Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([Si](C)(C)[O:24][CH2:25][CH2:26][O:27][NH:28][C:29](=[O:53])[C:30]1[CH:35]=[C:34]([CH2:36][NH:37][C:38](=[O:41])[CH2:39][OH:40])[C:33]([F:42])=[C:32]([F:43])[C:31]=1[NH:44][C:45]1[CH:50]=[CH:49][C:48]([I:51])=[CH:47][C:46]=1[F:52])(C)(C)C>O1CCCC1>[F:43][C:32]1[C:31]([NH:44][C:45]2[CH:50]=[CH:49][C:48]([I:51])=[CH:47][C:46]=2[F:52])=[C:30]([CH:35]=[C:34]([CH2:36][NH:37][C:38](=[O:41])[CH2:39][OH:40])[C:33]=1[F:42])[C:29]([NH:28][O:27][CH2:26][CH2:25][OH:24])=[O:53]
Reactant: CC(C)(C)[Si](C)(C)OCCONC(=O)c1cc(CNC(=O)CO)c(F)c(F)c1Nc1ccc(I)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(CO)NCc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Reaction time: 1.5 h
Yield: 39 %

Procedure:
Tetra-n-butylammonium fluoride (1 mol/L solution in tetrahydrofuran, 0.5 mL, 0.500 mmol) was added to a solution of N-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-[(2-hydroxy-acetylamino)-methyl]-benzamide (4.34 mg, 0.00665 mmol) obtained in Step C in tetrahydrofuran (anhydrous, 1 mL) at room temperature. The mixture was stirred for 1.5 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The resultant crude product was purified sequentially with silica gel flash chromatography (Mega Bond Elut, Varian, 5% methanol/methylene chloride as an eluent) and preparative TLC (No. 5715, Merck, 7% methanol/methylene chloride as a developing solvent) to give 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-[(2-hydroxy-acetylamino)-methyl]-N-(2-hydroxy-ethoxy)-benzamide (Compound E-5, 1.4 mg, 39%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[Br-].[CH2:11]([O:13][C:14](=[O:17])[CH2:15][Zn+])[CH3:12]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([CH2:15][C:14]([O:13][CH2:11][CH3:12])=[O:17])[CH:7]=[CH:6][N:5]=1
Reactant: COc1cc(Br)ccn1
Reactant: CCOC(=O)C[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccnc(OC)c1
Yield: 38.5 %

Procedure:
Combined 4-bromo-2-methoxypyridine (654 μl, 5.32 mmol), (2-ethoxy-2-oxoethyl)zinc(II) bromide (5850 μl, 5.85 mmol), and Pd(PPh3)4 catalyst (615 mg, 0.532 mmol) in THF (15.2 mL) and heated to 120° C. in a microwave for 5 minutes. The reaction was filtered through a course glass frit, concentrated to an oil and purified via flash chromatography (100 g silica gel using a 5% to 50% EtOAc in heptane gradient). The appropriate fractions were combined and concentrated to acquire ethyl 2-(2-methoxypyridin-4-yl)acetate (400 mg, 38.5% yield) as a colorless oil. MS m/z [M+H]+ 196.1.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[S:13][C:12]([NH:15][C:16](=[O:20])[NH:17][CH2:18][CH3:19])=[N:11][C:10]=2[CH:9]=[C:8]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][C:30]([CH3:38])([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH:7]=1)=[CH2:5])C>C1COCC1.O>[C:4]([C:6]1[C:14]2[S:13][C:12]([NH:15][C:16](=[O:20])[NH:17][CH2:18][CH3:19])=[N:11][C:10]=2[CH:9]=[C:8]([C:21]2[CH:26]=[N:25][C:24]([N:27]3[CH2:28][CH2:29][C:30]([CH3:38])([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:31][CH2:32]3)=[N:23][CH:22]=2)[CH:7]=1)(=[O:3])[CH3:5]
Reactant: C=C(OCC)c1cc(-c2cnc(N3CCC(C)(C(=O)OCC)CC3)nc2)cc2nc(NC(=O)NCC)sc12
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(C(C)=O)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
Ethyl 1-[5-[7-(1-ethoxyvinyl)-2-(ethylcarbamoylamino)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate was dissolved in THF (24 mL) and water (6 mL). Sulfonic acid resin MP (200 mg, 3.2 mmol/g) was added and the reaction stirred at rt for 1 h, after which time LCMS indicated clean conversion to the ketone. The reaction mixture was filtered and the solvent removed in vacuo to give a solid which was triturated with Et2O to give the desired product as a yellow solid (600 mg, 64% yield over 2 steps).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[CH3:16][N:17]1[C:21]2[CH:22]=[CH:23][C:24]([CH:26]=O)=[CH:25][C:20]=2[N:19]([CH3:28])[C:18]1=[O:29].C(=O)([O-])[O-]>ClCCl>[CH3:16][N:17]1[C:21]2[CH:22]=[CH:23][C:24]([CH:26]=[N:2][CH2:3][CH2:4][N:5]3[C:6](=[O:15])[C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:13]3=[O:14])=[CH:25][C:20]=2[N:19]([CH3:28])[C:18]1=[O:29]
Reactant: NCCN1C(=O)c2ccccc2C1=O
Reactant: Cn1c(=O)n(C)c2cc(C=O)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: Cn1c(=O)n(C)c2cc(C=NCCN3C(=O)c4ccccc4C3=O)ccc21
Temperature: 22 °C
Reaction time: 48 h
Yield: 80.2 %

Procedure:
To a dry flask charged with a stir bar was added 2-(2-amino-ethyl)-isoindole-1,3-dione hydrochloride salt (100 mg, 0.53 mmoles) (Burgess, K.; Ibarzo, J. D.; Linthicum S.; Russell, D. H.; Shin, H.; Shitangkoon, A.; Totani, R.; and Zhang, A.; J. Am. Chem. Soc. 1997, 119, 1556), 1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carbaldehyde (156 mg, 0.68 mmoles), MP-carbonate (254 mg, 0.79 mmoles) (Argonaut Tech), 3 Å sieves (1.2 g) and 4 mL of dichloromethane. The flask was sealed with a plastic cap and the resulting mixture was stirred for 48 hours at 22° C. The mixture was filtered through a nylon disk via syringes, rinsing with dichloromethane and the filtrate was concentrated to give 154 mg of 2-{2-[(1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-ylmethylene)-amino]-ethyl}-isoindole-1,3-dione as a light yellow solid.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[C:7]([CH:15]([OH:17])[CH3:16])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>C1(C)C=CC=CC=1.[O-2].[Mn+4].[O-2]>[C:1]([C:5]1[C:6]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[C:7]([C:15](=[O:17])[CH3:16])[CH:8]=[C:9]([C:11]([CH3:12])([CH3:13])[CH3:14])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCOc1c(C(C)O)cc(C(C)(C)C)cc1C(C)(C)C
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CCCCOc1c(C(C)=O)cc(C(C)(C)C)cc1C(C)(C)C
Temperature: 75 °C
Reaction time: 5 h
Yield: 82.8 %

Procedure:
2.77 g (9 mmol) of 1-(3,5-di-tert.-butyl-2-butyloxyphenyl)ethanol was dissolved in 120 ml of toluene that had been treated with 14 g of manganese(IV)oxide. This was well stirred at 75° C. for 5 hr. This was cooled and filtered through celite. Solvent was removed to give 2.27 g of 1-(3,5-di-tert.-butyl-2-butyloxyphenyl)ethanone. 1H NMR (CDCl3) δ 7.38 (dd,4H,aromatics), 2.62 (s,3H, CH3C—), 3.72 (t, 2H, —OCH2—).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:5]=O.[CH3:15][C:16]([C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=1)=[O:17].[OH-].[Na+]>CO>[OH:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:15]/[C:16]([C:18]2[CH:19]=[C:20]([O:26][CH3:27])[CH:21]=[C:22]([O:24][CH3:25])[CH:23]=2)=[O:17])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: COc1cc(OC)cc(C(C)=O)c1
Reactant: CCCCOc1ccc(C=O)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCOc1ccc(/C=C/C(=O)c2cc(OC)cc(OC)c2)cc1O
Yield: 48.1 %

Procedure:
A mixture of 3-hydroxy-4-butoxybenzaldehyde (0.4 g, 2.1 mmol), 3,5-dimethoxyacetophenone (0.371.9, 2.1 mmol) and 50% w/v of aqueous sodium hydroxide (3.3 ml, 0.206 mol) in methanol (10 ml) at room temperature for 18 h. The yellow solid that precipitated was filtered and sequentially washed with cold methanol and ether and finally dried in a vacuum dessicator. Purification was achieved using column chromatography (SiO2, petroleum:ether (40:60 v/v) with an increasing gradient of ethyl acetate) which gave 0.36 g (50%) of a yellow solid: 1H-NMR (CDCl3) δ 7.7 (d, 1H), 7.3 (m, 2H), 7.1 (d, 3H), 6.8 (d, 1H), 6.7 (t, 1H), 5.7 (s, 1H), 4.1 (t, 2H), 3.9 (s, 6H), 1.8 (m, 2H), 1.5 (m, 2H), 1.0 (t, 3H). 13C-NMR (CDCl3) δ 190.0, 160.9, 148.3, 146.0, 144.9, 140.5, 128.4, 122.6, 120.2, 112.9, 111.4, 106.2, 104.9, 68.8, 55.6, 31.1, 19.1. 13.7. Mass Spectrum m/e (M+1) 357. Anal. Calcd. for C21H24O5: C, 70.77, H, 6.79. Found C, 70.84; H, 6.81.
Reaction SMILES: Cl.Cl.Cl.[N:4]1([CH2:10][CH2:11][NH:12][C:13](=[O:22])[CH:14]=[CH:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[C:23]1([CH:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[C:33]1([CH:29]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:30]([N:7]2[CH2:8][CH2:9][N:4]([CH2:10][CH2:11][NH:12][C:13](=[O:22])[CH:14]=[CH:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[CH2:5][CH2:6]2)=[O:31])[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C(C=Cc1cccnc1)NCCN1CCNCC1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: O=C(C=Cc1cccnc1)NCCN1CCN(C(=O)C(c2ccccc2)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
8.0 g (22.6 mmol) N-[2-(piperazin-1-yl)-ethyl]-3-pyridin-3-yl-acrylic amide trihydrochloride (substance 317 as a trihydrochloride) and 13 ml (92.7 mmol) TEA are present in 100 ml absolute dichloromethane and cooled to ca. 0° C. under moisture exclusion. 6.3 g (24.9 mmol) diphenylacetyl chloride (90%) are dissolved in 70 ml absolute dichloromethane and added dropwise. The mixture is stirred overnight at RT without further cooling. Subsequently, 200 ml dichloromethane are added and the batch is washed three times each with 100 ml water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The residue is crystallized twice from 40 ml and 30 ml acetonitrile. Beige coloured crystals of MP. 1740° C. yield 4.6 g (44%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[CH:2].N1C2C(=CC=CC=2)C=CC=1>C(OCC)C.[Pd]>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=[CH2:2]
Reactant: C#Cc1ccc(O)c(C(=O)OC)c1
Agent: [Pd]
Solvent: CCOCC
Solvent: c1ccc2ncccc2c1
Product: C=Cc1ccc(O)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 5-ethynyl-2-hydroxybenzoate (8 g, 45.4 mmol), prepared according to Example 1b, was dissolved in a mixture of diethyl ether and light petroleum (200+200 ml) in a hydrogenation flask. Quinoline (1.7 ml) and palladium on CaCO3, poisoned with Pb (Lindlar catalyst; 200 mg) were added, and the flask was attached to an atmospheric pressure hydrogenation apparatus. The mixture was stirred for 2 h at room temperature, by then the calculated amount of hydrogen had been consumed. The catalyst was filtered off and the solution was evaporated to dryness. The product was purified by flash column chromatograpy on silica, using toluene as an eluent. A nearly quantitative yield was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([CH3:17])[CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:16][N:15]1[C:11]([C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([O:1][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][N:20]=3)[CH:3]=2)=[O:10])=[CH:12][C:13]([CH3:17])=[N:14]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Cc1cc(C(=O)Nc2cccc(O)c2)n(C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc([N+](=O)[O-])cn3)c2)n(C)n1
Temperature: 60 °C
Reaction time: 15 h
Yield: 98.3 %

Procedure:
A mixture of N-(3-hydroxyphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (1.58 g, 6.83 mmol), 2-chloro-5-nitropyridine (1.03 g, 6.51 mmol), potassium carbonate (1.42 g, 10.2 mmol) and N,N-dimethylformamide (10 mL) was stirred at 60° C. for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (hexane/ethyl acetate=70/30→0/100) to give the title compound (2.26 g, 94%) as a white solid.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:25])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([OH:24])[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:3][CH2:2]1.C(OC([NH:33][CH2:34][CH2:35]Br)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.C(OCC)(=O)C>[NH2:33][CH2:34][CH2:35][O:24][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][N:13]([C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=1[CH3:12])[C:5]([NH:4][CH:1]1[CH2:3][CH2:2]1)=[O:25])[C:22]2=[O:23]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(O)cc2c1=O
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OCCN)cc2c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.9 %

Procedure:
N-Cyclopropyl-3-(6-hydroxy-4-oxoquinazolin-3(4H)-yl)-4-methylbenzamide (0.621 g), 2-(tert-butoxycarbonylamino)ethyl bromide (0.5 g), potassium carbonate (2.06 g), and potassium iodide (0.025 g) were stirred in DMF (10 ml) at 60° C. for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with water (5×), brine (2×), dried (magnesium sulfate) and concentrated. The resulting solid was dissolved in a solution of 4N HCl in dioxane (4 ml) and methanol (3 ml) and stirred at room temperature for 16 hours. The precipitate was collected by filtration and washed with ethyl acetate. Purification by column chromatography on an ion exchange column (isolute SCX-2 column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) washing with methanol initially and then eluting with a 99:1 mixture of methanol and aqueous ammonia solution gave 3-[6-(2-aminoethoxy)-4-oxoquinazolin-3(4H)-yl]-N-cyclopropyl-4-methylbenzamide (AZ12278502) (0.343 g) as a white solid; NMR Spectrum: (DMSOd6) 0.55 (m, 2H), 0.69 (m, 2H), 1.81 (broad s, 2H), 2.14 (s, 3H), 2.87 (m, 1H), 2.93 (t, 2H), 4.08 (m, 2H), 7.52 (m, 2H), 7.59 (s, 1H), 7.73 (d, 1H), 7.84 (s, 1H), 7.91 (d, 1H), 8.19 (s, 1H), 8.43 (d, 1H); Mass Spectrum: M+H+ 379.
Reaction SMILES: Cl.[F:2][C:3]([F:20])([F:19])[C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][NH2:15])=[CH:10][CH:9]=1.N1C=CC=CC=1.Cl[C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29]>C(OCC)(=O)C>[F:2][C:3]([F:19])([F:20])[C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][NH:15][C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29])=[CH:12][CH:13]=1
Reactant: NNc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)OC(=O)NNc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of 4-[3-(trifluoromethyl)phenoxy]phenylhydrazine hydrochloride (11 g) and pyridine (6.0 mL) in ethyl acetate (100 mL) at 0° C. was added dropwise isopropyl chloroformate (38 mL, 1M in toluene) over a period of 30 min. The mixture was then stirred at room temperature for 5 hour, quenched with 1M aqueous HCl (100 mL). The organic layer was separated, washed twice with water (100 mL), dried over anhydrous sodium sulfate, and finally evaporated under reduced pressure to yield a light brown solid (11 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][C:11]2([CH2:23][C:22](=[O:24])[C:21]3[C:16](=[CH:17][CH:18]=[C:19](/[CH:25]=[CH:26]/[C:27](O)=[O:28])[CH:20]=3)[O:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:30][O:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1>>[CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][C:11]2([CH2:23][C:22](=[O:24])[C:21]3[C:16](=[CH:17][CH:18]=[C:19](/[CH:25]=[CH:26]/[C:27]([NH:30][O:31][CH:32]4[CH2:37][CH2:36][CH2:35][CH2:34][O:33]4)=[O:28])[CH:20]=3)[O:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(Cc3ccccc3)CC1)O2
Reactant: NOC1CCCCO1
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(Cc3ccccc3)CC1)O2)NOC1CCCCO1

Procedure:
(±)-(E)-3-[1′-Benzyl-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-acrylic acid (490 mg, 1.15 mmol) was reacted with NH2OTHP following the procedure described in Example 22, Step C, giving (E)-3-[1′-benzyl-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (270 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([CH2:23][OH:24])=[C:9]2[CH3:25])=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:28]=[C:29](O)[CH:30]=[CH:31][CH:32]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:26][C:27]1[CH:32]=[C:31]([CH:30]=[CH:29][CH:28]=1)[O:24][CH2:23][C:10]1[CH:11]=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:15][CH:14]=2)[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]=1[CH3:25]
Reactant: Cc1c(CO)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Reactant: Oc1cccc(Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1c(COc2cccc(Cl)c2)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 19.2 %

Procedure:
To a solution of 1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole-3-methanol (Example 21) (300 mg, 0.83 mmol), 3-chlorophenol (88 μl, 0.83 mmol), and triphenylphosphine (219 mg, 0.83 mmol) in THF (20 ml), diethyl azodicarboxylate (132 l, 0.83 mmol) was added. The mixture was stirred at room temperature for 48 hours. The solvent was removed under reduced pressure and the crude liquid (820 mg) was purified by chromatography (silica gel, hexane/ethyl acetate, 7/3) to give 3-[(3-chlorophenoxy)methyl]-1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole (75 mg, 19%): mp (DSC) 139° C. Anal Calc'd. for C25H21NSClFO3 : C, 63.89; H, 4.50; N, 2.98. Found: C, 63.85; H, 4.98; N, 2.76.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12](O)=[O:13])=[N:9][C:8]([C@@H:15]([NH:17][C:18]1[N:26]=[CH:25][N:24]=[C:23]3[C:19]=1[N:20]=[CH:21][N:22]3[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[CH3:16])=[CH:7]2.CN(C=O)C.C(Cl)(=O)C([Cl:44])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12]([Cl:44])=[O:13])=[N:9][C:8]([C@@H:15]([NH:17][C:18]1[N:26]=[CH:25][N:24]=[C:23]3[C:19]=1[N:20]=[CH:21][N:22]3[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[CH3:16])=[CH:7]2
Reactant: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(C(=O)O)n4)ncnc32)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(C(=O)Cl)n4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-8-chloro-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino)ethyl)isoquinoline-1-carboxylic acid 10 (160 mg, 0.327 mol, 1 eq) and DMF (0.1 mL) in DCM (10 mL), oxalyl chloride (83.1 mg, 0.654 mmol, 2 eq) was added and the resulting mixture was stirred at RT for 1 h. The mixture was concentrated in vacuo to afford the product (S)-8-chloro-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino)ethyl) isoquinoline-1-carbonyl chloride 11. The product obtained was used directly in the next step without purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])[N:6]=[CH:5]2.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[CH:27]([CH3:30])[CH:28]=[O:29]>>[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[CH:27]([CH3:30])[CH:28]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])[N:6]=[CH:5]2)[OH:29]
Reactant: CC(C=O)c1ccc(Cl)cc1Cl
Reactant: COc1ccccc1-n1ncc2cc(Br)ccc21
Product: COc1ccccc1-n1ncc2cc(C(O)C(C)c3ccc(Cl)cc3Cl)ccc21

Procedure:
In analogy to Example 186, 5-bromo-1-(2-methoxy-phenyl)-1H-indazole was reacted with 2-(2,4-dichloro-phenyl)-propionaldehyde to give 2-(2,4-dichloro-phenyl)-1-[1-(2-methoxy-phenyl)-1H-indazol-5-yl]-propan-1-ol which was oxidized to 2-(2,4-dichloro-phenyl)-1-[1-(2-methoxy-phenyl)-1H-indazol-5-yl]-propan-1-one and converted further to the title compound. Colorless solid. MS (m/e)=495.1 [M+H+].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:20])[CH:5]=[C:4]([CH3:27])[N:3]=1.Cl.CN.C[CH2:32][N:33](C(C)C)C(C)C>CN1C(=O)CCC1>[CH3:32][NH:33][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:20])[CH:5]=[C:4]([CH3:27])[N:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cc(NCc2cc3cccc(C)c3nc2-c2ccccc2)nc(Cl)n1
Agent: CN
Agent: Cl
Solvent: CN1CCCC1=O
Product: CNc1nc(C)cc(NCc2cc3cccc(C)c3nc2-c2ccccc2)n1
Temperature: 220 °C
Yield: 44 %

Procedure:
To a solution of Example 75 (50 mg, 0.13 mmol) in NMP (2 mL) was added methylamine hydrochloride (18 mg, 0.26 mmol) and DIPEA (0.5 mL). The mixture was heated in a microwave at 220° C. for 2 h. Purification by preparative HPLC (Method 1) gave the title compound as an off-white solid (23 mg, 44%). δH (CDCl3) 8.17 (s, 1H), 7.63-7.70 (m, 3H), 7.38-7.57 (m, 5H), 5.47 (s, 1H), 4.80-4.95 (m, 2H), 4.69 (d, J 5.8 Hz, 2H), 2.91 (d, J 5.1 Hz, 3H), 2.81 (s, 3H), 2.14 (s, 3H). LCMS (ES+) 370.2 (M+H)+, RT 2.34 minutes (Method 3).
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+]>CCO.O.[Fe]>[NH2:1][C:4]1[S:8][C:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)c1ccc([N+](=O)[O-])s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(N)s1
Temperature: 80 °C
Reaction time: 3 h
Yield: 76.4 %

Procedure:
To a suspension of tert-butyl 5-nitrothiophene-2-carboxylate (Int. 54) (2.230 g, 9.73 mmol) in a mixture of EtOH (60 ml) and water (30 ml), iron powder (3.26 g, 58.4 mmol) and ammonium chloride (0.364 g, 6.81 mmol) were added. The reaction was stirred at 80° C. for 3 hours and then at RT overnight. The mixture was filtered through a celite pad and the filtrate was evaporated to dryness. The crude was then dissolved in EtOAc and washed with brine; the organic phase was dried over sodium sulfate and the solvent evaporated under vacuum. The residue was purified by filtration through a silica gel cartridge (petroleum ether/EtOAc=9/1 to 6/4) to yield tert-butyl 5-aminothiophene-2-carboxylate (Int. 55) (1.481 g, 7.43 mmol, MS/ESI+200.0 [MH]+).