2]2.N1C=CC=CC=1.[FH:23]>ClCCl>[F:23][C@H:1]1[C@H:5]([OH:6])[CH2:4][N:3]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2]1
Reactant: O=C(OCc1ccccc1)N1CC2OC2C1
Reactant: F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OCc1ccccc1)N1C[C@@H](O)[C@H](F)C1
Reaction time: 8 h

Procedure:
benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (10.5 g, 47.9 mmol) and pyridine-hydrogen fluoride (14.2 g, 144.0 mmol) were added to a Teflon bottle containing dichloromethane and stirred vigorously overnight. After 20 hours, the reaction was slowly and carefully quenched with excess saturated solution of NaHCO3 over several minutes and allowed to stir for one hour, and then the organic layer was isolated and washed with NaHCO3 and a solution of brine. The combined organic layers were dried over MgSO4, filtered and evaporated to yield an oil. This crude oil was purified on silica gel using ethyl acetate-hexane to produce 2.0 g (17% isolated yield) of the desired product as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[C:13]([O:17][CH3:18])[C:14]=1[O:15][CH3:16])[CH:6]=[C:7]([C:10]#[N:11])[C:8]#[N:9].[OH:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][CH:24]=[N:25]2>>[NH2:9][C:8]1[O:19][C:20]2[C:21]3[CH:22]=[CH:23][CH:24]=[N:25][C:26]=3[CH:27]=[CH:28][C:29]=2[CH:6]([C:5]2[CH:12]=[C:13]([O:17][CH3:18])[C:14]([O:15][CH3:16])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:7]=1[C:10]#[N:11]
Reactant: Oc1cccc2ncccc12
Reactant: COc1cc(C=C(C#N)C#N)cc(OC)c1OC
Product: COc1cc(C2C(C#N)=C(N)Oc3c2ccc2ncccc32)cc(OC)c1OC

Procedure:
The title compound was prepared from 3,4,5-trimethoxybenzylidenemalononitrile (244 mg, 1 mmol) and 5-hydroxyquinoline by a procedure similar to that described for Example 145. 1H NMR (CDCl3): 8.96 (m, 1H), 8.52 (d, J=8.7, 1H), 7.82 (d, J=9.0, 1H), 7.52 (m, 1H), 7.33 (d, J=8.7, 1H), 6.43 (s, 2H), 4.83 (m, 3H), 3.83 (s, 3H), 3.80 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[N:8]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=O)[CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.[O:19]1CCOCC1>[OH-].[K+]>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([C:11]3[CH:13]=[CH:18][CH:17]=[CH:16][C:15]=3[CH:14]=[O:19])[CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)n1ccc2ccc(Br)nc21
Reactant: C1COCCO1
Agent: [K+]
Agent: [OH-]
Product: O=Cc1ccccc1-n1ccc2ccc(Br)nc21
Temperature: 25 °C

Procedure:
(6-bromo-1H-pyrrolo[2,3-b]pyridin-1-yl)(phenyl)methanone, 586 was dissolved in 20 mL of dioxane and 20 mL of 2M KOH (aq). This was stirred at ambient temperature until analysis indicated all of the starting material had been consumed (2 to 4 hours). The reaction was diluted with 50 mL of ethyl acetate and washed with 2×25 mL of NaHCO3 (aq. satd.) and 25 mL of brine. The organic layer was dried with sodium sulfate, evaporated and purified by column chromatography. Combined steps 2 and 3 gave approximately 65% overall yield.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(OC)C=CC=CC=1.[Cl:20][S:21](O)(=[O:23])=[O:22]>ClCCCl>[CH3:11][O:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]=1[S:21]([Cl:20])(=[O:23])=[O:22]
Reactant: COc1ccc([N+](=O)[O-])cc1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCCl
Solvent: COc1ccccc1
Product: COc1ccc([N+](=O)[O-])cc1S(=O)(=O)Cl
Temperature: 25 °C

Procedure:
To a solution of 4-nitroanisole (3.1 g; 20 mmol) in 1,2-dichloroethane (20 mL), 2 mL of chlorosulfonic acid was added at 0° C. The resulting reaction mixture was gradually warmed to room temperature and then heated to reflux for 2 h at which time all the anisole had been consumed. The reaction mixture was then cooled to room temperature and diluted with chloroform (30 mL). The contents were then transferred to a separatory funnel, washed with water (50 mL), and the layers were separated. The aqueous layer was then extracted with chloroform (30 mL). The combined organic layers was washed with brine (50 mL) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue obtained was purified by silica gel flash column chromatography using ethyl acetate/hexanes as eluant (1:5 to 1:1 gradient) to afford 2-methoxy-5-nitrobenzenesulfonyl chloride as a dark brown solid. 1H NMR (CDCl3, 400 MHz): δ 4.21 (s, 3H), 7.28 (d, 1H), 8.59 (dd, 1H), 8.88 (d, 1H) ppm.
Reaction SMILES: CN(C1C=CC=CN=1)C.[OH:10][CH2:11][C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1.[C:25](Cl)(=[O:29])[CH:26]([CH3:28])[CH3:27]>N1C=CC=CC=1>[C:25]([O:10][CH2:11][C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1)(=[O:29])[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CO)C1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: CC(C)C(=O)OC[C@H]1CCCN(C(=O)OC(C)(C)C)C1

Procedure:
170 mg of dimethylaminopyridine and 3.4 mg of pyridine are added to 3.0 g of t-butyl (S)-3-hydroxymethyl-l-piperidinecarboxylate. 1.66 ml of isobutyryl chloride are added dropwise thereto. The reaction mixture is then concentrated. The residue is taken up in ether and the ether phase is washed in succession with 20 ml of citric acid, water, sodium bicarbonate solution and water. After drying and evaporation of the ether phase there are obtained 3.9 g of t-butyl (S)-3-isobutyroxymethyl-1-piperidinecarboxylate, Rf=0.87 (ether). 3.09 g of this ester are dissolved in 80 ml of methylene chloride and treated with 20 ml of trifluoroacetic acid. After stirring for 30 minutes the solution is concentrated. 30 ml of methanol are added to the residue and saturated sodium bicarbonate solution is then added dropwise. The aqueous phase is extracted with methylene chloride and the methylene chloride extracts are dried and concentrated. There are obtained 2.82 g of (S)-3-iso- butyroxymethyl-1-piperidinecarboxylic acid trifluoroacetic acid salt, Rf=0.4 (Takeda solution).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([OH:37])([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:9]=2)=[O:5])C.[OH-].[Na+]>C1COCC1.C(O)C>[OH:37][C:7]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:21][CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:9]=2)[C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[C:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1(O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)C1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1(O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 45 %

Procedure:
1-Hydroxy-1,3-diphenyl-6-(3-phenyl-propoxy)-1H-indene-2-carboxylic acid ethyl ester (200 mg, 0.408 mmol) prepared in Example 7 was dissolved in THF, and an excess amount of sodium hydroxide dissolved in aqueous ethanol was added thereto in such a way not to cause layer separation. The mixture was stirred for 5 hrs at RT, and the pH was adjusted to 3˜4 using 2N hydrochloric acid. The resulting mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure, to obtain 85 mg of the titled compound (yield: 45%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH:14]=O.C1(C)C=CC=CC=1>C1(C)C=CC=CC=1>[C:13]([O:17][CH2:18][CH:19]=[N:7][C:6]1[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11])(=[O:16])[CH3:14]
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: CCOC(=O)C=O
Solvent: Cc1ccccc1
Product: COc1ccc(N=CCOC(C)=O)c([N+](=O)[O-])c1

Procedure:
A mixture of 4-methoxy-2-nitroaniline (1.68 g, 10.0 mmol), ethyl glyoxylate/toluene solution (50 wt %, 1.98 ml, 10.0 mmol) and toluene (20 ml) was heated under reflux under a nitrogen gas atmosphere for 17 hours while removing water using a Dean-Stark apparatus. The solvent was removed under reduced pressure to yield [(4-methoxy-2-nitrophenyl)imino]ethyl acetate crude product.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1[C:12]([C:13]2[N:14]([C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=3)[C:15]3[C:20]([C:21]=2[C:22](=O)[C:23]([NH2:25])=[O:24])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([CH3:34])[O:10][N:9]=1.Cl.[NH2:36][OH:37]>CCO>[CH3:7][C:8]1[C:12]([C:13]2[N:14]([C:27]3[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=3)[C:15]3[C:20]([C:21]=2[C:22](=[N:36][OH:37])[C:23]([NH2:25])=[O:24])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([CH3:34])[O:10][N:9]=1
Reactant: Cc1noc(C)c1-c1c(C(=O)C(N)=O)c2ccccc2n1-c1ccc(O)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: Cc1noc(C)c1-c1c(C(=NO)C(N)=O)c2ccccc2n1-c1ccc(O)cc1
Temperature: 150 °C
Reaction time: 0.08 h

Procedure:
50 μl Pyridine was added to 8.8 mg 2-(2-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl)-2-oxoacetamide and 32.6 mg hydroxylamine hydrochloride in 1.5 ml EtOH in a microwave vial. The vial was sealed and flushed with nitrogen. The mixture was heated to 150° C. for 7.5 min. and then to 150° C. for 5 min. in a Biotage Initiator microwave oven. The mixture was concentrated in vacuo and purified by preparative HPLC (formic acid buffer/acetonitrile). 2-(2-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl)-2(hydroxyimino)acetamide (E35) was obtained as a mixture of syn and anti oxime isomers. ES/MS m/z: 391.4 (M+H), 389.5 (M−H); 1H NMR (DMSO-d6, 500 MHz): 7.37 (m, 1H), 7.20-7.03 (m, 5H), 6.84 (m, 2H), 2.15 (s, 3H) and 1.77 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([C@@H:17]([NH2:19])[CH3:18])=[C:8]([C:11]3[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=3)[CH:9]=2)[CH:4]=[CH:3]1.[Cl:20][C:21]1[N:26]=[C:25](Cl)[C:24]([F:28])=[CH:23][N:22]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[Cl:20][C:21]1[N:26]=[C:25]([NH:19][C@H:17]([C:7]2[N:6]=[C:5]3[CH:4]=[CH:3][N:2]([CH3:1])[C:10]3=[CH:9][C:8]=2[C:11]2[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=2)[CH3:18])[C:24]([F:28])=[CH:23][N:22]=1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1-c1ccnn1C
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nc(Cl)ncc1F)c1nc2ccn(C)c2cc1-c1ccnn1C
Temperature: 120 °C
Yield: 99.9 %

Procedure:
(S)-1-(1-Methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (90 mg, 0.353 mmol), 2,4-dichloro-5-fluoropyrimidine (88 mg, 0.529 mmol), and N-ethyl-N-isopropylpropan-2-amine (190 μL, 1.058 mmol) were combined in acetonitrile (500 μL). The reaction mixture was heated to 120° C. in a microwave reactor for 1 hour. After removal of solvent, the residue was diluted with MeOH and dichloromethane, and was purified by preparative HPLC, eluting with a gradient of 15-25% ACN in H2O with 0.35% TFA. The fractions were collected and solvent was removed in vacuo to give the title compound (136 mg, 100%). ESI-MS m/z [M+H]+ calc'd for C18H17ClFN7, 386; found 386.
Reaction SMILES: ClC1C=CC([C@H]([C@H](CC)C=C)C(O)=O)=CC=1.[CH2:17]([OH:22])/[CH:18]=[CH:19]/[CH2:20][CH3:21].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](O)=[O:33])=[CH:27][CH:26]=1>>[CH2:17]([O:22][C:32](=[O:33])[CH2:31][C:28]1[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=1)[CH:18]=[CH:19][CH2:20][CH3:21]
Reactant: CC/C=C/CO
Reactant: COc1ccc(CC(=O)O)cc1
Agent: C=C[C@@H](CC)[C@H](C(=O)O)c1ccc(Cl)cc1
Product: CCC=CCOC(=O)Cc1ccc(OC)cc1

Procedure:
The ester I3a was prepared as described in Step A of example I2, using trans-2-penten-1-ol (49.6 ml; 487.6 mmol) and (4methoxy-phenyl)-acetic acid (81 g; 487.6 mmol) Yield: 57.7 g (52%) of a yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:27]=[CH:26][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([N:15]3[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]3)[S:12][C:13]=2[CH3:14])=[C:5]([O:28][CH3:29])[CH:4]=1.[OH:30][C:31]1[C:35]([CH:36]=[O:37])=[CH:34][N:33]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:32]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:36]([C:35]1[C:31]([O:30][CH2:2][C:3]2[CH:27]=[CH:26][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([N:15]4[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]4)[S:12][C:13]=3[CH3:14])=[C:5]([O:28][CH3:29])[CH:4]=2)=[N:32][N:33]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:34]=1)=[O:37]
Reactant: CCOC(=O)C1CCN(c2nc(COc3ccc(CCl)cc3OC)c(C)s2)CC1
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1CCN(c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)s2)CC1
Temperature: 90 °C
Reaction time: 2 h
Yield: 68.7 %

Procedure:
A mixture of ethyl 1-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-thiazol-2-yl}piperidine-4-carboxylate (0.40 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.18 g), anhydrous potassium carbonate (0.13 g), and N,N-dimethylformamide (10 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:2, v/v) to give ethyl 1-(4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-thiazol-2-yl}piperidine-4-carboxylate as colorless crystals (0.37 g, yield 69%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 126-127° C.
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH2:6])=[N+:2]=[N-:3].C(N(CC)CC)C.[C:14](Cl)(=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C(Cl)Cl>[N:1]([CH2:4][CH2:5][NH:6][C:14](=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCN
Reactant: CCCCCCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
To a 25 mL round-bottomed flask equipped with a magnetic stir bar was added 2-azidoethanamine (0.102 g, 1.18 mmol), DCM (5 mL) and then triethylamine (0.239 g, 2.37 mmol). To this reaction mixture, tetradecanoyl chloride (0.292 g, 1.18 mmol) was added dropwise and allowed to stir at room temperature for 24 hr. Then, the reaction mixture was concentrated de vacuo and then purified via silica gel column chromatography (100% dichloromethane to 1:40 methanol:dichloromethane) to give N-(2-azidoethyl)tetradecanamide (0.245 g, 79% yield). 1H NMR (300 MHz, CDCl3) δ 5.86 (s, 1H), δ 3.42 (s, 41-1), δ 2.18 (t, J=7.8 Hz, 2H), δ 1.62 (m, 2H), δ 1.24 (m, 20H), δ 0.87 (t, J=3.9 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 173.7, 51.2, 39.1, 36.9, 32.1, 29.9, 29.8, 29.7, 29.6, 29.5, 25.9, 22.9, 14.4 ppm; HRMS (ESI) calcd for C16H32N4O (M+) 296.2576. found 296.2566.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([CH:10]([NH:13][C:14]([N:16]1[C:24]2[C:19](=[CH:20][C:21]([O:25][C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH2:32])[CH:27]=3)=[CH:22][CH:23]=2)[CH:18]=[CH:17]1)=[O:15])[CH2:11][CH3:12])[CH3:9].Cl[C:34]([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:35]>O1CCCC1>[CH2:8]([CH:10]([NH:13][C:14]([N:16]1[C:24]2[C:19](=[CH:20][C:21]([O:25][C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:34](=[O:35])[O:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH:27]=3)=[CH:22][CH:23]=2)[CH:18]=[CH:17]1)=[O:15])[CH2:11][CH3:12])[CH3:9]
Reactant: CCC(CC)NC(=O)n1ccc2cc(Oc3ccnc(N)c3)ccc21
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(CC)NC(=O)n1ccc2cc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)ccc21
Temperature: 0 °C
Yield: 91.5 %

Procedure:
Tetrahydrofuran (20 ml) and triethylamine (1.73 ml, 12.4 mmol) were added to N1-(1-ethylpropyl)-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide (1.45 g, 4.29 mmol); phenyl chloroformate (1.15 ml, 9.1 mmol) was added thereto at 0° C. while stirring; and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned between ethyl acetate and water; and the organic layer was concentrated and subjected to silica gel column chromatography to yield a mixture (1.8 g) of phenyl N-(4-(1-((1-ethylpropyl)amino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate and phenyl N-(4-(1-((1-ethylpropyl)amino)carbonyl-1H-5-indolyl)-oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamate. A portion of 0.6 g of the mixture was dissolved in N,N-dimethylformamide (5 ml); 4-tetrahydro-1H-1-pyrrolylpiperidine (0.7 g, 4.7 mmol) and stirred for 2 hours; the reaction mixture was partitioned between ethyl acetate and water; the organic layer was concentrated; and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate:methanol=10:1) to yield as white crystals (202 mg, 0.391 mmol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][N:6]=[C:5]2[C:12]([OH:14])=[O:13].[CH3:15][O:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)[CH3:18].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CCO>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([C:12]([OH:14])=[O:13])=[N:6][NH:7]2)=[CH:3][C:2]=1[C:22]1[CH:23]=[CH:24][C:19]([CH:17]([O:16][CH3:15])[CH3:18])=[CH:20][CH:21]=1
Reactant: COC(C)c1ccc(B(O)O)cc1
Reactant: O=C(O)c1n[nH]c2cc(Cl)c(Br)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(C)c1ccc(-c2cc3c(C(=O)O)n[nH]c3cc2Cl)cc1
Temperature: 100 °C
Yield: 10.6 %

Procedure:
A mixture of 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (40.0 mg, 0.14 mmol), 4-(1-methoxyethyl)phenylboronic acid (27.4 mg, 0.152 mmol) and 2N aqueous potassium carbonate solution (0.2 mL, 0.4 mmol) in toluene (0.3 mL) and EtOH (0.7 mL) was purged with N2, and treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) under N2. The reaction mixture was heated to 100° C. for 48 hours, cooled to room temperature and concentrated in vacuo. The crude material was purified by reverse phase HPLC (Column: Waters Sunfire C18 19×100 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); 95.0% H2O/5.0% MeCN linear to 0% H2O/100% MeCN in 7.0 min, HOLD at 0% H2O/100% MeCN to 8.5 min. Flow: 25 mL/min) to afford the title compound (4.9 mg, 11% yield). MS (ES+) 331.1 (M+H)+. Retention time=2.71 minutes (Column: Waters Atlantis dC18 4.6×50 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2 mL/min).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=O)[CH3:20])[N:14]=1)[CH3:12].[CH2:22]([O:42][C:43]1[C:49]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[CH:48][C:46]([NH2:47])=[CH:45][C:44]=1[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[N:47][C:46]2[CH:45]=[C:44]([C:56]3[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=3)[C:43]([O:42][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[C:49]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[CH:48]=2)[CH3:20])[N:14]=1)[CH3:12]
Reactant: CCCCCCCCCCCCCCCCCCCCOc1c(-c2ccccc2)cc(N)cc1-c1ccccc1
Reactant: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2C)n1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCCCOc1c(-c2ccccc2)cc(N=C(C)c2cccc(C(C)=Nc3c(C)cc(C)cc3C)n2)cc1-c1ccccc1
Reaction time: 24 h

Procedure:
2-[1-(2,4,6-trimethylphenylimino)ethyl]-6-acetyl pyridine (3 g, 10.7 mmol), prepared according to the method disclosed in WO02/28805, and 4-eicosanoxy-3,5-diphenylaniline (5.8 g, 10.7 mmol) were dissolved in 200 ml of toluene. To this solution, 4 Å molecular sieves were added. After standing for 1 day the mixture was filtered. The solvent was removed in vacuo. The residue was crystallised from cold ethanol. The product, D, was isolated as a yellow treacle (6.5 g, 8.1 mmol, 76%) after drying at 60° C. in vacuo.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.Cl[C:20]1[N:25]=[CH:24][N:23]=[C:22]([C:26]([C:28]2[CH:37]=[C:36]([CH3:38])[C:31]3[NH:32][C:33](=[O:35])[O:34][C:30]=3[CH:29]=2)=[O:27])[CH:21]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:38][C:36]1[C:31]2[NH:32][C:33](=[O:35])[O:34][C:30]=2[CH:29]=[C:28]([C:26]([C:22]2[N:23]=[CH:24][N:25]=[C:20]([N:3]3[CH2:4][CH2:5][CH:6]([N:9]4[C:17]5[C:12](=[N:13][CH:14]=[CH:15][CH:16]=5)[NH:11][C:10]4=[O:18])[CH2:7][CH2:8]3)[CH:21]=2)=[O:27])[CH:37]=1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)[nH]c12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)cc2oc(=O)[nH]c12

Procedure:
64 mg (0.22 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one-dihydrochloride, 64 mg (0.221 mmol) 6-(6-chloropyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one and 0.174 mL (1.00 mmol) DIPEA were stirred overnight in 2.0 mL DMF at RT. The mixture was purified by preparative HPLC-MS. The fractions containing the product were combined, the organic solvent was eliminated i. vac. and the aqueous phase remaining was neutralised with 4N aqueous NaOH solution. The precipitate was suction filtered, washed with water and dried in the CAD.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:18])=[C:13]([CH:17]=1)[C:14]([OH:16])=O)=[O:7].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[N:42]1([CH2:47][CH2:48][NH:49][C:50]([C:52]2[CH:57]=[CH:56][C:55]([NH:58][C:59]3[N:64]=[CH:63][C:62]([NH2:65])=[CH:61][N:60]=3)=[CH:54][N:53]=2)=[O:51])[CH2:46][CH2:45][CH2:44][CH2:43]1>C(Cl)Cl>[N:42]1([CH2:47][CH2:48][NH:49][C:50]([C:52]2[CH:57]=[CH:56][C:55]([NH:58][C:59]3[N:60]=[CH:61][C:62]([NH:65][C:14](=[O:16])[C:13]4[CH:17]=[C:9]([NH:8][C:6](=[O:7])[C:5]5[CH:19]=[CH:20][CH:21]=[C:3]([C:2]([F:1])([F:23])[F:22])[CH:4]=5)[CH:10]=[CH:11][C:12]=4[CH3:18])=[CH:63][N:64]=3)=[CH:54][N:53]=2)=[O:51])[CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: Nc1cnc(Nc2ccc(C(=O)NCCN3CCCC3)nc2)nc1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1C(=O)O
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1C(=O)Nc1cnc(Nc2ccc(C(=O)NCCN3CCCC3)nc2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.9 %

Procedure:
Intermediate 3 (Example 5) (0.070 g, 0.215 mmol) was combined with 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (0.046 g, 0.26 mmol) and diluted with DCM (4 mL). This was immediately treated with 4-methyl morpholine (0.05 mL, 0.43 mmol) and allowed to stir at ambient temperature for 1 h. Intermediate 23 (Example 31) (0.074 g, 0.226 mmol) was then added in one portion. Stirring was continued overnight. After 18 h, reaction solvents were removed and resulting crude solids purified via HPLC to afford the title compound as a white solid (0.027 g, 20%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH2:9][C:10]#[N:11])=[CH:4][CH:3]=1.[S:13]1CC(O)S[CH2:15][CH:14]1O.C(NCC)C>C(O)C>[NH2:11][C:10]1[S:13][CH:14]=[CH:15][C:9]=1[C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:12]
Reactant: OC1CSC(O)CS1
Reactant: N#CCC(=O)c1ccc(F)cc1
Solvent: CCO
Solvent: CCNCC
Product: Nc1sccc1C(=O)c1ccc(F)cc1
Temperature: 50 °C
Yield: 86.2 %

Procedure:
Following a procedure described in J. Med. Chem. 2002, 45, 382-389; 0.44 g (2.7 mmol) 3-(4-fluoro-phenyl)-3-oxo-propionitrile (the preparation of which is described in example 17), 0.33 g (2.15 mmol) [1,4]dithiane-2,5-diol, 0.16 ml (2.15 mmol) diethyl-amine and 5 ml ethanol were charged in a sealed tube. The reaction mixture was heated at 50° C. for 6 h. The tube was then placed in a fridge (about 4° C.) for the night, and the product was collected by filtration and dried under vacuum to afford 0.41 g (69%) (2-amino-thiophen-3-yl)-(4-fluoro-phenyl)-methanone as a light brown crystals.