Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15](=O)[CH3:16])=[CH:10][CH:9]=1)=[O:4].[CH3:18][O-:19].[Na+]>CO>[CH3:1][O:2][C:3]([NH:5][CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]2[O:19][CH2:18]2)=[CH:10][CH:9]=1)=[O:4]
Reactant: COC(=O)NC=Cc1ccc(OC(C)=O)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)NC=Cc1ccc(OCC2CO2)cc1
Temperature: 50 °C

Procedure:
6.8 g (0.035 mol) of p-(2-methoxycarbonylaminovinyl)-acetoxybenzene are suspended in 100 ml of absolute methanol, a solution of 1.9 g (0.035 mol) of sodium methoxide in 15 ml of absolute methanol is added and thereafter the mixture is warmed to 50°C for 15 minutes. It is then evaporated to dryness in vacuo. The resulting, crude phenolate of p-(2-methoxycarbonylaminovinyl)-phenol is heated with 35 ml of epichlorohydrin to the boil for 24 hours under a reflux condenser, whilst stirring. Thereafter, the excess epichlorohydrin is removed by vacuum distillation. The residue is partitioned between water and methylene chloride and the organic phase is separated off, dried over sodium sulphate and evaporated. After crystallisation of the crude product thus obtained, from acetone-ether, 1-[p-(2-methoxycarbonylaminovinyl)-phenoxy]-2,3-epoxy-propane of melting point 125°-126°C is obtained.
Reaction SMILES: COC(/C=C/[C:7]1[CH:12]=[C:11](O)[C:10]2[O:14][CH:15](C3C=CC(O)=C(O)C=3)[CH:16](C(OC)=O)[C:9]=2[CH:8]=1)=O.O1C=CC=C1C=O.C(OCC)(=O)CCC(OCC)=O.CC(C)([O-])C.[K+].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C.C([O-])([O-])=O.[K+].[K+]>CCO.C(O)(C)(C)C>[O:14]1[C:10]2[CH:11]=[CH:12][CH:7]=[CH:8][C:9]=2[CH:16]=[CH:15]1
Reactant: COC(=O)/C=C/c1cc(O)c2c(c1)C(C(=O)OC)C(c1ccc(O)c(O)c1)O2
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(=O)CCC(=O)OCC
Product: c1ccc2occc2c1

Procedure:
As depicted in Scheme F, dihydrobenzofuran intermediate F-3 could be prepared starting from commercially available 2-furaldehyde and diethyl succinate. Treatment of 2-furaldehyde and diethyl succinate with potassium t-butoxide in refluxing t-butanol gives intermediate F-1. Treatment of F-1 with sodium acetate in refluxing acetic anhydride, followed by aqueous work-up and subsequently refluxing the residue in EtOH in the presence of K2CO3, gives benzofuran F-2. F-2 could be subjected to hydrogenation conditions to provide dihydrobenzofuran F-3.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=[O:52])[CH2:5][C:6]1[CH:11]=[C:10]([C@H:12]2[C@H:17]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@@H:16]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:15]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C@@H:14]([CH2:42][O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[O:13]2)[CH:9]=[CH:8][C:7]=1[Cl:51].[C:53](O)(=[O:60])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.Cl>CN(C=O)C>[Cl:51][C:7]1[CH:8]=[CH:9][C:10]([C@H:12]2[C@H:17]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C@@H:16]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:15]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C@@H:14]([CH2:42][O:43][CH2:44][C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[O:13]2)=[CH:11][C:6]=1[CH2:5][C:4](=[O:52])[CH2:3][NH:2][C:53](=[O:60])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: NCC(=O)Cc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(CNC(=O)c1ccccc1)Cc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.5 %

Procedure:
To a mixture of 1-amino-3-(2-chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)phenyl)propan-2-one hydrochloride (1.75 g, 2.35 mmol), benzoic acid (430 mg, 3.53 mmol), EDCI (901 mg, 4.70 mmol) and HOBt (699 mg, 5.17 mmol) in DMF (15 mL) was added NMM (1.29 mL, 11.8 mmol). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into 1.0 M HCl solution, and extracted with EtOAc. The organic phase was dried over anhydrous MgSO4 and evaporated under vacuum. The residue was further purified by silica column chromatography to provide the titled amide intermediate (980 mg, 51%). MH+706.
Reaction SMILES: BrCCCOC1C=CC2SC=[N:11]C=2C=1.[Na+].[I-].[Cl:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[N:25]1[CH2:31][CH2:30][CH2:29][N:28]([CH2:32][CH2:33][CH2:34][CH2:35][O:36][C:37]2[CH:46]=[C:45]3[C:40]([CH2:41]CC(=O)[NH:44]3)=[CH:39][CH:38]=2)[CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>CC#N>[Cl:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[N:25]1[CH2:31][CH2:30][CH2:29][N:28]([CH2:32][CH2:33][CH2:34][CH2:35][O:36][C:37]2[CH:46]=[C:45]3[C:40]([CH:41]=[N:11][NH:44]3)=[CH:39][CH:38]=2)[CH2:27][CH2:26]1
Reactant: O=C1CCc2ccc(OCCCCN3CCCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Reactant: BrCCCOc1ccc2scnc2c1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Clc1cccc(N2CCCN(CCCCOc3ccc4cn[nH]c4c3)CC2)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.6 %

Procedure:
A mixture of intermediate 51 (54.2 mg, 0.20 mmol) and NaI (60.3 mg, 0.40 mmol) in CH3CN (3 mL) was heated to reflux for 30 min and then cooled to rt. To this mixture was added intermediate 2 (62.4 mg, 0.22 mmol), followed then by DIEA (0.077 mL, 0.44 mmol). The resulting mixture was heated to reflux and stirred for 4 h. Precipitated crystals were filtered off and the filtrate was evaporated under reduced pressure. The residue was extracted with EtOAc. The combined EtOAc layers were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by ISCO to give 6-(4-(4-(2,3-dichlorophenyl)-1,4-diazepan-1-yl)butoxy)-1H-indazole (compound 47) (50.8 mg, 59%). HPLC: 99%, RT 4.526 min. MS (ESI) m/z 433.20 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([OH:14])=[O:13])=[CH:7]2.S(Cl)(Cl)=O.[CH3:19]O>>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([O:14][CH3:19])=[O:13])=[CH:7]2
Reactant: CO
Reactant: O=C(O)c1ccc2c(Br)cccc2c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc2c(Br)cccc2c1
Yield: 69 %

Procedure:
5-Bromo-2-naphthoic acid (17.33 g, 69 mmol) and 250 mL of MeOH were combined in a flask under N2 atmosphere. Thionyl chloride (5.84 mL, 80 mmol) was added dropwise over 15 minutes at a temperature of 25-30° C. resulting in a pale yellow mixture. The mixture was heated at reflux for 3¼ hours. The resulting yellow solution was concentrated under vacuum to 137.4 g of solution and then placed in the freezer overnight. The resulting thick mixture was filtered and the solid was washed with 100 mL of cold MeOH. The solid was dried under vacuum at 50° C. to give 11.39 g of the intermediate title compound as white crystals. A second crop was filtered and washed with 100 mL of cold MeOH. The solid was dried to 1.31 g of white crystals. Yield: 69%, 2 crops.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])[C:4](=[O:23])[CH:3]=1.S(OC)(O[C:28](SC)([S:31][CH3:32])[S:29][CH3:30])(=O)=O>C(O)(=O)C.N1C=CC=CC=1>[CH3:30][S:29][C:28]([S:31][CH3:32])=[C:3]1[C:2](=[O:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([N:12]2[C:13](=[O:22])[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]2=[O:21])[C:4]1=[O:23]
Reactant: COS(=O)(=O)OC(SC)(SC)SC
Reactant: O=C1c2ccccc2C(=O)N1n1c(=O)cc(O)c2ccccc21
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CSC(SC)=C1C(=O)c2ccccc2N(N2C(=O)c3ccccc3C2=O)C1=O
Temperature: 100 °C
Yield: 66 %

Procedure:
A solution of the product of Example 350B (0.6 g, 1.96 mmol) in acetic acid:pyridine (5:1, 15 mL) was treated with tris(methylthio)methyl methyl sulfate (prepared using the procedures in Synthesis, 22-25, 1988; M. Barbero, S. Cadamuro, I. Degani, R. Fochi, A. Gatti, V. Regondi)(1.6 g, 3 eq.) and heated at 100° C. for 2 hours. The reaction mixture was treated with ice, and the precipitated solids were filtered and dried in vacuum to give 0.53 g (66%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.63 (s, 6H), 7.34 (m, 1H), 7.55 (d, 1H), 7.61 (m, 1H), 8.08 (m, 5H). MS (DCI+) m/z 411 (M+H)+.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][CH3:11])[CH:5]=1>C(O)(=O)C>[Br:1][C:9]1[CH:8]=[CH:7][C:6]([S:10][CH3:11])=[CH:5][C:4]=1[CH3:3]
Reactant: CSc1cccc(C)c1
Reactant: BrBr
Solvent: CC(=O)O
Product: CSc1ccc(Br)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
Bromine (2.52 mL, 48.9 mmol) was added dropwise to a solution of 1-methyl-3-(methylthio)benzene (6.14 g, 44.4 mmol) in acetic acid (150 mL) at 0° C. The reaction was then stirred at ambient temperature for 2 h. The reaction was concentrated, and the resulting crude product was purified by chromatography on a silica gel column using 0 to 10% EtOAc/hexane to give 7.94 g (82%) of 1-bromo-2-methyl-4-(methylthio)benzene as a clear oil. 1H NMR (400 MHz, DMSO-d6): δ 7.40 (d, 1H, J=8.3 Hz), 7.10 (d, 1H, J=2.1 Hz), 6.92 (dd, 1H, Ja=8.3 Hz, Jb=2.2 Hz), 2.45 (s, 3H), 2.35 (s, 3H); LRMS (ESI), m/z 218 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[CH2:19]([O:7][C:6](=[O:8])[CH:5]=[CH:4][C:3]1[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:2]=1[F:1])[CH3:20]
Reactant: CCO
Reactant: O=C(O)C=Cc1ccc(F)cc1F
Agent: O=S(=O)(O)O
Product: CCOC(=O)C=Cc1ccc(F)cc1F
Yield: 97 %

Procedure:
2,4-Difluorocinnamic acid (10.1 g) was dissolved in ethanol (100 ml), and conc. sulfuric acid (1 ml) was added thereto, and the resulting mixture was refluxed for 3 hours. The solvent was evaporated under reduced pressure and the residue was poured into ice-cold water and extracted with ethyl acetate. The extract was washed successively with 5% aqueous sodium hydrogencarbonate and a saturated aqueous NaCl solution, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain the title compound (11.2 g, 97%) as a colorless oil.
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:23][OH:24])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1)[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:10].C(OC(N1CCCC(N(OCC2COCO2)C(=O)C2C=C(OC)C=CC2(C)C)C1)=O)(C)(C)C.Cl.O1CCOCC1.C(O[C:68](=O)[C:69]1[CH:74]=[C:73]([O:75][CH2:76][CH3:77])[C:72]([Cl:78])=[C:71]([O:79][CH2:80][CH3:81])[CH:70]=1)C.ClC1C(OCC)=CC(CN2CCC(NC(=O)C3C=C(OC)C=C(CO)C=3)CC2)=CC=1OCC.C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>CCO.C(O)(=O)C>[Cl:78][C:72]1[C:73]([O:75][CH2:76][CH3:77])=[CH:74][C:69]([CH2:68][N:15]2[CH2:16][CH2:17][CH:12]([NH:11][C:9](=[O:10])[C:8]3[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=[C:6]([O:5][CH2:4][CH:3]([OH:2])[CH2:23][OH:24])[CH:7]=3)[CH2:13][CH2:14]2)=[CH:70][C:71]=1[O:79][CH2:80][CH3:81]
Reactant: COc1cc(OCC(O)CO)cc(C(=O)NC2CCNCC2)c1
Reactant: CCOC(=O)c1cc(OCC)c(Cl)c(OCC)c1
Agent: CCOc1cc(CN2CCC(NC(=O)c3cc(CO)cc(OC)c3)CC2)cc(OCC)c1Cl
Agent: COC1=CC(C(=O)N(OCC2COCO2)C2CCCN(C(=O)OC(C)(C)C)C2)C(C)(C)C=C1
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: CCO
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(OCC(O)CO)c3)CC2)cc(OCC)c1Cl

Procedure:
In analogy to the procedure described in example 50k), rac-3-(2,3-dihydroxy-propoxy)-5-methoxy-N-piperidin-4-yl-benzamide hydrochloride (prepared from rac-4-[3-(2,2-dimethyl-[dioxolan-4-ylmethoxy)-5-methoxy-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (example 175a) by reaction with HCl/dioxane in EtOH in analogy to the procedure described in example 250b)] was reacted with 4-chloro-3,5-diethoxy-benzaldehyde (example 219), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as light brown solid. MS: 537.4 (MH+).
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([C:7]2[S:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)=[CH:3][CH:2]=1.[C:17]([OH:27])(=[O:26])[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.CC(C)([O-])C.[K+]>C(O)(=O)C>[C:17]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[CH:16][C:1]2[CH:2]=[CH:3][C:4]([C:7]3[S:8][C:9]4[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=4[CH:11]=3)=[CH:5][CH:6]=2)=[CH:20][CH:19]=1)([OH:27])=[O:26]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: Cc1ccc(-c2cc3ccccc3s2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: O=C(O)c1ccc(C=Cc2ccc(-c3cc4ccccc4s3)cc2)cc1
Temperature: 35 °C
Reaction time: 2 h

Procedure:
A stirred solution of 2.24 g (0.01 mole) of 2-(p-tolyl)benzothiophene and 2.25 g (0.01 mole) of the anil derivative of terephthalaldehydic acid in 150 ml of freshly distilled, dry dimethylformamide was flushed with nitrogen for 10 minutes. The solution was heated to 35°C and 6.72 g (0.06 mole) of potassium tert-but-oxide was added. The color of the reaction mixture changed from violet to brown. Analysis of an aliquot by ultraviolet spectroscopy showed that the reaction was completed after 2 hours of stirring. Glacial acetic acid was added in amount sufficient to neutralize excess potassium tert-butoxide, and the reaction mixture was heated to reflux and filtered while hot to collect the resulting precipitate. The filter cake was washed with hot dimethylformamide containing two percent aniline, then slurried in hot ten percent aqueous hydrochloric acid and refiltered. The collected precipitate was washed on the filter with water until free of acid and then dried in vacuo. The product was finally purified by sublimation to obtain 2-[4-(4-carboxystyryl)phenyl]benzothiophene which remained unmelted at 350°C. The wavelength of maximum excitation of this compound was 367 nm and the wavelength of maximum emission was 423 nm.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11](=[O:23])[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=1.I[CH2:25][CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH3:9][O:10][C:11](=[O:23])[C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:19]([O:21][CH3:22])=[O:20])[CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:14][CH:13]=1
Reactant: COC(=O)Cc1ccc(C(=O)OC)cc1
Reactant: ICC1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(CC2CCCC2)C(=O)OC)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 67.2 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (2.3 mL of a 0.31 M stock solution, 0.71 mmol) cooled to −78° C. was treated with a solution of 4-methoxycarbonylmethyl-benzoic acid methyl ester (66 mg, 0.31 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.85 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of iodomethylcyclopentane (86 mg, 0.40 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 mL). The reaction mixture was then stirred at −78° C. for 4 h. The reaction was then warmed to 25° C. and stirred at 25° C. for 18 h. At this time, the reaction mixture was quenched by the slow addition of a saturated aqueous ammonium chloride solution (10 mL). The reaction mixture was then poured into water (50 mL). This solution was extracted into ethyl acetate (3×25 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded 4-(2-cyclopentyl-1-methoxycarbonyl-ethyl)-benzoic acid methyl ester (60.5 mg, 65.7%) as a clear oil: EI-HRMS m/e calcd for C17H22O4 (M+) 290.1518, found 290.1518.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][C@@:15]4([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[C:19](=[O:26])[O:18]4)[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.O1CCCC1.[CH3:32][C:33]1[C:37](B2OC(C)(C)C(C)(C)O2)=[C:36]([CH3:47])[O:35][N:34]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[F-].[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]>[CH3:32][C:33]1[C:37]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3([C:11]([N:13]4[CH2:17][CH2:16][C@@:15]5([C:21]6[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=6[C:19](=[O:26])[O:18]5)[CH2:14]4)=[O:12])[CH2:10][CH2:9]3)=[CH:6][CH:7]=2)=[C:36]([CH3:47])[O:35][N:34]=1
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(Br)cc4)CC3)C2)c2ccccc21
Reactant: Cc1noc(C)c1B1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1ccc(C2(C(=O)N3CC[C@@]4(C3)OC(=O)c3ccccc34)CC2)cc1
Temperature: 150 °C

Procedure:
To a solution of (1R)-1′-{[1-(4-bromophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (20 mg, 0.00005 mol) in tetrahydrofuran (1.0 mL, 0.012 mol) were added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (11.9 mg, 0.0000534 mol), tris(dibenzylideneacetone)dipalladium(0) (0.2 mg, 0.0000002 mol), tri-tert-butylphosphine (0.12 mg, 5.8E-7 mol) and potassium fluoride (9.3 mg, 0.00016 mol), and the resulting mixture was heated at 150 Celsius under microwave for 50 minutes. The mixture then was cooled down to r.t. and filtered. The filtrate was diluted with methanol, and the desired compound was obtained by revised phase prep-HPLC. MS (ESI): 429.2 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[CH:9](=O)[CH:10]([CH3:12])[CH3:11]>C1(C)C=CC=CC=1>[CH:9](=[C:4]1[C:3]([CH2:2][NH2:1])=[CH:8][CH:7]=[CH:6][NH:5]1)[CH:10]([CH3:12])[CH3:11]
Reactant: NCc1cccnc1
Reactant: CC(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)C=C1NC=CC=C1CN
Yield: 99 %

Procedure:
The procedure as in Example 1(a) is carried out except that 54.07 g (0.5 mol) of 3-aminomethylpyridine, 40 g (0.55 mol) of isobutyraldehyde and 75 ml of toluene are used. Distillation yields 80.1 g (0.495 mol) of isobutylidene-3-aminomethylpyridine; yield 98.8% of theory; b.p 106°-108° C./1.8×103Pa; nD20 =1.5103.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]([CH3:37])[CH2:8][CH2:9][N:10]([CH3:36])[C:11]1[C:12]([NH2:35])=[CH:13][C:14]([NH:19][C:20]2[N:25]=[C:24]([C:26]3[CH:27]=[N:28][N:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=34)[CH:23]=[CH:22][N:21]=2)=[C:15]([O:17][CH3:18])[CH:16]=1>C(Cl)Cl.CO.C(Cl)Cl>[CH3:37][N:7]([CH3:6])[CH2:8][CH2:9][N:10]([CH3:36])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([NH:19][C:20]2[N:25]=[C:24]([C:26]3[CH:27]=[N:28][N:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=34)[CH:23]=[CH:22][N:21]=2)=[CH:13][C:12]=1[NH:35][C:1](=[O:4])[CH:2]=[CH2:3]
Reactant: COc1cc(N(C)CCN(C)C)c(N)cc1Nc1nccc(-c2cnn3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: CO
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cnn4ccccc34)n2)c(OC)cc1N(C)CCN(C)C
Reaction time: 0.5 h
Yield: 63.3 %

Procedure:
A solution of acryloyl chloride (63 μL, 0.78 mmol) in CH2Cl2 (3.60 mL) was added dropwise over 5 minutes to N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,2,4-triamine (Intermediate 158, 320 mg, 0.74 mmol) in CH2Cl2 (10.8 mL), which was cooled in an ice/CH3OH bath. The mixture was stirred for 0.5 h, and was then diluted with 10% CH3OH/CH2Cl2. The resulting solution was washed with sat. NaHCO3, dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-5% methanolic ammonia in CH2Cl2 gave the title compound (228 mg, 63%) as a pale pink solid after trituration with diethyl ether; 1H NMR: 2.22 (6H, s), 2.33 (2H, t), 2.74 (3H, s), 2.91 (2H, t), 3.82 (3H, s), 5.73 (1H, dd), 6.19 (1H, dd), 6.41 (1H, dd), 7.02-7.06 (2H, m), 7.25 (1H, d), 7.29-7.34 (1H, m), 8.17 (1H, s), 8.34 (1H, d), 8.44 (1H, d), 8.75-8.79 (2H, m), 8.82 (1H, s), 10.06 (1H, br s); m/z: ES+ MH+ 487.72.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:42])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH:41]=[N:40][CH:39]=[N:38]2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:18])[CH3:19])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:42])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH:41]=[N:40][CH:39]=[N:38]2)[CH:32]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2cncn2)c1
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cncn3)c2)cc1Cl

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(isobutyl-methyl-amino)-phenyl]-carbamic acid tert-butyl ester (Example J27) (500 mg, 1.53 mmol) and 3-oxo-3-(3-[1,2,4]triazol-1-yl-phenyl)-propionic acid tert-butyl ester (Example K25) (438 mg, 1.53 mmol) according to the general procedure M. Obtained as a light orange foam (700 mg, 85%).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH2:18][C:19]2[CH:28]=[C:27]3[C:22]([CH:23]=[CH:24][N:25]=[CH:26]3)=[CH:21][CH:20]=2)=[C:5]([C:14]([O:16]C)=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].O1CCCC1.[OH-].[Na+].O.CO.C(O)(=O)C>>[C:1]([C:3]1[C:4]([CH2:18][C:19]2[CH:28]=[C:27]3[C:22]([CH:23]=[CH:24][N:25]=[CH:26]3)=[CH:21][CH:20]=2)=[C:5]([C:14]([OH:16])=[O:15])[S:6][C:7]=1[N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)#[N:2]
Reactant: COC(=O)c1sc(N2CCOCC2)c(C#N)c1Cc1ccc2ccncc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1c(N2CCOCC2)sc(C(=O)O)c1Cc1ccc2ccncc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.5 %

Procedure:
To the solution of methyl 4-cyano-3-(isoquinolin-7-ylmethyl)-5-(morpholin-4-yl)thiophene-2-carboxylate (0.103 g, 0.246 mmol) in tetrahydrofuran (15.0 mL, 185 mmol) was added 1.00 M of sodium hydroxide in water (3.80 mL, 3.80 mmol), followed by water (4.0 mL, 220 mmol) and methanol (4.0 mL, 99 mmol). The homogeneous solution was stirred at room temperature for 18 hours. Acetic acid (270 mg, 4.5 mmol) was added and the mixture was concentrated in rotavapor. The residue was dissolved in DCM-MeOH and then concentrated with celite. The mixture was loaded in a cartridge and chromatographed in a silica gel column using AcOH/MeOH/DCM (0/0/100 to 0.5/4.5/95) to afford a white solid product (56.5 mg, yield 60.3%). LC/MS: (FA) ES+ 380; ES− 378. 1H NMR (400 MHz, d-chloroform) δ 9.23 (s, 1H), 8.45 (d, J=5.77 Hz, 1H), 7.90 (d, J=8.53 Hz, 1H), 7.84 (s, 1H), 7.76 (d, J=5.77 Hz, 1H), 7.65 (dd, J=8.53, 1.76 Hz, 1H), 4.53 (s, 2H), 3.72 (m, 4H), 3.52 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([CH3:17])[CH:15]=3)[O:10][C:9](=[O:20])[C:8]=2[C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:39]1[CH2:43][N:42]([CH2:44][CH2:45]Cl)[CH2:41][CH2:40]1.Cl.O>CCO.C(Cl)Cl.O>[CH3:19][O:18][C:13]1[CH:12]=[C:11]2[C:16]([C:7]([CH2:6][C:5]3[CH:31]=[CH:32][C:2]([O:1][CH2:45][CH2:44][N:42]4[CH2:43][CH2:39][CH2:40][CH2:41]4)=[CH:3][CH:4]=3)=[C:8]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][CH:22]=3)[C:9](=[O:20])[O:10]2)=[CH:15][C:14]=1[CH3:17]
Reactant: COc1cc2oc(=O)c(-c3ccc(C(F)(F)F)cc3)c(Cc3ccc(O)cc3)c2cc1C
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: COc1cc2oc(=O)c(-c3ccc(C(F)(F)F)cc3)c(Cc3ccc(OCCN4CCCC4)cc3)c2cc1C
Temperature: 55 °C
Reaction time: 5 h
Yield: 60.9 %

Procedure:
A mixture of 4-(4-hydroxybenzyl)-7-methoxy-6-methyl-3-(4-trifluoromethyl-phenyl)-chromen-2-one (50 mg, 0.113 mmol), K2CO3 (48 mg, 0.35 mmol) and 1-(2-chloroethyl)pyrrolidine.HCl (24 mg, 0.14 mmol) in EtOH (1 mL) containing water (100 μL) was stirred at 55° C. for 5 h. The mixture was cooled to room temperature and was poured into CH2Cl2—H2O. The layers were separated and the aqueous phase was extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4) and the solvent was removed in vacuo. The residue was purified using flash chromatography (silica gel, 40:1 CH2Cl2:MeOH) to provide the title compound as a beige solid (37 mg, 61%). MS (ESI) m/z 537.9 (M+H)+; HPLC tR 5.22 min.