Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:15]2([CH2:18][NH2:19])[CH2:17][CH2:16]2)=[N:4][CH:5]=[C:6]([CH:8]2[CH2:10][CH:9]2[C:11]([F:14])([F:13])[F:12])[CH:7]=1.Cl.C(N=C=NCCCN(C)C)C.[Cl:32][C:33]1[C:34]([C:39](O)=[O:40])=[N:35][CH:36]=[CH:37][N:38]=1.ON1C2C=CC=CC=2N=N1>ClCCl.O.C(N(CC)CC)C>[Cl:32][C:33]1[C:34]([C:39]([NH:19][CH2:18][C:15]2([C:3]3[C:2]([Cl:1])=[CH:7][C:6]([CH:8]4[CH2:10][CH:9]4[C:11]([F:14])([F:12])[F:13])=[CH:5][N:4]=3)[CH2:17][CH2:16]2)=[O:40])=[N:35][CH:36]=[CH:37][N:38]=1
Reactant: NCC1(c2ncc(C3CC3C(F)(F)F)cc2Cl)CC1
Reactant: O=C(O)c1nccnc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(NCC1(c2ncc(C3CC3C(F)(F)F)cc2Cl)CC1)c1nccnc1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
147 mg [1-[3-chloro-5-[2-(trifluoromethyl)cyclopropyl]-2-pyridyl]cyclopropyl]methanamine (step 3) was dissolved in 3 ml of dichloromethane and 0.142 ml triethylamine was added. After cooling to 0° C., 193 mg 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride, 84 mg 3-chloropyrazine-2-carboxylic acid and 141 mg 1-hydroxybenzotriazole were added. The mixture was stirred overnight at ambient temperature. Then water was added. The layers were separated, the organic layer was dried over anhydrous sodium sulphate, filtered and concentrated. Crude material was obtained as an orange oil, which was purified by flash chromatography on silica gel with heptane/ethyl acetate as a solvent. Thus, 161 mg of 3-chloro-N-[[1-[3-chloro-5-[2-(trifluoromethyl)cyclopropyl]-2-pyridyl]cyclopropyl]methyl]pyrazine-2-carboxamide was obtained as a yellow sticky solid. 1H-NMR (CDCl3): 8.42 ppm (d, 1H), 8.38 ppm (d, 1H), 8.18 ppm (s, 1H), 7.78 ppm (s, 1H, broad), 7.31 ppm (s, 1H), 3.66 ppm (d, 1H), 2.26 ppm (m, 1H), 1.78 ppm (m, 1H), 1.57 ppm (m, 1H), 1.39 ppm (m, 1H), 1.18 ppm (m, 4H).
Reaction SMILES: C([Si](CC)(CC)[C:4]1[NH:12][C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[C:5]=1[CH2:13][CH2:14][OH:15])C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[NH:12]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[C:5]([CH2:13][CH2:14][OH:15])=[CH:4]1
Reactant: CC[Si](CC)(CC)c1[nH]c2ncccc2c1CCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: OCCc1c[nH]c2ncccc12
Reaction time: 10 h
Yield: 78.3 %

Procedure:
2-(2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethanol (1.00 g, 3.62 mmole) was stirred with TBAF (10.86 ml, 10.86 mmole; 1M solution in THF) for 6 hours at 50° C. and then for 10 hours at RT. The solvent was removed on a rotary evaporator and the residue was purified by column chromatography (DCM/MeOH=9:1, then 1:1). 2-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethanol (0.46 g, 79%) was formed as a white solid.
Reaction SMILES: COC1C=CC=CC=1C(Cl)=O.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:42]([N:44]=[C:45]=[S:46])=[O:43]>C1(C)C=CC=CC=1.C(O)C>[CH3:34][O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:42]([N:44]=[C:45]=[S:46])=[O:43].[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31][C:45]([NH:44][C:42](=[O:43])[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[O:35][CH3:34])=[S:46])=[CH:29][CH:28]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: COc1ccccc1C(=O)Cl
Agent: COc1ccccc1C(=O)N=C=S
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4OC)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
2-Methoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2-methoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-methoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (83 mg, yield 96%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([NH:11][CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:23][CH3:24])[C:18]=2[NH2:22])[CH2:13]1)(=O)[CH2:8][CH3:9].[OH-].[Na+]>O1CCCC1>[CH2:7]([NH:11][CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:23][CH3:24])[C:18]=2[NH2:22])[CH2:13]1)[CH2:8][CH3:9]
Reactant: CCC(=O)NC1CCc2c(ccc(OC)c2N)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCNC1CCc2c(ccc(OC)c2N)C1

Procedure:
0.46 g of lithium aluminium hydride is introduced into 30 ml of tetrahydrofuran, a solution of 2.56 g of 2-propanoylamino-5-amino-6-methoxy-1,2,3,4-tetrahydronaphthalene in 50 ml of tetrahydrofuran is then added and the mixture is heated under reflux for 24 hours. It is then cooled and hydrolysed with a 2 N solution of sodium hydroxide, in an ice-bath. The organic phase is separated off, dried and concentrated to dryness. After chromatography on silica with a 1/1 diethyl ether/methanol mixture, 1.8 g of a yellowish oil are collected.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH:12]([O:16]CC)OCC)=[C:6]([CH:9]=1)[CH:7]=O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:11]([CH:12]=[O:16])=[CH:7][C:6]=2[CH:9]=1
Reactant: CCOC(COc1ccc(Cl)cc1C=O)OCC
Solvent: CC(=O)O
Product: O=Cc1cc2cc(Cl)ccc2o1
Yield: 20.2 %

Procedure:
A stirred solution of 33 (4.10 g, 15.07 mmol) in acetic acid (20 mL) was refluxed for 24 h. After cooling, the solution was evaporated to dryness. The crude product was adsorbed on silica gel and purified by flash chromatography, eluting with hexane/EtOAc (4:1) to give 34 (550 mg, 20%) as a white solid. 1H NMR (500 MHz, CDCl3): δ: 9.91 (1H, s, CHO), 7.76 (1H, d, J=1.85 Hz, ArH), 7.57 (1H, d, J=8.90 Hz, ArH), 7.53 (1H, s, ArH), 7.50 (1H, dd, J=8.90 & 2.10 Hz, ArH).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[CH3:33][N:34]1[CH2:39][CH2:38][N:37]([CH:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH2:36][CH2:35]1.[CH2:46]([C:48]1[CH:49]=[C:50]([CH2:56][CH:57]([NH:61][C:62]([N:64]2[CH2:69][CH2:68][CH:67]([N:70]3[CH2:79][C:78]4[C:73](=[CH:74][CH:75]=[CH:76][CH:77]=4)[NH:72][C:71]3=[O:80])[CH2:66][CH2:65]2)=[O:63])[C:58](O)=[O:59])[CH:51]=[CH:52][C:53]=1[CH2:54][CH3:55])[CH3:47]>C1COCC1.C(N(CC)CC)C>[CH2:46]([C:48]1[CH:49]=[C:50]([CH:51]=[CH:52][C:53]=1[CH2:54][CH3:55])[CH2:56][CH:57]([NH:61][C:62]([N:64]1[CH2:69][CH2:68][CH:67]([N:70]2[CH2:79][C:78]3[C:73](=[CH:74][CH:75]=[CH:76][CH:77]=3)[NH:72][C:71]2=[O:80])[CH2:66][CH2:65]1)=[O:63])[C:58]([N:43]1[CH2:44][CH2:45][CH:40]([N:37]2[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]2)[CH2:41][CH2:42]1)=[O:59])[CH3:47]
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: CCc1ccc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCc1ccc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C)CC3)CC2)cc1CC
Temperature: 40 °C
Reaction time: 2 h

Procedure:
336 mg (1.05 mmol) of TBTU, 161 mg (1.05 mmol) of HOBt, 0.75 mL of triethylamine and 192 mg (1.05 mmol) of 1-methyl-4-piperidin-4-yl-piperazine were added to a solution of 500 mg (1.05 mmol) of 3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid in 100 mL of THF, and stirred for 4 h at RT and 2 h at 40° C. The solvent was removed in vacuo, the residue taken up in 40 mL of saturated NaHCO3 solution, exhaustively extracted with EtOAc and dried over MgSO4. After elimination of the desiccant and solvent the crude product was purified by chromatography (silica gel, MeOH/NH3 100:3).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[C:8]([N:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH2:13][C:14]#[N:15])[CH:5]=1)#[N:2].Cl.N[C:18]1[C:23]([F:24])=[C:22]([F:25])[CH:21]=[C:20]([F:26])[C:19]=1[SH:27]>>[F:24][C:23]1[C:18]2[N:2]=[C:1]([CH2:3][C:4]3[CH:5]=[C:6]([CH2:13][C:14]#[N:15])[CH:7]=[C:8]([N:10]([CH3:11])[CH3:12])[CH:9]=3)[S:27][C:19]=2[C:20]([F:26])=[CH:21][C:22]=1[F:25]
Reactant: CN(C)c1cc(CC#N)cc(CC#N)c1
Reactant: Nc1c(F)c(F)cc(F)c1S
Agent: Cl
Product: CN(C)c1cc(CC#N)cc(Cc2nc3c(F)c(F)cc(F)c3s2)c1
Yield: 29.4 %

Procedure:
The procedure of Example 22-i) was repeated using 1,3-biscyanomethyl-5-dimethylaminobenzene (440 mg, 2.2 mmol) and 2-amino-3,4,6-trifluorothiophenol hydrochloride (474 mg, 2.2 mmol) and the resultant product was crystallized from isopropyl ether to give 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]-5-dimethylaminophenylacetonitrile (234 mg, 30%) as a colorless powder.
Reaction SMILES: Cl.[CH:2]1[C:12]2[CH:11]=[CH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[C:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])[CH2:19][CH2:18]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH:13]1[C:9]2[CH:10]=[CH:11][C:12]3[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=3[C:7](=[C:17]3[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH2:21][CH2:22]3)[C:8]=2[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)CCN1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCN1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Yield: 100.1 %

Procedure:
A mixture of 5.30 g of ethyl 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinepropionate hydrochloride, 19.3 ml of 2N sodium hydroxide aqueous solution and 30 ml of methanol was refluxed for 1 hr and concentrated. Water was added to the residue, washed with ethyl acetate and adjusted to pH 4 to 5 with 10% hydrochloric acid. The precipitate was collected by filtration to give 4.47 g of pale yellow crystals, which were recrystallized from a mixture of water and N,N-dimethylformamide to give 4.23 g of pale yellow needles, mp 201°-203° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].[N+:10]([C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=O)([O-:12])=[O:11]>CO.O.C(O)(=O)C.CO.O.CCO.Cl>[CH3:9][C:3]1[C:2]2[NH:1][C:15]([C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[N+:10]([O-:12])=[O:11])=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cccc(N)c1N
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Solvent: CCO
Product: Cc1cccc2nc(-c3ccccc3[N+](=O)[O-])[nH]c12
Temperature: 25 °C
Yield: 71.1 %

Procedure:
2,3-Diaminotoluene (12.2 g, 0.1 mol) was dissolved in the mixture of MeOH/H2O (500 mL, v/v=1:1), acetic acid (10 mL) was added to the stirring mixture. 2-Nitrobenzaldehyde (21.1 g, 0.14 mol) in MeOH (250 mL) and Cu(OAc)2H2O (28.0 g, 0.14 mmol) in water (250 mL) were added subsequentially to the mixture. It was then heated to reflux for 3 h under vigously stirring, a pale yellow precipitate was formed. Filtered while it was hot and washed with water to afford a gray-yellow solid. Redissolved the precipitate in EtOH (600 mL) and HCl (75 mL, Conc.), a solution of Na2S.9 H2O (48.0 g, 0.2 mol) in water (300 mL) were added. The mixture was heated to reflux for 1 h resulted in a black slurry. Cooled down to room temperature, it was filtered through a pad of celite to remove of CuS. The filtrate was neutralized with ammonium hydroxide to PH=8-9. Concentration using a rotary evaporator, a green-yellow precipitate was formed. After filtration and dried in vaccum oven, the crude product was purified by column chromatography on silica gel using a mixture of hexane/ethyl acetate (1:1) as the eluent to give 4-methyl-2-(2-nitrophenyl)-benzimidazole (18 g, 72%) as a yellow needle crystal. Rf=0.21 (hexane/ethyl acetate=1:1); 1H NMR (250 MHz, CDCl3) δ 2.60 (s, 3H), 7.10 (d, J=8.2 Hz, 1H), 7.20 (t, J=7.9 Hz, 1H), 7.41 (bs, 1H), 7.52-7.66(m, 2H), 7.89-7.97 (m, 2H), 10.41 (bs, 1H); HRMS: Calcd for C14H11N3O2 253.0851, found 253.0854.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[SH:9].Br[CH2:11][C:12](O)=[O:13]>O>[Cl:8][C:7]1[C:2]2[NH:1][C:12](=[O:13])[CH2:11][S:9][C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: Nc1c(S)cccc1Cl
Reactant: O=C(O)CBr
Solvent: O
Product: O=C1CSc2cccc(Cl)c2N1
Temperature: 70 °C
Reaction time: 3 h
Yield: 78.3 %

Procedure:
The zine salt (2.0 g) of 2-amino-3-chlorothiophenol was suspended in water (30 ml), and bromoacetic acid (1.6 g) was added thereto, followed by stirring at 70° C. for 3 hours. The precipitated crystals were filtered, washed with water and dried to obtain 1.8 g of the objective 5-chloro-2,3-dihydro-1,4-benzothiazine-3-one (m.p. 160°-161° C.).
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.[CH:41]([S:43]([CH:46]=[CH2:47])(=[O:45])=[O:44])=[CH2:42]>CCO>[CH3:20][C@:17]12[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:22])([CH3:23])[C:11]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5][C@@H:4]1[C@H:3]1[C@H:35]([C:38]([CH3:40])=[CH2:39])[CH2:36][CH2:37][C@:2]1([NH:1][CH2:47][CH2:46][S:43]([CH:41]=[CH2:42])(=[O:45])=[O:44])[CH2:19][CH2:18]2
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: C=CS(=O)(=O)C=C
Solvent: CCO
Product: C=CS(=O)(=O)CCN[C@]12CC[C@@H](C(=C)C)[C@@H]1[C@H]1CC[C@@H]3[C@@]4(C)CC=C(c5ccc(C(=O)OC)cc5)C(C)(C)[C@@H]4CC[C@@]3(C)[C@]1(C)CC2
Temperature: 100 °C
Yield: 68.7 %

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (30 mg, 0.055 mmol), TEA (0.023 mL, 0.165 mmol) and vinylsulfonylethene (19.5 mg, 0.165 mmol) in EtOH (1 mL) was heated for 3 h at 100° C. The reaction mixture was quenched with water, extracted with DCM (3×2 mL). The organic phases were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound as a brown oil (25 mg, 68%). LCMS: m/e 662.42 (M+H)+, 3.45 min (method 10).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[CH:14]([CH3:16])[CH3:15].Br[CH2:22][CH2:23][Cl:24].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Cl:24][CH2:23][CH2:22][C:14]([CH3:16])([CH3:15])[C:13]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: ClCCBr
Reactant: CCOC(=O)C(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C)(C)CCCl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 22.2 ml of diisopropylamine in 150 ml of tetrahydrofuran being stirred, 93.6 ml of a 1.6 M solution of n-butyl lithium in hexane was added at -5° to 0° C., followed by stirring for 30 minutes. After the reaction mixture was cooled to -78° C. and 19.0 ml of ethyl isobutyrate was added dropwise to the mixture and stirred for 45 minutes. A solution of 11.9 ml of 1-bromo-2-chloroethane in 10 ml of tetrahydrofuran was added dropwise to the reaction mixture. After the reaction mixture was stirred at -78° C. for 1 hour and then at roomtemperature (15° to 20° C.) for 2 hours, an excess amount of an aqueous solution of ammonium chloride was added, followed by extractionwith ethyl acetate. After the extract was washed with water and dried over MgSO4, the solvent was distilled off; the residue was then distilled under reduced pressure, to yield 24.7 g of the title compound in the form of a colorless oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:15][N:14]=[C:13]([CH3:16])[C:12]=2[NH2:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24](Cl)=[O:25]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:15][N:14]=[C:13]([CH3:16])[C:12]=2[NH:17][C:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=2)=[O:25])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2[nH]nc(C)c2N)cc1OC
Reactant: O=C(Cl)c1ccccn1
Product: COc1ccc(-c2[nH]nc(C)c2NC(=O)c2ccccn2)cc1OC

Procedure:
The preparation took place in analogy with Example 15a), starting with 200 mg of 5-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrazol-4-ylamine (44) and 168 mg of pyridine-2-carbonyl chloride*HCl. The following was obtained: 55 C18H18N4O3 (338.37); MS (ESI) 339 (M+H)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]2[C:10]3([CH2:20][O:21][C:5]=2[CH:4]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:12][C:11]3=[O:19].Br.Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.BrCC1CCCCO1>>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]2[C:10]3([CH2:20][O:21][C:5]=2[CH:4]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[N:12]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)[C:11]3=[O:19]
Reactant: COc1cc2c(cc1C)C1(CO2)C(=O)Nc2ccccc21
Reactant: BrCc1ccccn1
Agent: Br
Agent: BrCC1CCCCO1
Product: COc1cc2c(cc1C)C1(CO2)C(=O)N(Cc2ccccn2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, 6-methoxy-5-methyl-1′-(pyridin-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (82%) as a colorless solid: mp 142-144° C.; 1H NMR (300 MHz, CDCl3) δ 8.56 (d, J=4.8 Hz, 1H), 7.67-7.60 (m, 1H), 7.28-7.11 (m, 4H), 7.00 (dd, J=7.5, 7.5 Hz, 1H), 6.90 (d, J=7.8 Hz, 1H), 6.50 (s, 2H), 5.09 (ABq, 2H), 4.84 (ABq, 2H), 3.79 (s, 3H), 2.00 (s, 3H); 13C NMR (75 MHz, CDCl3) δ178.0, 160.3, 159.2, 155.7, 149.5, 142.5, 142.2, 137.1, 132.6, 128.7, 124.3, 123.8, 123.5, 122.8, 121.7, 119.5, 119.2, 109.5, 93.8, 80.3, 58.0, 46.1, 22.6, 16.0; MS (ES+) m/z 373.3 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6](Br)=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:8]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:10]=1.[C:21]1(OB(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd][P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:8]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:10]=1
Reactant: COCOc1cc(CC(=O)OC)c(Br)c(OCOC)c1
Reactant: OB(O)Oc1ccccc1
Agent: Cc1ccccc1[P]([Pd][P](c1ccccc1C)(c1ccccc1C)c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: COCOc1cc(CC(=O)OC)c(-c2ccccc2)c(OCOC)c1
Temperature: 25 °C
Reaction time: 16.5 h

Procedure:
Methyl 3,5-bis(methoxymethoxy)-2-bromophenylacetate (15.0 g, 43.0 mmol) obtained in Example 3, Step 1 was dissolved in a mixed solvent of 1,2-dimethoxymethane (0.15 L) and water (6.0 mL). To the solution were added phenylboric acid (7.3 g, 60 mmol), bis(tri-o-tolylphosphine)palladium (II) dichloride (0.68 g, 0.86 mmol) and cesium carbonate (42 g, 0.13 mol) in an atmosphere of argon, followed by stirring for 16.5 hours under heating and reflux. After cooling to room temperature, the reaction mixture was filtered under reduced pressure, and the filtrate was concentrated under reduced pressure. To the resulting residue was added water (0.50 L), followed by extraction with ethyl acetate (0.40 L×2). The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/4-1/3) to obtain a quantitative yield of methyl 3,5-bis(methoxymethoxy)-2-phenylphenylacetate.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[C:12]([C:17]#N)[CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH:6]=CC=[CH:3][CH:2]=1.C(OC([C:31]1C2C(=CC=CC=2)C=C[N:32]=1)(C)C)(=O)C1C=CC=CC=1>>[CH:1]([C:7]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:17][C:31]#[N:32])[C:11]=2[CH:10]=[CH:9][N:8]=1)([CH2:2][CH3:3])[CH3:6]
Reactant: CC(C)(OC(=O)c1ccccc1)c1nccc2ccccc12
Reactant: N#Cc1cccc2c(-c3ccccc3)nccc12
Product: CCC(C)c1nccc2c(CC#N)cccc12

Procedure:
1-sec-Butylisoquinoline and N-hydroxymethyl dichloroacetamide were reacted in the same way as in step (b) of Example 18 to afford 1-sec-butyl-5-dichloroacetylaminomethylisoquinoline. The product was reacted successively in the same way as in steps (c), (d), (e) and (f) of Example 18 to obtain 1-sec-butylisoquinoline-5-acetonitrile. The product was treated in the same way as in Example 3 to afford 1-sec-butylisoquinoline-5-acetic acid as an oil.
Reaction SMILES: Cl.[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:4][CH2:3]1.Cl[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>CN1CCCC1=O>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([N:22]2[CH2:23][CH2:24][CH:19]([N:5]([CH:2]3[CH2:4][CH2:3]3)[C:6](=[O:18])[C:7]3[CH:8]=[CH:9][C:10]([C:13]4[O:17][CH:16]=[N:15][CH:14]=4)=[CH:11][CH:12]=3)[CH2:20][CH2:21]2)=[N:27][CH:28]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Agent: Cl
Solvent: CN1CCCC1=O
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2ccc(Cl)cn2)CC1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide hydrochloride and 2,5-dichloro-pyridine following a procedure analogous to that described in Example 19 using N-methylpyrrolidinone as solvent. LC (method 16): tR=0.43 min; Mass spectrum (ESI+): m/z=423 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>CC([O-])=O.CC([O-])=O.[Pd+2]>[C:8]([C:5]1[CH:6]=[CH:7][C:2](/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: C=Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(/C=C/c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
An oven dried Schlenk flask was charged with Pd(OAc)2 (2.2 mg, 0.01 mmol, 1 mol %) and tethered ligand 2 (45.8 mg, 0.0044 mmol, 0.44 mol %). The flask was evacuated and backfilled with nitrogen and then capped with a rubber septum. Dry dimethylformamide (5 ml) was added and the mixture was stirred for 60 min at room temperature under nitrogen. 4′-Bromoacetophenone (0.199 g, 1.0 mmol), styrene (0.137 ml, 1.2 mmol), and triethylamine (0.195 ml, 1.4 mmol) were added successively. The rubber septum was replaced with a glas stopper, the flask was sealed, and the mixture was stirred at 120° C. for 20 h. After cooling to room temperature, the mixture was filtered, and the solid was washed with methyl-t-butyl ether (MTBE), water, MeOH, acetone, and once more with MTBE. The phases of the filtrate were separated and the aqueous phase was extracted with MTBE (2×30 ml). The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (hexane/EtOAc, 10/1 to 1/1) to give E-4-acetylstilbene (0.192 g, 86%) as a white solid.
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:6]=[C:7]([CH:11]=[O:12])[CH:8]=[N:9][CH:10]=1>C1COCC1>[Br:4][C:5]1[CH:6]=[C:7]([CH:11]([OH:12])[CH3:1])[CH:8]=[N:9][CH:10]=1
Reactant: C[Mg]Br
Reactant: O=Cc1cncc(Br)c1
Solvent: C1CCOC1
Product: CC(O)c1cncc(Br)c1
Temperature: 0 °C

Procedure:
Methylmagnesium bromide (1M in THF, 12 mL, 12 mmol) was added dropwise to a solution of 5-bromo-pyridine-3-carbaldehyde (1.85, 10 mmol) in dry THF (20 mL) at −78° C. The resulting mixture was slowly warmed up to 0° C. during a 2 hour period and then quenched by aq. satd. NH4Cl solution. After extraction with DCM, the organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give title compound as a crude product (1.9 g, 98%).