Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([N:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)=[C:4]([C@H:10]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[O:29]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])([O-])=O.[Na+].[Na+]>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>[C:17]([O:16][C@@H:10]([C:4]1[C:5]([CH3:9])=[N:6][C:7]([CH3:8])=[C:2]([C:39]2[CH:40]=[CH:41][C:36]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:37][CH:38]=2)[C:3]=1[N:21]1[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH3:20])([CH3:19])[CH3:18]
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(Br)c1N1CCC(C)(C)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(Oc3ccccc3)cc2)c1N1CCC(C)(C)CC1
Reaction time: 2 h
Yield: 29.7 %

Procedure:
A mixture of (S)-ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (0.0462 g, 0.101 mmol), (4-phenoxyphenyl)boronic acid (0.033 g, 0.152 mmol) and 2M Na2CO3 (0.127 ml, 0.254 mmol) degassed for 10 min. Then, Pd(Ph3P)4 (0.012 g, 10.14 μmol) added, degassed for 5 min and placed in a pre-heated oil bath 110° C. After 2 h, cooled and purified by pre-HPLC to afford (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(4-phenoxyphenyl)pyridin-3-yl)acetate (0.0162 g, 0.030 mmol, 29.3% yield) as white solid. 1H NMR (500 MHz, CDCl3 δ7.34-7.39 (m, 2H), 7.24-7.28 (m, 1H), 7.09-7.17 (m, 4H), 7.04-7.08 (m, 2H), 6.09 (s, 1H), 4.14-4.30 (m, 2H), 3.20 (d, J=12.3 Hz, 1H), 2.88 (t, J=11.7 Hz, 1H), 2.62 (s, 3H), 2.33 (d, J=11.5 Hz, 1H), 2.25 (s, 3H), 2.12 (t, J=11.4 Hz, 1H), 1.57 (dt, J=4.3, 12.5 Hz, 1H), 1.37-1.44 (m, 1H), 1.26 (t, J=7.1 Hz, 4H), 1.19-124 (m, 1H), 1.22 (s, 9H), 1.12 (d, J=12.1 Hz, 1H), 0.93 (s, 3H), 0.72 (s, 3H). LCMS (M+H)=545.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].Br[CH:11]([Cl:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Cl:13][CH2:11][CH2:12][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: CC(Cl)Br
Reactant: COc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1ccccc1OCCCl
Temperature: 25 °C
Yield: 34.9 %

Procedure:
To a solution of 2-methoxyphenol (14.4 g, 116 mmol) in 2-butanone (200 mL) was added bromochloroethane (69.0 g, 480 mmol) followed by the addition of potassium carbonate (40.0 g, 280 mmol). The reaction mixture was mechanically stirred and heated to reflux for 24 h, then cooled to room temperature. The solids were filtered off and the solvent was removed under vacuum. The residue was dissolved in diethyl ether and washed with 10% of NaOH, dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by silica gel column chromatography (25% EtOAc/hexane) afforded 7.55 g (35%) of a solid: mp 36-38°C. (Lit.2 41-43° C,); 1H NMR (DMSO, 400 MHz), 3.75 (s, 3H), 3.91 (dd, 2H), 4.20 (dd, 2H), 6.86-6.99 (m, 4H); MS (EI) m/z 186 (M+).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[F:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][OH:31]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:31][CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=2[F:27])[CH:7]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Reactant: OCc1ccccc1F
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCc3ccccc3F)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (70 mg; 0.184 mmol), intermediate 42.1, and 2-fluorobenzyl alcohol (94.8 mg; 0.736 mmol), example 710 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13](=O)[CH3:14])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.[CH3:17][O:18][NH2:19]>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:17][O:18][N:19]=[C:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[CH3:14]
Reactant: CON
Reactant: CC(=O)c1ccccc1N1CCOCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CON=C(C)c1ccccc1N1CCOCC1
Yield: 93.4 %

Procedure:
A mixture of Example 49A (1.22 g, 5.94 mmol) and methoxyamine hydrochloride (550 mg, 6.59 mmol) in pyridine (20 mL) was stirred at room temperature for 12 h. The reaction was diluted with ethyl acetate and washed sequentially with 3 N HCl, 1 N HCl and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure to give 1.3 g of the title compound. MS (ESI+) m/z 235 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].Cl[CH2:15][CH2:16][CH2:17][S:18](Cl)(=[O:20])=[O:19]>>[O:19]=[S:18]1(=[O:20])[CH2:17][CH2:16][CH2:15][N:1]1[C:2]1[CH:12]=[C:11]([N:13]2[CH2:15][CH2:16][CH2:17][S:18]2(=[O:20])=[O:19])[CH:10]=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CCOC(=O)c1ccc(N)cc1N
Product: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1N1CCCS1(=O)=O

Procedure:
Using ethyl 2,4-diaminobenzoate (2.21 g) and 3-chloropropane-1-sulfonyl chloride (4 mL) and by the reaction and treatment in the same manner as in Preparation Example 16, the title compound (1.33 g) was obtained.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C([O-])(=O)C.[Na+].[F:17][C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=1[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][OH:38])=[CH:27][CH:26]=1>C(Cl)Cl>[F:17][C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=1[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]=[O:38])=[CH:27][CH:26]=1
Reactant: OCCCCCCOc1ccc(-c2cccc(F)c2F)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=CCCCCCOc1ccc(-c2cccc(F)c2F)cc1
Reaction time: 18 h
Yield: 42.9 %

Procedure:
First, 6.4 g of pyridinium chlorochromate, 0.48 g of sodium acetate, and 10 ml of methylene chloride were placed in a 200 ml flask. Then, 50 ml of a methylene chloride solution containing 6 g of 2,3-difluoro-4'-(6-hydroxyhexyl)oxybiphenyl obtained in Example 2-(f) was added dropwise to the reaction mixture. The reaction mixture was stirred for 18 hours. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography (eluent: toluene) and recrystallized from a mixed solvent of hexane and acetone to obtain 2.56 g of 2,3-difluoro-4'-(5-formylpentyl)oxybiphenyl (Y: 42.9%). The compound thus obtained had a purity of 95.1% by GC.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[Cl:27])=[CH:14][CH:15]=1)=O)C.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH:42]C(C3C4N=CC=NC=4C(C4C(Cl)=C(OC)C=C(OC)C=4Cl)=CC=3)=O)=[N:40][CH:41]=2)[CH2:31][CH2:30]1.C[Al](C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH:42][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=4[Cl:27])=[CH:14][CH:15]=3)=[O:3])=[N:40][CH:41]=2)[CH2:31][CH2:30]1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2Cl)c2nccnc12
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nccnc23)c1Cl
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nccnc23)c1F
Temperature: 80 °C
Reaction time: 4 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 144.1), 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Example 31; purified by silica gel column chromatography), 2 equiv of trimethyl aluminum, stirring the reaction mixture for 4 h at 80° C., pouring it onto a saturated aqueous solution of NaHCO3 and DCM. Title compound: ESI-MS: 551.1 [M+H]+; tR=3.50 min (System 1); TLC: Rf=0.20 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4](O)=[O:5].CN(C=O)C.C(Cl)(=O)C([Cl:21])=O>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4]([Cl:21])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1c(F)cc(F)cc1F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1c(F)cc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a DCM 200 mL solution of 2,4,6-trifluorobenzoic acid (20 g, 0.11 mol) and DMF (0.5 mL, 6.46 mmol) was added oxalyl chloride (21.6 g, 0.17 mol) dropwise. The reaction mixture was stirred at room temperature for 1 hr and the solvent was removed under reduced pressure to give the title compound as crude product (22 g).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][N:7]=1)=[O:4].[CH:13]([N:16]1[CH2:21][CH2:20][CH:19]([NH:22][S:23]([CH2:26][CH2:27][NH:28][C:29]([C:31]2[S:32][C:33]([Cl:36])=[CH:34][CH:35]=2)=[O:30])(=[O:25])=[O:24])[CH2:18][CH2:17]1)([CH3:15])[CH3:14]>>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3]([CH2:2][N:22]([CH:19]2[CH2:20][CH2:21][N:16]([CH:13]([CH3:15])[CH3:14])[CH2:17][CH2:18]2)[S:23]([CH2:26][CH2:27][NH:28][C:29]([C:31]2[S:32][C:33]([Cl:36])=[CH:34][CH:35]=2)=[O:30])(=[O:24])=[O:25])=[O:4])=[N:7][CH:8]=1
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Reactant: CC(C)N1CCC(NS(=O)(=O)CCNC(=O)c2ccc(Cl)s2)CC1
Product: CC(C)N1CCC(N(CC(=O)Nc2ccc(Cl)cn2)S(=O)(=O)CCNC(=O)c2ccc(Cl)s2)CC1

Procedure:
5-Chloro-thiophene-2-carboxylic acid {2-[[(5-chloro-pyridin-2-ylcarbamoyl)-methyl]-(1-isopropyl-piperidin-4-yl)-sulfamoyl]-ethyl}-amide was prepared by an analogous procedure as described in example 15 starting from 168 mg (2 equiv.) 2-bromo-N-(5-chloro-pyridin-2-yl)-acetamide and 133 mg (0.34 mmol) 5-chloro-thiophene-2-carboxylic acid [2-(1-isopropyl-piperidin-4-ylsulfamoyl)-ethyl]-amide. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.1% TFA) gave pure 5-chloro-thiophene-2-carboxylic acid {2-[[(5-chloro-pyridin-2-ylcarbamoyl)-methyl]-(1-isopropyl-piperidin-4-yl)-sulfamoyl]-ethyl}-amide. The title compound was obtained as its trifluoroacetate in form of a colorless amorphous material.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([OH:24])([CH3:23])[CH3:22])=[C:17]([O:25][CH3:26])[CH:16]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([OH:24])([CH3:23])[CH3:22])=[C:17]([O:25][CH3:26])[CH:16]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(C(C)(C)O)c(OC)c3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(-c2cc3c(C(=O)O)c[nH]c3cc2Cl)ccc1C(C)(C)O
Temperature: 70 °C

Procedure:
To a flask containing methyl 6-chloro-5-(4-(2-hydroxypropan-2-yl)-3-methoxyphenyl)-1H-indole-3-carboxylate (24.0 mg, 0.064 mmol) was added methanol (0.64 mL), and 1N NaOH (0.19 mL, 0.19 mmol). The reaction was heated at 70° C. for 18 h. The reaction was then concentrated to remove most of the methanol and then dissolved in water. 0.19 mL of 1N HCl was then added to the mixture to pH 2. Solid precipitated out. The solid was collected with a Buchner funnel and washed with water to provide crude 6-chloro-5-(4-(2-hydroxypropan-2-yl)-3-methoxyphenyl)-1H-indole-3-carboxylic acid. The crude material was purified by reverse phase chromatography to give the title compound. MS (ES−) 358.1 (M−H)−: Retention time: 1.40 min. Column: Waters XBridge dC18 4.6×50 mm, 5 μm. Modifier: NH4OH 0.03%. Gradient: 95% H2O/5% MeCN linear to 5% H2O/95% MeCN over 4.0 min, HOLD at 5% H2O/95% MeCN to 5.0 min. Flow: 2.0 mL/min.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:4][C:5]([NH2:8])=[CH:6][CH:7]=1.Br[C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH2:18][CH2:19][N:20]([CH2:26][CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH2:21]2.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:4][C:5]([NH:8][C:16]2[C:17]3[CH2:18][CH2:19][N:20]([CH2:26][CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH2:21][C:22]=3[CH:23]=[CH:24][CH:25]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(N)nc1-c1ccccn1
Reactant: CS(=O)(=O)CCN1CCc2c(Br)cccc2C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1ccc(Nc2cccc3c2CCN(CCS(C)(=O)=O)C3)nc1-c1ccccn1
Temperature: 96 °C
Reaction time: 18 h

Procedure:
To a reaction tube under argon containing 3-methyl-2,2′-bipyridin-6-amine (20 mg, 0.11 mmol), 5-bromo-2-(2-(methylsulfonyl)ethyl)-1,2,3,4-tetrahydroisoquinoline (35 mg, 0.11 mmol), Pd2(dba)3 (11 mg, 0.011 mmol), xantphos (20 mg, 0.022 mmol), potassium phosphate (66 mg, 0.33 mmol) is added anhydrous dioxane (0.6 ml). The mixture is stirred at 96° C. for 18 hours, cooled to room temperature and filtered through a celite pad to remove any solids. The filtrate is concentrated and purified by preparative HPLC to afford N-(3-methyl-2,2′-bipyridin-6-yl)-2-(2-(methylsulfonyl)ethyl)-1,2,3,4-tetrahydroisoquinolin-5-amine as a white solid. LC-MS m/z: 423.2 (M+1); 1H NMR 400 MHz (CDCl3) δ 8.69 (d, 1H, J=5.2 Hz), 7.78 (td, 1H, J=1.6, 7.6 Hz), 7.68 (d, 1H, J=8.0 Hz), 7.39 (d, 1H, J=8.4 Hz), 7.32-7.24 (m, 3H), 7.13 (t, 1H, J=7.6 Hz), 6.79 (d, 1H, J=7.6 Hz), 6.72 (d, 1H, J=8.4 Hz), 6.19 (s, 1H), 3.69 (s, 2H), 3.22-3.20 (m, 2H), 3.03 (t, 2H, J=6.4 Hz), 2.99 (s, 3H), 2.80-2.74 (m, 4H), 2.32 (s, 3H).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:48]([O:49][Si](C(C)(C)C)(C)C)[CH:41]6[CH:42]([O:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:57]([CH3:59])[CH3:58])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>O1CCCC1>[C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:48]([OH:49])[CH:41]6[CH:42]([O:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:57]([CH3:58])[CH3:59])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCOC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(c4ccccc4)c4ccccc4)OC2OC1C3O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCCOC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(c4ccccc4)c4ccccc4)OC2OC1C3O
Yield: 118.9 %

Procedure:
20 mg of compound (36) was stirred together with 242 μl of dry tetrahydrofuran and 36 μl of 1M tetrabutylammonium fluoride-tetrahydrofuran solution at room temperature for 1 hour. The reaction solution was concentrated in vacuo to give the crude reaction product. It was charged onto a silica gel column (Kieselgel 60, Merck, 1.5φ×15 cm) and eluted with n-hexane-ethyl acetate (3:1) to give 20.5 mg of compound (37) as a colorless oily substance.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2[O:8][C:9]3[C:14]([N+:15]([O-])=O)=[CH:13][CH:12]=[CH:11][C:10]=3[C:4]=2[CH2:3]1.C(N(CC)CC)C.S1C=CC=C1>C1COCC1.[Pd]>[NH2:15][C:14]1[C:9]2[O:8][C:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][C:4]=3[C:10]=2[CH:11]=[CH:12][CH:13]=1
Reactant: CN1CCc2oc3c([N+](=O)[O-])cccc3c2C1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: c1ccsc1
Solvent: C1CCOC1
Product: CN1CCc2oc3c(N)cccc3c2C1
Yield: 96.6 %

Procedure:
A mixture of 1,2,3,4-tetrahydro-2-methyl-6-nitrobenzofuro[3,2-c]pyridine (0.0215 mol) and triethylamine (2 g) in THF (200 ml) was hydrogenated with palladium-on-charcoal catalyst 10% (2 g) as a catalyst in the presence of thiophene 4% (2 ml). After uptake of H2 (3 equivalents), the catalyst was filtered off and the filtrate was evaporated, yielding 4.2 g 1,2,3,4-tetrahydro-6-amino-2-methylbenzofuro[3,2-c]pyridine (interm. 7).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[OH:11])(=[O:3])[CH3:2].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(Cl)(Cl)Cl>[C:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[O:11][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)COc1ccc(Br)cc1C(C)=O
Yield: 90.2 %

Procedure:
13.31 g of 2-acetyl-4-bromophenol, 11.0 g of ethyl bromoacetate and 9.7 g of anhydrous potassium carbonate were refluxed under heating in 70 ml of acetone for 2 hours. Insoluble materials were removed by filtration, and the resulting filtrate was concentrated and dried. The residue thus obtained was dissolved in chloroform, washed with water, and then dried to remove the solvent. The thus treated residue was washed with a mixed solvent system of ethanol and n-hexane to isolate insoluble crystals by filtration. In this way, 16.82 g of ethyl (2-acetyl-4-bromophenyl)oxyacetate was obtained in the form of colorless plate crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[C:11]([CH3:13])[C:10]([C:14]([OH:16])=O)=[CH:9][N:8]=1.[F:17][C:18]1[N:23]=[C:22]2[C:24]([CH3:28])=[CH:25][N:26]([NH2:27])[C:21]2=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:17][C:18]1[N:23]=[C:22]2[C:24]([CH3:28])=[CH:25][N:26]([NH:27][C:14]([C:10]3[C:11]([CH3:13])=[N:12][C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:8][CH:9]=3)=[O:16])[C:21]2=[CH:20][CH:19]=1
Reactant: Cc1cn(N)c2ccc(F)nc12
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2ccccn2)ncc1C(=O)Nn1cc(C)c2nc(F)ccc21
Yield: 57.8 %

Procedure:
A solution of 2-pyridin-2-yl-4-methyl-pyrimidine-5-carboxylic acid (1.36 mmol), 5-fluoro-3-methyl-pyrrolo[3,2-b]pyridin-1-ylamine (1.36 mmol), DIPEA (158 mg, 4.07 mmol) and HATU (1.63 mmol) in anhydrous DMF (8 mL) is stirred at 90° C. for 15 hours. DMF is evaporated in vacuo. The residue is dissolved in EtOAc (40 mL), washed with water (3×15 mL) and brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue is recrystallized from EtOAc to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (5-fluoro-3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide (285 mg) as a solid. MS: 363 (M+H); 1H NMR (300 MHz, CD3OD): δ 2.35 (s, 3H), 2.87 (s, 3H), 6.92 (d, H), 7.51 (s, H), 7.60 (t, H), 7.97 (t, H), 8.05 (t, H), 8.65 (d, H), 8.78 (d, H), 9.23 (s, H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[N:23]=[CH:24][CH:25]=[C:26]4[CH2:30][CH2:29][O:28][C:27]=34)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:32]>ClCCl>[ClH:32].[ClH:32].[ClH:32].[O:28]1[C:27]2=[C:22]([N:19]3[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][C@H:11]4[CH2:12][CH2:13][C@H:8]([NH2:7])[CH2:9][CH2:10]4)[CH2:17][CH2:18]3)[N:23]=[CH:24][CH:25]=[C:26]2[CH2:30][CH2:29]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Solvent: ClCCl
Product: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reaction time: 3 h

Procedure:
To a mixture of trans-(4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-carbamic acid tert-butyl ester (1.3 g, 3.02 mmol) in dichloromethane (21 ml) was added at room temperature hydrochloric acid solution (4M in dioxane, 11.3 ml, 45.3 mmol) and the mixture was allowed to stir for 3 h, the solvent was evaporated, diethyl ether (50 ml) was added and the mixture was allowed to stir for 30 min at room temperature. The precipitate was collected by filtration, washed with diethyl ether and dried to yield the title compound as off-white solid (1.29 g, 97%), MS (ISP) m/z=331.3 [(M+H)+], mp 318.5° C.
Reaction SMILES: [CH2:1]=O.[F:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]4[CH:20]=[N:21][N:22]([CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[CH:23]=4)[CH:18]=3)[O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1.[Na].N>ClCCl.CO>[F:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]4[CH:20]=[N:21][N:22]([CH:24]5[CH2:25][CH2:26][N:27]([CH3:1])[CH2:28][CH2:29]5)[CH:23]=4)[CH:18]=3)[O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: C=O
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(F)cccc2o1
Agent: N
Agent: [Na]
Solvent: CO
Solvent: ClCCl
Product: CN1CCC(n2cc(-c3cnc(N)c(-c4nc5c(F)cccc5o4)c3)cn2)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
37% aqueous formaldehyde (0.015 ml) at 0° C., was added to a stirred solution of 3-(4-fluoro-1,3-benzoxazol-2-yl)-5-[1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amine dissolved in dichloromethane (6 ml) and methanol (6 ml) over a period of 5 minutes. The resulting mixture was stirred at 0° C. for 10 minutes. Sodium triacetoxyhydroborate (233 mg) was added at 0° C. to the mixture and stirred at 0° C. for 1 hour. A solution of 7N ammonia in methanol (20 ml) was added to the mixture and adsorbed on silica gel. The crude product was purified by flash chromatography on silica gel eluting with 2 to 6% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness and tritured in hot acetonitrile, filtered and dried under reduce pressure to afford 3-(4-fluoro-1,3-benzoxazol-2-yl)-5-[1-(1-methyl-4-piperidyl)pyrazol-4-yl]pyridin-2-amine (268 mg) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:13])[N:9]([CH2:14][CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:19][CH2:18]1)[C:8]2=[O:32].[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1>C(O)(=O)C>[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=[CH:13][C:10]2[N:9]([CH2:14][CH2:15][CH2:16][CH:17]3[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][N:26]4[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]4)[CH2:21][CH2:22]3)[C:8](=[O:32])[C:7]3[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=3)[N:11]=2)=[CH:36][CH:35]=1
Reactant: COc1cccc2c(=O)n(CCCC3CCN(CCCN4CCCCC4)CC3)c(C)nc12
Reactant: O=Cc1ccc(Cl)cc1
Solvent: CC(=O)O
Product: COc1cccc2c(=O)n(CCCC3CCN(CCCN4CCCCC4)CC3)c(C=Cc3ccc(Cl)cc3)nc12

Procedure:
A solution of the product from Step C (144 mg, 0.33 mmol) and 4-chlorobenzaldehyde (46 mg, 0.33 mmol) in acetic acid (15 mL) was heated at 120° C. for 17 h. The reaction mixture was concentrated under vacuum and the residue was diluted with CHCl3. The organic solution was washed with sat'd aq NaHCO3, sat'd aq NaCl, dried and concentrated. Purification via SiO2-gel chromatography using EtOAc/NEt3 (10:1) yielded the desired product. API-MS: 563 (M+1). 1H NMR (300 MHz, CDCl3): d 8.0 (d, 2 H), 7.8 (d, 1 H), 7.5 (d, 2 H), 7.38 (m, 3 H), 7.15 (d, 1 H), 7.0 (d, 2 H), 4.1 (t, 2 H), 4.0 (s, 3 H), 2.85 (m), 2.3 (m), 1.9-1.2 (m).