Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.O[CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[O:27][C:26](=[O:34])[CH:25]=1>C(O)(=O)C.CN(C)C=O>[OH:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[O:27][C:26](=[O:34])[C:25]=1[CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1c2ccccc2C(O)N1c1ccccc1
Reactant: O=c1cc(O)c2ccccc2o1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(c2c(O)c3ccccc3oc2=O)N1c1ccccc1
Temperature: 20 °C
Reaction time: 15 h
Yield: 85.8 %

Procedure:
Sulphuric acid (210 cc) is added dropwise to a suspension of 3-hydroxy-2-phenylisoindolin-1-one (67.5 g) and 4-hydroxycoumarin (97.3 g) in acetic acid (675 cc) whilst maintaining the temperature between 15° and 18° C, and the mixture is stirred for 15 hours at a temperature of about 20° C. The reaction mixture is then run into icewater (3000 cc) and the precipitate is filtered off and washed with water (2500 cc). The filter cake is dried in a stream of air at a temperature of about 20° C. The product obtained is dissolved in dimethylformamide (800 cc) at 90° C. The solution is filtered and acetonitrile (900 cc) is then added. After cooling in an ice-bath for 2 hours, the solid is filtered off and washed with acetonitrile (1000 cc). It is dried under reduced pressure (0.1 mm Hg) for 15 hours at 20° C and then for 4 hours at 55° C and 2 hours at 80° C. 3-(4-Hydroxycoumarin-3-yl)-2-phenylisoindolin-1-one (95 g), melting at 335°-337° C, is thus obtained.
Reaction SMILES: C([O:5][C:6](=[O:40])[C@@H:7]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:33])=[O:32])[CH2:8][NH:9][C:10](=[O:29])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C@@H:19]([NH:21]C(OC(C)(C)C)=O)[CH3:20])=[CH:13][CH:12]=1)(C)(C)C.[ClH:41]>O1CCOCC1>[NH2:21][C@@H:19]([CH3:20])[CH2:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([NH:9][CH2:8][C@H:7]([NH:30][S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:33])=[O:32])[C:6]([OH:40])=[O:5])=[O:29])=[CH:12][CH:13]=1.[ClH:41]
Reactant: C[C@@H](COc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2ccccc2)C(=O)OC(C)(C)C)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](N)COc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2ccccc2)C(=O)O)cc1

Procedure:
22-5 (545 mg, 0.94 mmol) in 6N HCl (25 mL) and dioxane (25 mL) was stirred overnight at ambient temperature. Concentration followed by trituration with ether gave 22-6 as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[NH:4][C@H:5]([C:10]([NH:12][NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)=[O:11])[C:6]([CH3:9])([CH3:8])C.CCO[CH2:26][CH3:27].C([O-])(O)=O.[Na+]>C1COCC1.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[CH2:1]([O:2][C:3](=[O:22])[NH:4][C@H:5]([C:10]([NH:12][NH:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:11])[CH:6]([CH3:8])[CH3:9])[C:27]1[CH:26]=[CH:8][CH:6]=[CH:5][CH:10]=1
Reactant: CCOCC
Reactant: COC(=O)N[C@H](C(=O)NNCc1cccc(Br)c1)C(C)(C)C
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NNCc1ccccc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
(2S)-2-Benzyl-oxirane-N-[(1S,2R)-2-hydroxy-indan-1-yl]-2-carboxylic acid amide (0.930 g, 3.01 mmol) and compound 25 (1.23 g, 3.31 mmol) were dissolved in dry THF (40 mL), Ti(OiPr)4 (1.79 mL, 6.02 mmol) was added and the mixture was stirred at 40° C. for 2 h. Et2O (100 mL) and saturated NaHCO3 (aq., 100 mL) was added to the reaction mixture and the phases were separated. The organic phase was then washed with H2O (2×200 mL). All water phases were reextracted with CHCl3 (100 mL), and the combined organic phases were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (RP-silica, CH3CN/H2O, 50:50-70:30) affording 3 (0.95 g, 46%) as a light yellow solid.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12](=[O:45])[C@@H:13]([NH:15][C:16]([C:18]2[N:22]3[C@@:23]([CH2:36][C:37]4[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=4)([CH3:35])[C:24](=[O:34])[N:25]([C:26]4[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=4)[C:21]3=[N:20][CH:19]=2)=[O:17])[CH3:14])[CH2:7]1)=O)C.[NH3:46]>CO>[C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12](=[O:45])[C@@H:13]([NH:15][C:16]([C:18]2[N:22]3[C@@:23]([CH2:36][C:37]4[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=4)([CH3:35])[C:24](=[O:34])[N:25]([C:26]4[CH:27]=[C:28]([Cl:33])[CH:29]=[C:30]([Cl:32])[CH:31]=4)[C:21]3=[N:20][CH:19]=2)=[O:17])[CH3:14])[CH2:7]1)(=[O:3])[NH2:46]
Reactant: N
Reactant: CCOC(=O)[C@@H]1CCCN(C(=O)[C@H](C)NC(=O)c2cnc3n2[C@](C)(Cc2ccc(C#N)cc2)C(=O)N3c2cc(Cl)cc(Cl)c2)C1
Solvent: CO
Product: C[C@H](NC(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)N1CCC[C@@H](C(N)=O)C1
Temperature: 70 °C

Procedure:
(R)-1-((S)-2-{[(R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-propionyl)-piperidine-3-carboxylic acid ethyl ester was dissolved in 7N NH3 in MeOH (5 mL) and heated to 70° C. for 48 h. The volatiles were removed in vacuo and the crude residue was purified by reverse phase HPLC to afford 0.049 g of the title compound as a white foam, m/z 622.3 [M+1]+.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].C(NC(C)C)(C)C.C([Li])CCC.[Si:19]([O:26][CH:27]([C:37]([F:40])([F:39])[F:38])[CH2:28][CH:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)[CH3:30])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].CI>>[Si:19]([O:26][CH:27]([C:37]([F:38])([F:40])[F:39])[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)([CH3:1])[CH3:30])([C:22]([CH3:25])([CH3:23])[CH3:24])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[O-]
Reactant: CC(CC(O[Si](C)(C)C(C)(C)C)C(F)(F)F)c1ccccn1
Agent: [K+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CI
Product: CC(C)(CC(O[Si](C)(C)C(C)(C)C)C(F)(F)F)c1ccccn1
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
To a solution of 3.87 mL (3.87 mmol, 1.5 eq.) of potassium tert-butoxide (1.0 M solution in THF) and 542 μL (3.87 mmol, 1.5 eq.) of diisopropylamine, 1.55 mL (3.87 mmol, 1.5 eq) of n-butyl lithium (2.5 M solution in hexanes) was added dropwise at −75° C. The resulting mixture was allowed to warm to −50° C. over 15 minutes. Then the reaction mixture was treated with 860 mg (2.58 mmol) of 2-[3-(tert-butyldimethylsilanyloxy)-4,4,4-trifluoro-1-methylbutyl]pyridine at −50° C. and the resulting mixture was stirred for 30 minutes at −50° C. The reaction mixture was cooled to −75° C. and treated with 482 μL (7.74 mmol) of methyl iodide and stirred for 1 minute. The reaction mixture was quenched with saturated NH4Cl solution and the product was extracted into ether. The ethereal layer was washed with water and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to give 555 mg (62%) of 2-[3-(tert-butyldimethylsilanyloxy)-4,4,4-trifluoro-1,1-dimethylbutyl]pyridine as a colorless oil.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[CH:14]([C:15]3[C:20]4[O:21][CH2:22][CH:23]=[CH:24][CH2:25][C:19]=4[CH:18]=[CH:17][CH:16]=3)[C:13]([CH3:27])([CH3:26])[C:12]1=[O:28])[CH2:8]2>CO>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[CH:14]([C:15]3[C:20]4[O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:19]=4[CH:18]=[CH:17][CH:16]=3)[C:13]([CH3:26])([CH3:27])[C:12]1=[O:28])[CH2:8]2
Reactant: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)C1c1cccc2c1OCC=CC2
Solvent: CO
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)C1c1cccc2c1OCCCC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.2 %

Procedure:
A solution of 1-(adamantan-2-yl)-4-(2,5-dihydrobenzo[b]oxepin-9-yl)-3,3-dimethylazetidin-2-one (21.1 mg, 0.0560 mmol) in methanol (2 mL) was added with palladium carbon ethylenediamine complex (catalyst amount), and the resultant was stirred at room temperature for 6 hours under a hydrogen atmosphere. The reaction solution was filtered using celite, concentrated in vacuo, and 1-(adamantan-2-yl)-3,3-dimethyl-4-(benzo[b]oxepan-9-yl)azetidin-2-one (16.2 mg, 76.2%) was obtained as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[S:17][C:10]=12.FC1C=C(NC(=O)CC(NC2C=CC=CC=2OC)=O)C=CC=1OC1C=CN=C2C=C(C3N(C)C=CN=3)SC=12.COC1C=CC=CC=1NC(=O)CC(O)=O.[CH3:78][CH:79]([C:83](=[O:91])[NH:84][C:85]1[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=1)[C:80](O)=[O:81]>>[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:80](=[O:81])[CH:79]([CH3:78])[C:83]([NH:84][C:85]2[CH:86]=[CH:87][CH:88]=[CH:89][CH:90]=2)=[O:91])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[S:17][C:10]=12
Reactant: CC(C(=O)O)C(=O)Nc1ccccc1
Reactant: Cn1ccnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Agent: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4nccn4C)sc23)c(F)c1
Agent: COc1ccccc1NC(=O)CC(=O)O
Product: CC(C(=O)Nc1ccccc1)C(=O)Nc1ccc(Oc2ccnc3cc(-c4nccn4C)sc23)c(F)c1

Procedure:
Starting from the amine 9 and following the procedure described above for compound 28a (example 8, step 2) but substituting acid 27 for the acid 37, title compound 38 was obtained as a white solid (20% yield). 1H NMR (d6-DMSO) δ (ppm): 10.99 (s, 1H), 10.51 (s, 1H), 8.64 (d. 1H), 8.25 (s, 1H), 7.94 (s, 1H), 7.80 (s, 1H), 7.65 (d, 2H) 7.57-7.48 (m, 2H), 7.28 (t, 2H), 7.03 (t, 1H), 6.88 (d, 1H), 4.08 (s, 3H), 1.18 (s, 3H). MS (m/z): 516.1 (M+H).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:22]#[C:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:30]([O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][C:45](Cl)=[O:46])=[CH:40][CH:39]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:30]([O:37][C:38]1[CH:39]=[CH:40][C:41]([CH2:44][C:45]([NH:21][C:18]2[C:17]([C:22]#[C:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])=[CH:14][CH:13]=3)=[CH:20][N:19]=2)=[O:46])=[CH:42][CH:43]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(C#Cc3ccccc3)n2)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2C#Cc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 20 h
Yield: 60 %

Procedure:
Under an argon atmosphere, to a mixture of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-(phenylethynyl)pyrazin-2-amine (7p) (300 mg, 747 μmol) and 4-(dimethylamino)pyridine (13.8 mg, 113 μmol) dissolved in anhydrous pyridine (15 mL) was added 2-[4-(tert-butyldimethylsilyl oxy)phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was heated with stirring at 50° C. for 20 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (100 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=3/1) to give Compound 11p (291 mg, 448 μmol, 60.0%) as a brown solid. Rf=0.19 (n-hexane/ethyl acetate=3/1); 1H NMR (400 MHz, DMSO-d6) δ 0.10 (s, 6H), 0.20 (s, 6H), 0.90 (s, 9H), 0.93 (s, 9H), 3.65 (s, 2H), 6.63-6.73 (AA′BB′, 2H), 6.92-7.02 (AA′BB′, 2H), 7.17-7.27 (AA′BB′, 2H), 7.33-7.48 (m, 5H), 7.96-8.05 (AA′BB′, 2H), 8.99 (s, 1H), 10.69 (s, 1H); 13C NMR (67.8 MHz, DMSO-d6) δ −4.60 (2C), −4.61 (2C), 17.8, 17.9, 25.5 (6C), 41.7, 85.8, 94.5, 119.5 (2C), 120.4 (2C), 121.2, 128.2, 128.28 (2C), 128.34, 128.6 (2C), 129.5, 130.3 (2C), 131.8 (2C), 133.1, 138.5, 146.6, 148.0, 153.8, 156.9, 169.4; IR (KBr, cm−1) 530, 689, 756, 781, 839, 914, 1007, 1125, 1169, 1258, 1379, 1433, 1510, 1605, 1672, 2214, 2857, 2930, 2955, 3235.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][C:13]=2[O:23][CH3:24])[N:3]=1.[CH2:25](B(O)O)[CH3:26].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[CH2:25]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][C:13]=2[O:23][CH3:24])[N:3]=1)[CH3:26]
Reactant: CCB(O)O
Reactant: COc1cc(OC(F)(F)F)ccc1-c1nc(Cl)c([N+](=O)[O-])cc1C
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: [K+]
Solvent: Cc1ccccc1
Product: CCc1nc(-c2ccc(OC(F)(F)F)cc2OC)c(C)cc1[N+](=O)[O-]

Procedure:
Tetrakistriphenylphosphinepalladium(0) (0.03 g, 0.03 mmol) is added to 2-chloro-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-3-nitro-pyridine (0.10 g, 0.27 mmol) in toluene (5 mL). Ethyl boronic acid (0.1 g, 1.1 mmol) and potassium carbonate (0.07 g, 0.55 mmol)) are added to this solution, and the reaction is heated to reflux for 17 hours. The product is extracted with ethyl acetate (20 mL). Combined extracts are washed with brine (20 mL), dried over sodium sulfate, and concentrated in vacuo. Purification by flash column chromatography (5% EtOAC-hexane) yields 2-ethyl-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-3-nitro-pyridine as a yellow solid TLC Rf 0.55 (elution with 10% ethyl acetate-hexane)
Reaction SMILES: I[C:2]1[C:7]2[C:8](=O)[C:9]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17]C(=O)OCC4C=CC=CC=4)[C:10]=3[CH2:11][CH2:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.O.[NH2:30][NH2:31]>>[N:30]1[NH:31][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[CH2:12][CH2:11][C:10]4=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=[C:9]4[C:8]=1[C:7]=23
Reactant: NN
Reactant: O=C(Nc1cccc2c1CCc1cccc(I)c1C2=O)OCc1ccccc1
Solvent: O
Product: Nc1cccc2c1CCc1cccc3[nH]nc-2c13

Procedure:
50 mg of benzyl N-(6-iodo-5-oxo-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-1-yl)carbamate prepared in Example 8-a was treated with hydrazine monohydrate by the procedure of Example 1-h and purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:2), to give 15 mg of the title compound as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[CH:17]=[CH:16][C:10]([CH:11]=[CH:12][C:13]([OH:15])=O)=[CH:9][CH:8]=1)=[O:4].S(Cl)(Cl)=O.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH2:29])[CH:23]=1>CN(C)C=O.ClCCl.C(OCC)(=O)C>[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH:29][C:13](/[CH:12]=[CH:11]/[C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])=[CH:17][CH:16]=2)=[O:15])[CH:23]=1
Reactant: COC(=O)CCc1ccc(C=CC(=O)O)cc1
Reactant: NCc1cccnc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)CCc1ccc(/C=C/C(=O)NCc2cccnc2)cc1
Yield: 85.6 %

Procedure:
A solution of 4-[2-(methoxycarbonyl)ethyl]cinnamic acid (2.38 g), thionyl chloride (0.82 ml) and dimethylformamide (2 drops) in 50 ml dichloromethane was heated at reflux for 30 minutes. After evaporation of dichloromethane and low-boiling components, the residue was dried under reduced pressure to give a solid, which was then dissolved in 20 ml ethyl acetate and stirred with 1.10 g of 3-picolylamine in 20 ml ethyl acetate at room temperature for 30 minutes. After the reaction mixture was washed with saturated aqueous sodium bicarbonate, the resulting aqueous layer was extracted with 40 ml ethyl acetate. The combined organic layers were washed with saturated aqueous sodium carbonate and brine, and then dried over sodium sulfate. The drying agent was filtered off and the solvent was evaporated to give crude crystals (3.23 g), which were then recrystallized from ethyl acetate to provide methyl 3-[4-[(E)-2-[N-(3-pyridylmethyl)carbamoyl]ethenyl]phenyl]propionate (2.82 g, 86%) as colorless plate crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](OC)=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][CH2:21][CH2:20][C:19]2=[O:23])=[C:14]([CH3:24])[CH:13]=1.[CH3:25][N:26]1[CH2:31][CH2:30][C:29]2([C:42]3[C:34](=[CH:35][C:36]4[CH2:37][CH2:38][NH:39][C:40]=4[CH:41]=3)[O:33][CH2:32]2)[CH2:28][CH2:27]1>>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH:27]2[CH2:28][C:29]3([C:42]4[C:34](=[CH:35][C:36]5[CH2:37][CH2:38][NH:39][C:40]=5[CH:41]=4)[O:33][CH2:32]3)[CH2:30][CH2:31][N:26]2[CH3:25])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][CH2:21][CH2:20][C:19]2=[O:23])=[C:14]([CH3:24])[CH:13]=1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Reactant: COC(=O)c1ccc(-c2ccc(N3CCCC3=O)c(C)c2)c(C)c1
Product: Cc1cc(C(=O)C2CC3(CCN2C)COc2cc4c(cc23)NCC4)ccc1-c1ccc(N2CCCC2=O)c(C)c1

Procedure:
The title compound was prepared from methyl 2,3'-dimethyl-4'-(2-oxopyrrolidin-1-yl)biphenyl-4-carboxylate (D32) and 1'-methyl-2,3,6,7-tetrahydrospiro[filro[2,3-f]indole-3,4'-piperidine] (D7) following the method of Example 1. This was obtained as a yellow oil (77%), which was converted to its hydrochloride salt, crystallising from acetone.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>>[Br:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([N:20]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH2:18][CH3:19])=[O:27])=[CH:24][CH:23]=1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: O=C(Cl)c1ccc(Br)cc1
Product: CCOC(=NC(=O)c1ccc(Br)cc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and p-bromobenzoyl chloride, there is obtained ethyl N-(p-bromobenzoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate, m.p. 116°-117° C.;
Reaction SMILES: [Mg].BrC1C=C(OC)C(OC)=C(C2OCCCO2)C=1.[O:19]1[CH2:24][CH2:23][CH2:22][O:21][CH:20]1[C:25]1[CH:26]=[C:27]([CH:35]([C:37]2[CH:42]=[C:41]([C:43]3[O:44][CH:45]=[CH:46][CH:47]=3)[CH:40]=[CH:39][C:38]=2[O:48][CH3:49])[OH:36])[CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl.C(OCC)C>[O:19]1[CH2:24][CH2:23][CH2:22][O:21][CH:20]1[C:25]1[CH:26]=[C:27]([C:35]([C:37]2[CH:42]=[C:41]([C:43]3[O:44][CH:45]=[CH:46][CH:47]=3)[CH:40]=[CH:39][C:38]=2[O:48][CH3:49])=[O:36])[CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32]
Reactant: COc1ccc(-c2ccco2)cc1C(O)c1cc(OC)c(OC)c(C2OCCCO2)c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: COc1cc(Br)cc(C2OCCCO2)c1OC
Agent: [Mg]
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(-c2ccco2)cc1C(=O)c1cc(OC)c(OC)c(C2OCCCO2)c1

Procedure:
As shown in Reaction 1, first, magnesium was added to 2-(5-bromo-2,3-dimethoxyphenyl)-1,3-dioxane as a starting material, which substituted an aldehyde group with an acetyl group. Then, Compound (III) derivative was substituted thereto to synthesize (3-(1,3-dioxan-2-yl)-4,5-dimethoxyphenyl)(5-(furan-2-yl)-2-methoxyphenyl)methanol. Thus obtained (3-(1,3-dioxan-2-yl)-4,5-dimethoxyphenyl)(5-(furan-2-yl)-2-methoxyphenyl)methanol (1.7 g, 4.0 mmol) was dissolved in 40 ml of anhydrous dichloromethane, whereto 4 Å molecular sieves (0.6 g) and pyridinium dichromate (PDC) (2.24 g, 6.0 mmol) were added sequentially at 0° C. The mixture was reacted at room temperature for 24 hours. After completion of the reaction, diethylether (150 ml) was added to the reaction mixture, and the precipitates were filtered off using Celite. An organic layer was extracted out from the filtrate using brine, and the organic layer was dried over Na2 SO3. The solvent was removed, and the resulting residue was purified by column chromatography (SiO2, n-Hex/EA=1/1) to synthesize Compound 233 (1.02 g, 60%).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:9]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[F:21])=[O:13])=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH2:31])=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1>[Cl:8][C:6]1[CH:7]=[C:2]([NH:31][CH2:30][C:27]2[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[C:3]2[N:4]([C:9]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[F:21])=[O:13])=[CH:10][N:11]=2)[N:5]=1
Reactant: O=C(Nc1ccncc1F)c1cnc2c(Br)cc(Cl)nn12
Reactant: COc1ccc(CN)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(CNc2cc(Cl)nn3c(C(=O)Nc4ccncc4F)cnc23)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
To a suspension of 8A (300 mg, 0.920 mmol) in NMP (2 mL) was added (4-methoxyphenyl)methanamine (0.120 mL, 0.920 mmol) and DIEA (0.161 mL, 0.920 mmol). The reaction mixture was stirred at 80° C. for 1 h, and then cooled to room temperature. Water was added. The light yellow solid was collected by filtration, rinsed with water and dried under vacuum to give 19A (348 mg, 89%). [M+H]=426. HPLC Peak Rt=3.000 minutes. (Chromolith column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 254 nm.)
Reaction SMILES: [NH3:1].Cl[C:3]1[C:4]2[N:5]([C:9]([CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[N:10][C:11]=2[C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[CH:6]=[CH:7][N:8]=1>O.CC(O)C>[CH:25]1([C:9]2[N:5]3[CH:6]=[CH:7][N:8]=[C:3]([NH2:1])[C:4]3=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)[N:10]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: Clc1nccn2c(C3CCCC3)nc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: N
Solvent: O
Solvent: CC(C)O
Product: Nc1nccn2c(C3CCCC3)nc(-c3ccc(Oc4ccccc4)cc3)c12
Reaction time: 8 h

Procedure:
20 M NH3 in H2O (2 mL) was added to a suspension of 8-chloro-3-cyclopentyl-1-(4-phenoxyphenyl)-imidazo[1,5-a]pyrazine (21 mg, 0.054 mmol) in i-PrOH (2 mL). The mixture was heated in an oil bath set at 105° C. overnight. Reaction mixture was concentrated in vacuo and purification by prep TLC using 10% MeOH in DCM afforded 9 mg of the title compound as an off white solid. The compound was registered as OSIP 700099. 1H NMR (400 MHz, CDCl3): δ=1.61-1.95 (m, 4H), 2.02-2.23 (m, 4H), 3.30-3.43 (m, 1H), 5.07 (br. s., 2H), 7.03-7.08 (m, 3H), 7.08-7.16 (m, 3H), 7.23 (d, J=5.05 Hz, 1H), 7.30-7.41 (m, 2H), 7.61 (d, 2H). MS (ES+): m/z 370.83 (100)[MH+]. HPLC: tR=2.61 min (Open Lynx polar—5 min).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:13][C:12]2=[O:25])=[CH:5][CH:4]=1.[CH2:26]([N:28](CC)[CH2:29][CH3:30])[CH3:27].CS(Cl)(=O)=O.N1CCCC1>C(Cl)Cl>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][N:11]([CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:28]4[CH2:29][CH2:30][CH2:27][CH2:26]4)=[CH:4][CH:5]=3)[C:12](=[O:25])[CH:13]=2)[CH:20]=1
Reactant: CCN(CC)CC
Reactant: O=c1cc(OCc2cccnc2)ccn1CCc1ccc(CO)cc1
Agent: CS(=O)(=O)Cl
Solvent: C1CCNC1
Solvent: ClCCl
Product: O=c1cc(OCc2cccnc2)ccn1CCc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 50 mg (0.15 mmol) 1-[2-(4-hydroxymethyl-phenyl)-ethyl]-4-(pyridin-3-ylmethoxy)-1H-pyridin-2-one (example 11.1a) in 3.0 mL DCM is added 62 μL triethylamine (0.45 mmol) and subsequently 23 μL (0.30 mmol) methanesulfonyl chloride at RT. The reaction mixture is stirred 1 h at RT, and then 25 μL (0.30 mmol) pyrrolidine is added. The mixture is stirred additional 2 h at RT and is directly transferred to a reverse HPLC for purification (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).