Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=O)=[CH:11][CH:10]=2)[CH:6]=[N:5][CH:4]=1)#[N:2].[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH:26]([NH2:28])[CH3:27]>>[C:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([CH3:20])([CH3:19])[C:16]([NH:28][CH:26]([C:22]3[O:21][CH:25]=[CH:24][CH:23]=3)[CH3:27])=[O:18])=[CH:13][CH:14]=2)[CH:6]=[N:5][CH:4]=1)#[N:2]
Reactant: CC(N)c1ccco1
Reactant: CC(C)(C(=O)O)c1ccc(-c2cncc(C#N)n2)cc1
Product: CC(NC(=O)C(C)(C)c1ccc(-c2cncc(C#N)n2)cc1)c1ccco1
Yield: 35 %

Procedure:
Prepared in a similar manner to Example 20 from 2-(4-(6-Cyanopyrazin-2-yl)phenyl)-2-methylpropanoic acid (example 20a) and 1-(furan-2-yl)ethanamine. Yield 35%. 1H NMR (400 MHz, dMSO): δ 1.32-1.33 (d, 3H), 1.49-1.52 (d, 6H), 5.09 (m, 1H), 6.06 (d, 1H), 6.33-6.35 (dd, 1H), 7.49-7.51 (d, 2H), 7.54 (d, 1H), 8.12-8.14 (d, 2H), 9.16 (s, 1H), 9.56 (s, 1H); MS+H (361).
Reaction SMILES: [OH:1][C:2]([CH3:13])([CH3:12])[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1.[OH-].[Na+].OO>O1CCCC1.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>[OH:1][C:2]([CH3:13])([CH3:12])[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8](/[CH:12]=[CH:2]/[CH2:3][CH2:4][CH3:5])=[CH:7][CH:6]=1
Reactant: CC(C)(O)C#Cc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC/C=C/c1ccc(C#CC(C)(C)O)cc1
Temperature: 25 °C
Yield: 163.5 %

Procedure:
In a four necked flask equipped with a stirrer, a reflux condenser and a thermometer which had been replaced by a nitrogen atmosphere, 4-(3-hydroxy-3,3-dimethyl-1-propynyl)-1-bromobenzene (3.6 g, 15 mmol), tetrakis(triphenylphosphine)palladium (0.06 g, 0.05 mmol), sodium hydroxide (0.8 g, 20 mmol) and tetrahydrofuran (60 ml) were charged. Then, to the mixture, a solution of E-1-pentenylcatecholborane prepared in Reference Example 1 (20 mmol) in tetrahydrofuran (50 ml) was dropwise added at room temperature, followed by heat refluxing for 6 hours while stirring. After cooling the reaction mixture to room temperature, 30% aqueous hydrogen peroxide (2 ml) was added to the mixture, followed by stirring for 1 hour. The mixture was extracted with toluene and water. The organic layer was washed with water twice and dried over anhydrous magnesium sulfate. After removing the solvents, the residue was purified by silica gel column chromatography to obtain 4-(3-hydroxy-3,3-dimethyl-1-propynyl)-1-(1-trans-pentenyl)benzene (2.8 g). Yield: 83%. Melting point: 65° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:25][C:26]([C:28]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:29]=1[N:30]=[C:31]([NH:39][C:40]([CH3:43])([CH3:42])[CH3:41])[C:32]([CH3:38])=[N:33]2)=[O:27].C1COCC1>[NH4+].[Cl-].CCO>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10](=[O:17])[CH:11]([CH2:25][C:26]([C:28]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:29]=1[N:30]=[C:31]([NH:39][C:40]([CH3:43])([CH3:42])[CH3:41])[C:32]([CH3:38])=[N:33]2)=[O:27])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1nc2cccc(C(=O)CBr)c2nc1NC(C)(C)C
Reactant: CCOC(=O)CC(=O)CNC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C(CC(=O)c1cccc2nc(C)c(NC(C)(C)C)nc12)C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 25-mL round-bottomed flask was added ethyl 4-((tert-butoxycarbonyl)amino)-3-oxobutanoate (601) (0.47 g, 1.91 mmol), K2CO3 (0.41 g, 2.97 mmol), 2-bromo-1-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)ethanone (606) (0.40 g, 1.19 mmol), THF (3 mL), and EtOH (3 mL). The reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with sat NH4Cl (5 mL) and extracted with EtOAc (10 mL). The organic extract was washed with water (5 mL), dried over Na2SO4 and concentrated. Ethyl 4-((tert-butoxycarbonyl)amino)-2-(2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-2-oxoethyl)-3-oxobutanoate (334a) was obtained as a light yellow oil and used without further purification. m/z (ESI, +ve) 501.3 (M+H)+. To a 15-mL glass tube was added ethyl 4-((tert-butoxycarbonyl)amino)-2-(2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-2-oxoethyl)-3-oxobutanoate (334a), crude from previous step, NH4OAc (0.36 g, 4.71 mmol), EtOH (2 mL), and AcOH (1 mL). The tube was sealed and heated at 50° C. for 3 h. The reaction mixture was cooled to RT and was concentrated to half of its volume. The mixture was diluted with EtOAc (10 mL) and water (5 mL). The organic extract was washed with NaOH (1N, 5 mL), water (5 mL), brine (5 mL), dried over Na2SO4, and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (24 g), eluting with a gradient of 0% to 30% EtOAc in hexanes to give ethyl 2-(((tert-butoxycarbonyl)amino)methyl)-5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (334b) (0.33 g, 59% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.64 (br. s., 1H), 7.82 (dd, J=1.17, 7.43 Hz, 1H), 7.58-7.64 (m, 1H), 7.41 (d, J=2.74 Hz, 1H), 7.35 (s, 1H), 6.94 (br. s., 1H), 4.53 (d, J=5.28 Hz, 2H), 4.21 (q, J=7.04 Hz, 2H), 2.56 (s, 3H), 1.58 (s, 9H), 1.39 (s, 9H), 1.30 (t, J=7.10 Hz, 3H). m/z (ESI, +ve) 482.2 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:21]1[N:30]=[CH:29][C:28]2[C:23](=[C:24]([F:35])[CH:25]=[C:26]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:27]=2)[C:22]1=[O:36])(=[O:3])[CH3:2].Cl[C:38]1[CH:39]=[C:40]([NH:46][C:47]2[CH:59]=[C:50]3[CH2:51][N:52]([CH:55]4[CH2:58][O:57][CH2:56]4)[CH2:53][CH2:54][N:49]3[N:48]=2)[C:41](=[O:45])[N:42]([CH3:44])[N:43]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[Cl-].[NH4+]>C(O)CCC.O>[C:31]([C:26]1[CH:27]=[C:28]2[C:23](=[C:24]([F:35])[CH:25]=1)[C:22](=[O:36])[N:21]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:38]3[CH:39]=[C:40]([NH:46][C:47]4[CH:59]=[C:50]5[CH2:51][N:52]([CH:55]6[CH2:58][O:57][CH2:56]6)[CH2:53][CH2:54][N:49]5[N:48]=4)[C:41](=[O:45])[N:42]([CH3:44])[N:43]=3)[C:6]=1[CH2:5][O:4][C:1](=[O:3])[CH3:2])[N:30]=[CH:29]2)([CH3:33])([CH3:32])[CH3:34]
Reactant: Cn1nc(Cl)cc(Nc2cc3n(n2)CCN(C2COC2)C3)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CCCCO
Product: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(C3COC3)C4)c(=O)n(C)n2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
A solution of 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (249 mg, 0.50 mmol), 6-chloro-2-methyl-4-(5-oxetan-3-yl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-2H-pyridazin-3-one (113 mg, 0.34 mmol), potassium phosphate (178 mg, 0.84 mmol) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (16.0 mg, 0.03 mmol) in butanol (8 ml) and water (2 mL) was flushed with argon before (bis[dibenzylideneacetone]dipalladium) (9.65 mg, 0.02 mmol) was added and the resulting solution heated at 100° C. in for 2 h. The resulting mixture was cooled, poured into a saturated solution of ammonium chloride and extracted with methylene chloride (2×100 mL). The layers were separated and the organic phase dried over magnesium sulfate. The mixture was filtered and concentrated in vacuo. The residue was dissolved in dioxane (10 mL) and treated with a lithium hydroxide solution (0.5 mL, 2.0 M), and the resulting mixture was stirred at room temperature overnight. The resulting mixture was poured into a saturated ammonium chloride solution and extracted with methylene chloride (2×100 mL). The layers were separated and the organic phase dried over magnesium sulfate. The mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 24 g, 1% to 10% methanol in dichloromethane) to give acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-[1-methyl-5-(5-oxetan-3-yl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-benzyl ester (113 mg, 54%) as a light yellow solid: mp. 180-185° C.; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.37 (s, 9H) 2.66-2.92 (m, 2H) 3.40-3.83 (m, 6H) 3.98 (t, J=5.48 Hz, 2H) 4.26-4.82 (m, 7H) 6.01 (s, 1H) 7.36-8.00 (m, 6H) 8.50 (d, J=2.64 Hz, 1H) 9.25 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([NH2:7])=[N:4][N:3]=1.[H-].[Na+].[N+](C1C=CC([O:19][C:20]([N:22]2[CH2:25][CH:24]([O:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[F:39])=[CH:29][N:28]=3)[CH2:23]2)=O)=CC=1)([O-])=O>CN(C=O)C>[CH3:1][C:2]1[O:6][C:5]([NH:7][C:20]([N:22]2[CH2:23][CH:24]([O:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[F:39])=[CH:29][N:28]=3)[CH2:25]2)=[O:19])=[N:4][N:3]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CC(Oc2ccc(-c3ccccc3F)cn2)C1
Reactant: Cc1nnc(N)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nnc(NC(=O)N2CC(Oc3ccc(-c4ccccc4F)cn3)C2)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 11 %

Procedure:
To a solution of 5-Methyl-[1,3,4]oxadiazol-2-ylamine (31 mg, 0.31 mmol, [Cas. No. 52838-39-8]) in DMF (3 mL) at 0° C. was added sodium hydride (20 mg, 0.5 mmol, 60% disp. in mineral oil). After stirring at 0° C. for 15 min. a solution of 3-[5-(2-Fluoro-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylic acid 4-nitro-phenyl ester (102 mg, 0.25 mmol) in DMF (4 mL) was added dropwise. After stirring for 16 hrs at ambient temperature the reaction mixture was concentrated in vacuo, diluted with ethyl acetate (50 mL) and washed sequentially with sat. aqueous sodium hydrogen carbonate solution (2×50 mL) then sat. sodium chloride solution (50 mL). Mixture dried over magnesium sulphate and filtered. Filtrate solvents were removed in vacuo and the residue was purified by preparative HPLC to give the title compound (10 mg, 11%)
Reaction SMILES: ClC1C(C)=C(C=CC=1)C(O)=O.C1(N)CC1.[Cl:16][C:17]1[C:18]([CH3:29])=[C:19]([CH:26]=[CH:27][CH:28]=1)[C:20]([NH:22][CH:23]1[CH2:25][CH2:24]1)=O>>[Cl:16][C:17]1[C:18]([CH3:29])=[C:19]([CH:26]=[CH:27][CH:28]=1)[CH2:20][NH:22][CH:23]1[CH2:24][CH2:25]1
Reactant: Cc1c(Cl)cccc1C(=O)NC1CC1
Agent: Cc1c(Cl)cccc1C(=O)O
Agent: NC1CC1
Product: Cc1c(Cl)cccc1CNC1CC1

Procedure:
Prepared from 3-chloro-2-methylbenzoic acid (4.80 g, 28.1 mmol) and cyclopropylamine according to above-described procedures C and E (5.50 g, quantitative over 2 steps). LC-MS (3-chloro-N-cyclopropyl-2-methylbenzamide): tR=0.81 min, ES+: 210.11; LC-MS (title compound): tR=0.62 min, ES+: 196.05.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:15]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)([CH3:17])[CH3:16]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([O:31][C:28]2[CH:27]=[CH:26][C:25]([C:15]([C:18]3[CH:19]=[CH:20][C:21]([O:24][S:11]([C:8]4[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=4)(=[O:13])=[O:12])=[CH:22][CH:23]=3)([CH3:17])[CH3:16])=[CH:30][CH:29]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Oc2ccc(C(C)(C)c3ccc(OS(=O)(=O)c4ccc(C(C)(C)C)cc4)cc3)cc2)cc1
Yield: 70.4 %

Procedure:
An oven-dried 50 ml 3 necked flask is equipped with a magnetic stirring bar and reflux condenser carrying a CaCl2 drying tube and is charged with 4-tert-butylbenzenesulfonyl chloride 9.3 grams (40 mmol), 4,4'-isopropylidenediphenol (4.11 grams, 18 mmol), 4-dimethylaminopyridine 0.11 gram, 0 9 mmol), and anhydrous pyridine (20 ml). and the mixture is stirred and heated at reflux for 14 hours. Workup consists of partitioning the mixture between Et2O and H2O (50 ml each), washing the organic phase successively with 100 ml portions of H2O (2×), 5 percent HCl (2×). H2O, saturated (2×), H2O and brine, then drying (MgSO4). filtration and concentration. This gives 10.41 grams of a pale yellow sold. Three consecutive recrystallizations from EtOH-MeOH (2:1) affords 7.87 grams (70 percent yield) of the title compound as white prisms. m.p. 124° C. to 127° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:18])([CH3:17])[CH2:10]/[C:11](/[CH3:16])=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:41][N:42]([C@@H:59]([C:67](=[O:70])[NH:68][CH3:69])[CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:43](=[O:58])[CH:44]([NH:56][CH3:57])[CH2:45][C:46]1[CH:55]=[CH:54][C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:18])([CH3:17])[CH2:10]/[C:11](/[CH3:16])=[CH:12]/[C:13](=[O:15])[N:56]([CH3:57])[C@@H:44]([C:43](=[O:58])[N:42]([CH3:41])[C@@H:59]([C:67](=[O:70])[NH:68][CH3:69])[CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[CH2:45][C:46]1[CH:55]=[CH:54][C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)C(Cc1ccc2ccccc2c1)NC
Reactant: C/C(=C\C(=O)O)CC(C)(C)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C(\C)CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.2 %

Procedure:
(2E)-5-tert-Butoxycarbonylamino-3,5-dimethylhex-2-enoic acid (0.30 g; 1.17 mmol.) was dissolved in methylene chloride (10 mL). 1-Hydroxy-7-azabenzotriazol (0.16 g; 1.17 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.26 g; 1.28 mmol) were added and the reaction mixture was stirred for 15 min at room temperature. N-Methyl-2-methylamino-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(2-naphthyl)propionamide (0.47 g; 1.67 mmol) was dissolved in methylene chloride (10 mL) and added. Diisopropylethylamine (0.20 mL; 1.66 mmol ) was added and the reaction was stirred for 12 hours at room temperature. Methylene chloride (10 mL) was added and the reaction was washed with water (10 mL), an aqueous solution of sodium hydrogen sulfate (10%; 10 mL) and an aqueous solution of sodium hydrogen carbonate (pH 8; 10 mL) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was chromatographed on silica (3×30 cm) using ethyl acetate/methylene chloride (1:1) as eluent to afford 0.37 g of ((3E)-1,1,3-trimethyl-4-(methyl-((1R)-1-(methyl-((1R)-1-methylcarbamoyl-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)but-3-enyl)carbamic acid tert butylester.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:7]2[O:8][CH2:9][CH:10]([OH:11])[CH:6]2[O:5][CH2:4]1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:19][S:20]([O:11][CH:10]1[CH2:9][O:8][CH:7]2[CH:3]([O:2][CH3:1])[CH2:4][O:5][CH:6]12)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: COC1COC2C(O)COC12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1COC2C(OS(C)(=O)=O)COC12
Temperature: 25 °C
Reaction time: 6 h
Yield: 71.8 %

Procedure:
To a solution of 6-methoxyhexahydrofuro[3,2-b]furan-3-ol (1.03 g, 6.43 mmol) in anhydrous DCM (30 mL) were added N,N-diethylethanamine (1.3 mL, 9.4 mmol) and methanesulfonyl chloride (0.58 mL, 7.5 mmol). The reaction was stirred at rt for 6 h. The reaction was quenched with NaHCO3 (sat, 50 mL), and then extracted with EtOAc (80 mL×3). The organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound as colorless oil (1.1 g, 71.9%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[CH:10][C:9]=1[NH2:19])(C)(C)C.CC1(C)O[C:26](=[O:28])[CH:25]=[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]3[O:36][CH:37]=[CH:38][N:39]=3)[CH:30]=2)O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:36]1[CH:37]=[CH:38][N:39]=[C:35]1[C:31]1[CH:30]=[C:29]([C:24]2[CH2:25][C:26](=[O:28])[NH:19][C:9]3[CH:10]=[C:11]([N:14]4[CH:18]=[CH:17][CH:16]=[CH:15]4)[CH:12]=[CH:13][C:8]=3[N:7]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: CC1(C)OC(=O)C=C(c2cccc(-c3ncco3)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3ncco3)c2)=Nc2ccc(-n3cccc3)cc2N1

Procedure:
The title compound was prepared from (2-amino-4-pyrrol-1-yl-phenyl)-carbamic acid tert.-butyl ester (Example J2) (137 mg) and 2,2-dimethyl-6-(3-oxazol-2-yl-phenyl)-[1,3]dioxin-4-one (Example L5) (271 mg) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (83 mg).
Reaction SMILES: C(O[C:4](=[O:35])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]3[C:13]=2[CH:14]=[CH:15][C:16]([C:24]([F:27])([F:26])[F:25])=[N:17]3)[CH2:8][C@@H:7]1[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)C.[NH3:36].[C-]#N.[Na+]>CO>[CH2:28]([C@H:7]1[CH2:8][N:9]([C:12]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]3[C:13]=2[CH:14]=[CH:15][C:16]([C:24]([F:26])([F:25])[F:27])=[N:17]3)[CH2:10][CH2:11][N:6]1[CH2:5][C:4]([NH2:36])=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOC(=O)CN1CCN(c2ccc(OC)c3nc(C(F)(F)F)ccc23)C[C@@H]1Cc1ccccc1
Reactant: N
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Product: COc1ccc(N2CCN(CC(N)=O)[C@@H](Cc3ccccc3)C2)c2ccc(C(F)(F)F)nc12
Reaction time: 24 h
Yield: 79 %

Procedure:
[(S)-2-Benzyl-4-(8-methoxy-2-trifluoromethyl-quinolin-5-yl)-piperazin-1-yl]-acetic acid ethyl ester in a 7 N solution of ammonia in MeOH (10 mL) was treated with catalytic amount of sodium cyanide and allowed to stir for 24 h. The reaction mixture was then evaporated, washed with water and air dried to afford the title compound as a yellow solid (180 mg, 79%). LC/MS (Method B) 2.57 min, [M+1]+ 459.
Reaction SMILES: [C:1]([N:4]1[CH2:25][CH2:24][C:7]2[N:8]=[C:9](S(C)(=O)=O)[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[NH2:26][CH2:27][CH2:28][NH:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][N:31]=1>>[C:1]([N:4]1[CH2:25][CH2:24][C:7]2[N:8]=[C:9]([NH:26][CH2:27][CH2:28][NH:29][C:30]3[N:31]=[CH:32][C:33]([C:36]#[N:37])=[CH:34][CH:35]=3)[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2nc(S(C)(=O)=O)nc(-c3ccc(Cl)cc3Cl)c2C1
Reactant: N#Cc1ccc(NCCN)nc1
Product: CC(=O)N1CCc2nc(NCCNc3ccc(C#N)cn3)nc(-c3ccc(Cl)cc3Cl)c2C1

Procedure:
Following Example 7, reaction of 6-acetyl-4-(2,4-dichlorophenyl)-2-(methylsulfonyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidine and 2-(2-aminoethyl-amino)-5-cyanopyridine gave 6-[(2-{[6-acetyl-4-(2,4-dichlorophenyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-2-yl]amino}ethyl)amino]pyridine-3-carbonitrile.
Reaction SMILES: CO[C:3]([C:5]1[N:10]=[CH:9][C:8]2[N:11]=[CH:12][NH:13][C:7]=2[CH:6]=1)=[O:4].[N:14]1([CH2:20][CH2:21][NH2:22])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>CO>[N:14]1([CH2:20][CH2:21][NH:22][C:3]([C:5]2[N:10]=[CH:9][C:8]3[N:11]=[CH:12][NH:13][C:7]=3[CH:6]=2)=[O:4])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: NCCN1CCOCC1
Reactant: COC(=O)c1cc2[nH]cnc2cn1
Solvent: CO
Product: O=C(NCCN1CCOCC1)c1cc2[nH]cnc2cn1

Procedure:
2.0 g of methyl-1H-imidazo[4,5-c]pyridine-6-carboxylate (example D2), 22.1 g of 2-morpholin-4-ylethanamine and 70 ml methanol were placed in an autoclave for 2 h at 140° C. The methanol and 2-morpholin-4-ylethanamine were distilled off the reaction mixture under reduced pressure and the residue was purified by flash chromatography. After crystallization from ethyl acetate/n-hexane the title compound was obtained.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:26][O:27][C:28]([N:30]1[C@@H:38]2[C@@H:33]([C@@:34](O)([C:39]#[C:40][C:41]3[CH:42]=[C:43]([CH3:47])[CH:44]=[CH:45][CH:46]=3)[CH2:35][CH2:36][CH2:37]2)[CH2:32][CH2:31]1)=[O:29]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:26][O:27][C:28]([N:30]1[C@H:38]2[C@H:33]([C@:34]([O:9][C:8](=[O:10])[CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)([C:39]#[C:40][C:41]3[CH:42]=[C:43]([CH3:47])[CH:44]=[CH:45][CH:46]=3)[CH2:35][CH2:36][CH2:37]2)[CH2:32][CH2:31]1)=[O:29]
Reactant: O=C(O)CCN1CCCC1
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)CCN1CCCC1
Temperature: 22 °C
Reaction time: 50 h
Yield: 35 %

Procedure:
3-Pyrrolidin-1-yl-propionic acid (143 mg, 1.0 mmol) and dicyclohexylcarbodiimide (247 mg, 1.2 mmol) were dissolved in dichloromethane (5 mL). Subsequently, 4-dimethylaminopyridine (97 mg, 0.8 mmol) and (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester (250 mg, 0.8 mmol) were added. The resulting suspension was stirred at room temperature (22° C.) for 50 h. The precipitation was then removed by filtration and the clear filtrate was subjected to silica gel flash chromatography [ISCO CombiFlash Companion; 40 g silica gel; methylenechloride/methanol; methanol 0% (4 min), 1% (4 min), 2% (4 min), 2-5% (2 min), 5% (5 min) and 10% (8 min)]. Then, the solvents were evaporated to yield (3aR,4S,7aR)-4-(3-pyrrolidin-1-yl-propionyloxy)-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester (123 mg, 0.28 mmol, 35% yield). MS [M+H]=439; RT=6.122 min (LC-MS Method III). 1H-NMR (600 MHz; DMSO-d6) ppm 1.23 (m, 1H), 1.65 (broad s, 4H), 1.80 to 2.10 (m, 5H), 2.30 (s, 3H), 2.46 (m, 4H), 2.49 (m, 4H), 2.67 (m, 2H), 3.13 (m, 1H), 3.30 (m, 1H), 3.42 (q, 1H), 3.55 (s, 3H), 3.88 (m, 1H), 7.22 (broad s, 2H) and 7.27 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]2=[CH:13][S:14][CH:15]=[C:4]2[C:3]1=[O:16].[C:17]1([CH2:23][C:24](Cl)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1C=CC=CC=1>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:24](=[O:25])[CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]2=[CH:13][S:14][CH:15]=[C:4]2[C:3]1=[O:16]
Reactant: CN1C(=O)c2cscc2Nc2ccccc21
Reactant: O=C(Cl)Cc1ccccc1
Solvent: c1ccccc1
Product: CN1C(=O)c2cscc2N(C(=O)Cc2ccccc2)c2ccccc21
Reaction time: 5 h

Procedure:
A slurry of 6.90 g. of 4,9-dihydro-9-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 4.36 ml. (5.10 g.) of phenylacetyl chloride in 100 ml. of benzene is refluxed with stirring for 5 hours. The reaction mixture is filtered while hot through diatomaceous earth. The filtrate is washed twice with aqueous sodium bicarbonate and dried over magnesium sulfate causing crystals to form. The drying agent and crystals are washed with chloroform and then chloroform:methanol (9:1). The washings are evaporated to residual crystals which are combined twice with ethanol and filtered giving the desired product as tan crystals, mp. 210°-212° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20])[NH2:6].[C:21](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:21][NH:6][C:5]1[CH:7]=[CH:8][C:9]([N:10]2[C:11](=[O:20])[C:12]3=[CH:19][CH:18]=[CH:17][CH:16]=[C:13]3[C:14]2=[O:15])=[C:3]([CH3:2])[CH:4]=1
Reactant: Cc1cc(N)ccc1N1C(=O)c2ccccc2C1=O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CNc1ccc(N2C(=O)c3ccccc3C2=O)c(C)c1

Procedure:
To a mixture of the product aniline of Example 31 (15 g) and 18 g of anhydrous potassium carbonate suspended in 400 ml of dimethylformamide was added 11 g of methyl iodide in 30 ml of dimethylformamide. After 16 hours the mixture was concentrated to an oily residue which solidified upon trituration with water. The crude solid was purified by chromatography as in Example 34 to give the title compound. Samples prepared by the methods of Examples 34 and 36 were identical.