Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH2:13][OH:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH:17]1([N:20]2[C:24](S(C)(=O)=O)=[N:23][N:22]=[C:21]2[C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[CH2:19][CH2:18]1>>[CH:17]1([N:20]2[C:24]([O:14][CH2:13][C:10]3[N:11]=[N:12][N:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=4)[N:9]=3)=[N:23][N:22]=[C:21]2[C:29]2[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=2)[CH2:19][CH2:18]1
Reactant: CS(=O)(=O)c1nnc(-c2ccncc2)n1C1CC1
Reactant: OCc1nnn(-c2cccc(I)c2)n1
Agent: [H-]
Agent: [Na+]
Product: Ic1cccc(-n2nnc(COc3nnc(-c4ccncc4)n3C3CC3)n2)c1

Procedure:
The title compound is prepared from [2-(3-iodo-phenyl)-2H-tetrazol-5-yl]-methanol (1 mmol), sodium hydride (1.5 mmol) and 4-(4-cyclopropyl-5-methanesulfonyl-4H-[1,2,4]triazol-3-yl)-pyridine (1.25 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH2:11][CH2:12][C:13]#[N:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].Cl[C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][C:22]([Br:28])=[CH:21][N:20]=1>O1CCCC1>[Br:28][C:22]1[CH:23]=[C:24]([N+:25]([O-:27])=[O:26])[C:19]([C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:15])([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:11][CH2:12][C:13]#[N:14])=[N:20][CH:21]=1
Reactant: CCOC(=O)C(CCC#N)C(=O)OCC
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCC#N)(C(=O)OCC)c1ncc(Br)cc1[N+](=O)[O-]
Yield: 73 %

Procedure:
A solution of 2-(2-cyanoethyl)malonic acid diethyl ester (24.2 g) in tetrahydrofuran (15 ml) was added to a suspension of sodium hydride (2.45 g) in tetrahydrofuran (30 ml) at 20° C under nitrogen. To this was added 2-chloro-3-nitro-5-bromopyridine (22 g) and the mixture so obtained was heated to 93°-95° C. A small amount of tetrahydrofuran was allowed to distil off. The mixture was heated under Reflux for 2.5 hr. The reaction mixture was poured into water and neutralised to pH 7 with concentrated hydrochloric acid. The aqueous phase was extracted with chloroform, dried (MgSO4) decolourised with charcoal and filtered through a silica column. The chloroform eluant was evaporated to yield an oil which slowly crystallised The crystals were washed in petroleum ether (40°-60° C.) and dried to yield 4-(5-bromo-3-nitropyrid-2-yl)-4,4-bis(carbethoxy)butyronitrile (28 g) m.p. 58°-62° C.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[O:28])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[CH3:14][O:13][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[O:11][CH3:12])[O:4][CH2:3][CH2:2][N:32]1[CH2:33][CH2:34][N:29]([C:27](=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=2)[C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[CH2:30][CH2:31]1
Reactant: O=C(CCCCC(c1ccc(F)cc1)c1ccc(F)cc1)N1CCNCC1
Reactant: COc1ccc(OCCBr)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(OCCN2CCN(C(=O)CCCCC(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1OC
Temperature: 120 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To a solution of 4-(2-bromo-ethoxy)-1,2-dimethoxy benzene (1.41 g, 4.86 mmol) and 6,6-bis-(4-fluorophenyl)-1-piperazin-1-yl-hexan-1-one (1.81 g, 4.86 mmol.) in dry DMF (40 ml) was added K2CO3 (0.8 g, 5.83 mmol.) and the mixture stirred at 120° C. overnight. EtOAc was added, washed with water (2×30 ml), brine (3×10 ml), dried over MgSO4, and evaporated under reduced pressure. The produce was purified by column chromatography on silica (hexane:EtOAc 1:1), followed by EtOAc to give the desired product in 57% yield.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[NH:17]1[C:25](=[O:26])[C:23](=[O:24])[C:21](=[O:22])[NH:20][C:18]1=[O:19].Cl>CCCCCC.O1CCCC1>[OH:24][C:23]1([C:9]2[O:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:11][CH:10]=2)[C:21](=[O:22])[NH:20][C:18](=[O:19])[NH:17][C:25]1=[O:26]
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Reactant: c1ccc(-c2ccco2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1NC(=O)C(O)(c2ccc(-c3ccccc3)o2)C(=O)N1
Temperature: 25 °C
Yield: 82.1 %

Procedure:
2-Phenylfuran (5.76 g., 40 mmoles) was combined with 100 ml. of tetrahydrofuran and cooled to -30° C. Butyl lithium in hexane (2.3 M, 19.1 ml.) was added dropwise over 5 minutes, keeping the temperature between -20° and -30° C. The reaction mixture was allowed to warm to room temperature and then recooled to -30° C. Sublimed alloxan (5.96 g., 42 mmoles) in 40 ml. of tetrahydrofuran was added over 5 minutes, again keeping the temperature -20° to -30° C. The reaction mixture was again allowed to warm to room temperature, then recooled to 0° C. and 50 ml. of 1 N hydrochloric acid added portionwise over 2-3 minutes. The quenched reaction mixture was extracted with 100 ml. of ethyl acetate. The extract was filtered through a bed of anhydrous magnesium sulfate, and evaporated to yield 5-hydroxy-5-(5 -phenyl-2-furyl)-2,4,6(1H,3H,5H)pyrimidinetrione [9.4 g., gummy solid, Rf 0.75 (1:1 hexane ethyl acetate/5% acetic acid)] contaminated with starting material (Rf 0.45).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14]([OH:23])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:26]I>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14]([O:23][CH3:26])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1nc2c(cc1O)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(nc1C)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 90.0 mg (0.28 mmol) (4R,9aR)-7-hydroxy-4,6-dimethyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (example 7, intermediate) in 1.0 mL N,N-dimethylformamide was added 14.8 mg (0.34 mmol) sodium hydride (55–65% dispersion in oil) and the reaction was stirred for 30 min. Then, 35 μl (80.0 mg, 0.56 mmol) methyl iodide was added. After 2 h the reaction mixture was diluted with ethyl acetate, washed with 10% aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and filtered. The solvent was removed at a rotary evaporator and the residue was purified by column chromatography on silica gel (0.032–0.063 mm) with ethyl acetate:n-hexane (1:1) as eluant.
Reaction SMILES: [CH2:1]([CH:3]1[C:8]([C:9]2[CH:24]=[CH:23][C:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=4)[O:15][C:11]=3[CH:10]=2)=[N:7][NH:6][C:5](=[O:25])[CH2:4]1)[CH3:2].Cl[CH2:27][C:28](=[O:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH2:1]([CH:3]1[C:8]([C:9]2[CH:24]=[CH:23][C:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:27][C:28](=[O:30])[CH3:29])=[CH:18][CH:17]=4)[O:15][C:11]=3[CH:10]=2)=[N:7][NH:6][C:5](=[O:25])[CH2:4]1)[CH3:2]
Reactant: CC(=O)CCl
Reactant: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(O)cc3)oc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(OCC(C)=O)cc3)oc2c1

Procedure:
100 mg (298 μmol) 5-ethyl-6-[2-(4-hydroxy-phenyl)-benzoxazol-6-yl]-4,5-dihydro-2H-pyridazin-3-one, 24 μL (301 μmol) chloroacetone, 83 mg (601 μmol) potassium carbonate, 50 mg (301 μmol) potassium iodide and 10 ml acetone are heated together at 60° C. overnight. Then the mixture is extracted with 10% sodium carbonate solution and EA. The org. phase is washed with sat. saline solution, dried on sodium sulphate and then the solv. is totally eliminated i.V. The residue is purified through silica gel (eluant: DCM/methanol)
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:13]([O:15][CH2:16][CH2:17][CH3:18])=O>N1C=CC=CC=1>[CH2:16]([O:15][C:13]1[O:5][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=2[N:1]=1)[CH2:17][CH3:18]
Reactant: Cc1ccc(N)c(C(=O)O)c1
Reactant: CCCOC(=O)Cl
Solvent: c1ccncc1
Product: CCCOc1nc2ccc(C)cc2c(=O)o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.3 %

Procedure:
A solution of 2-amino-5-methylbenzoic acid (1.0 g, 6.6 mmol) in pyridine (10 ml) was cooled to 0° C. and treated dropwise with propyl chloroformate (3.0 ml, 26 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 4 h, after which time the pyridine was removed in vacuo. The residue was washed with water (25 ml) and dried in vacuo to afford the desired product as an off-white solid (0.96 g, 66%); δH (400 MHz, DMSO-D6) 1.03 (3H, t, J 7, CH2CH3), 1.82 (2H, tq, J, J′7, CH2CH3), 2.46 (3H, s, CH3), 4.42 (2H, t, J 7, OCH2), 7.40 (1H, d, J 8, Ph), 7.71 (1H, d, J 8, Ph), 7.89 (1H, s, Ph); m/z (ES+) 219 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][C:36]1[CH:41]=[CH:40][N:39]2[N:42]=[CH:43][C:44](B3OC(C)(C)C(C)(C)O3)=[C:38]2[CH:37]=1.C(=O)([O-])[O-].[K+].[K+].C(N[C@H](C(O)=O)CS)(=O)C>O.CC(N(C)C)=O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:44]2[CH:43]=[N:42][N:39]3[CH:40]=[CH:41][C:36]([CH3:35])=[CH:37][C:38]=23)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: Cc1ccn2ncc(B3OC(C)(C)C(C)(C)O3)c2c1
Agent: CC(=O)N[C@@H](CS)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1ccn2ncc(-c3nc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)c(F)c4c3C(=O)N(C(=O)OC(C)(C)C)C4)c2c1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 46.1 %

Procedure:
To a 25 mL reaction flask equipped with magnetic stir bar and thermometer was added tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (200 mg, 0.401 mmol) and 5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (124 mg, 0.481 mmol), followed by potassium carbonate (325 mesh powder) (111 mg, 0.802 mmol), DMA (6 mL), and water (0.400 mL). The mixture was stirred at room temperature for 3 min before degassing with vacuum and N2 back-fill (5×). To the resulting deep purple mixture was added Pd-118 (10.93 mg, 0.016 mmol). The reaction mixture was degassed again with vacuum and N2 back-fill (5×). The flask was wrapped tightly with plastic film, placed in an oil bath, and the reaction mixture was stirred at 80° C. for 18 hours. Solid N-acetyl cysteine (65.4 mg, 0.401 mmol) was added and the mixture was stirred at 70° C. for 2 h. The mixture was subsequently diluted with water and extracted with EtOAc (200 mL). The organic layer was dried and concentrated to give a residue, which was purified by preparative HPLC, eluting with a gradient of 55-80% ACN (0.035% TFA) and water (0.05% TFA). The fractions were collected to give, upon basic work-up, the title compound as a light yellow solid (110 mg, 46%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([OH:19])[C:5]2[N:6]=[CH:7][N:8]([C:17]=2[N:18]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]1.[CH2:20]([NH2:29])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[CH2:20]([NH:29][C:2]1[NH:3][C:4](=[O:19])[C:5]2[N:6]=[CH:7][N:8]([C:17]=2[N:18]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)nc(Cl)nc32)C[C@@H]1O
Reactant: CCCCCCCCCN
Product: CCCCCCCCCNc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1

Procedure:
The compound 115 is prepared from compound 102 (9.5 g, 22 mmol) and nonylamine (9.58 g, 67 mmole) as per example 103. The crude product was evaporated to dryness and the residue was co-evaporated with a mixture of ethanol and toluene (three times). The resulting residue was dissolved in ethanol and cooled to yield a small amount of product. It was filtered and the filtrate evaporated to dryness. The residue was used without characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:15]=[CH:14][N:13]([CH2:16][C@@H:17]([NH:19][C:20]([C:22]3[CH:26]=[C:25]([C:27]([OH:30])([CH3:29])[CH3:28])[O:24][N:23]=3)=[O:21])[CH3:18])[N:12]=2)[CH:5]=[C:6](F)[C:7]=1[C:8]#[N:9].[C:31](=O)([O-])[O-:32].[Cs+].[Cs+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:15]=[CH:14][N:13]([CH2:16][C@@H:17]([NH:19][C:20]([C:22]3[CH:26]=[C:25]([C:27]([OH:30])([CH3:29])[CH3:28])[O:24][N:23]=3)=[O:21])[CH3:18])[N:12]=2)[CH:5]=[C:6]([O:32][CH3:31])[C:7]=1[C:8]#[N:9]
Reactant: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cc(C(C)(C)O)on1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Product: COc1cc(-c2ccn(C[C@H](C)NC(=O)c3cc(C(C)(C)O)on3)n2)cc(Cl)c1C#N
Reaction time: 144 h
Yield: 60.3 %

Procedure:
A mixture of (S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(2-hydroxypropan-2-yl)isoxazole-3-carboxamide (50 mg, 0.116 mmol), 5 ml of dry methanol and cesium carbonate (75 mg, 0.232 mmol) was reacted with stirring for 6 days keeping the temperature at 60° C. during the day and at RT during the night. The mixture was evaporated dissolved in DCM, extracted with water and dried. The product was purified by flash chromatography. Yield 60.3%. 1H-NMR (400 MHz; DMSO-d6): δ 1.15 (d, 3H), 1.46 (s, 6H), 4.01 (s, 3H), 4.32 (d, 2H), 4.40-4.51 (m, 1H), 5.68 (s, 1H), 6.49 (s, 1H), 7.00 (d, 1H), 7.54 (d, 1H), 7.67 (d, 1H), 7.83 (d, 1H), 8.75 (d, 1H).
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:22]5[CH2:27][CH2:26][CH:25]([C:28]([F:31])([F:30])[F:29])[CH2:24][CH2:23]5)=[CH:17][CH:16]=4)=[CH:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:32][N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1>C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:32][N:33]1[CH:37]=[C:36]([C:2]2[N:10]=[CH:9][C:8]3[NH:7][C:6]4[N:11]=[CH:12][C:13]([C:15]5[CH:20]=[CH:19][C:18]([CH2:21][N:22]6[CH2:27][CH2:26][CH:25]([C:28]([F:30])([F:29])[F:31])[CH2:24][CH2:23]6)=[CH:17][CH:16]=5)=[CH:14][C:5]=4[C:4]=3[CH:3]=2)[CH:35]=[N:34]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: FC(F)(F)C1CCN(Cc2ccc(-c3cnc4[nH]c5cnc(Br)cc5c4c3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cn1cc(-c2cc3c(cn2)[nH]c2ncc(-c4ccc(CN5CCC(C(F)(F)F)CC5)cc4)cc23)cn1
Temperature: 130 °C
Yield: 31.3 %

Procedure:
A degassed mixture of 6-bromo-3-[4-(4-trifluoromethylpiperidin-1-ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (0.15 g, 0.30 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.13 g, 0.60 mmol) and 1,1′-[bis(diphenyl phosphino)ferrocene]dichloropalladium(II)(25 mg, 0.03 mmol) in acetonitrile (3 mL) and saturated aqueous sodium carbonate solution (3 mL) was heated under microwave irradiation at 130° C. for 30 minutes. The cooled reaction mixture was partitioned between DCM and water then separated on a hydrophobic frit. The organic phase was evaporated then the resultant residue was purified by flash chromatography (silica, 12 g column, ISCO, 0-10% methanol in DCM) to afford a residue which was purified by HPLC (C18 column, 50-98% MeCN in water (plus 20 mM triethylamine) to afford the title compound (46 mg, 31%). 1H NMR (DMSO-D6, 400 MHz): 12.15 (s, 1H), 8.94-8.88 (m, 2H), 8.86 (d, J=1.1 Hz, 1H), 8.51 (d, J=1.1 Hz, 1H), 8.21 (s, 1H), 7.99 (d, J=0.8 Hz, 1H), 7.78 (d, J=8.0 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H), 3.92 (s, 3H), 3.56 (s, 2H), 2.99-2.88 (m, 2H), 2.39-2.19 (m, 1H), 2.00 (t, J=1.5 Hz, 2H), 1.85-1.94 (m, 2H), 1.57-1.38 (m, 2H). LCMS (Method A): RT=5.22 min, M+H+=491.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)[C:5]#[N:6]>CC(O)=O.CCOC(C)=O.[Fe]>[NH2:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(C#N)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)ccc1N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.1 %

Procedure:
To a solution of 3-methyl-4-nitro-benzonitrile (20 g, 0.123 mol) in HOAc (200 mL) was added iron powder (17.55 g, 0.309 mol). After 10 min, the reaction was exothermic and turned to dark color. The reaction mixture was allowed to stir at room temperature for 14 h and then diluted with EtOAc (200 mL). The brown precipitate was filtered through a pad of celite and the filtercake was rinsed with EtOAc. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (40% EtOAc/hexane) to yield the title compound (15.3 g, 92%). 1H NMR (300 MHz, CDCl3) δ 7.30–7.34 (2H, m), 6.64 (1H, d, J=8.7 Hz), 2.16 (3H, s). LCMS (M+H)+ m/z 133 (t=0.93 min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][NH2:28])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.[C:29](Cl)(=[O:31])[CH3:30]>C1COCC1.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][NH:28][C:29](=[O:31])[CH3:30])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:18][CH2:19]1)[N:11]=2
Reactant: CC(=O)Cl
Reactant: NCCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)NCCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(3-Fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)-ethanamine (90 mg, 0.23 mmol) was dissolved in THF (2.3 mL) before acetyl chloride (33 μl, 0.462 mmol) was added and stirred at ambient temperature for 2 h. The reaction mixture was diluted with 100 mL of DCM, added to a separatory funnel, partitioned with sodium bicarbonate (saturated, aqueous), washed 2 times with 75 mL of sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated via rotovap to give the title compound after purification via preparatory LC. MS (ESI) m/z: Calculated: 431.1; Observed: 432.1 (M++H).
Reaction SMILES: [C:1]([N:6]1[C@H:10]([C:11]2[CH:16]=[C:15]([F:17])[C:14]([F:18])=[C:13]([F:19])[CH:12]=2)[CH2:9][CH2:8][C@@H:7]1/[CH:20]=C/C(OCC)=O)(=[O:5])[CH2:2][CH:3]=C.C(N(CC)CC)C>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.C(Cl)Cl>[F:17][C:15]1[CH:16]=[C:11]([C@H:10]2[N:6]3[C@@H:7]([CH:20]=[CH:3][CH2:2][C:1]3=[O:5])[CH2:8][CH2:9]2)[CH:12]=[C:13]([F:19])[C:14]=1[F:18]
Reactant: C=CCC(=O)N1[C@@H](/C=C/C(=O)OCC)CC[C@H]1c1cc(F)c(F)c(F)c1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CC=C[C@H]2CC[C@@H](c3cc(F)c(F)c(F)c3)N12
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
A solution of ethyl (E)-3-[(2R,5S)-1-(3-butenoyl)-5-(3,4,5-trifluorophenyl)pyrrolidin-2-yl]acrylate (1.33 g) and Grubbs catalyst 2nd generation (153 mg) in methylene chloride (60 mL) was heated under reflux for two hours. The reaction solution was left to cool to room temperature. Then, triethylamine (0.5 mL) was added to the reaction solution, and the mixture was stirred for one hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=1:1->ethyl acetate) to obtain 680 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH:1](=[N:8][N:9]1[CH:13]=[CH:12][N:11]([N:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]1=[S:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][B-:24]([F:27])([F:26])[F:25].[CH3:28][O+](C)C>ClCCl>[F:23][B-:24]([F:27])([F:26])[F:25].[CH:15](=[N:14][N+:11]1[CH:12]=[CH:13][N:9]([N:8]=[CH:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:10]=1[S:22][CH3:28])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[O+](C)C
Reactant: S=c1n(N=Cc2ccccc2)ccn1N=Cc1ccccc1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CSc1n(N=Cc2ccccc2)cc[n+]1N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3.06 g of 1,3-bis(benzylideneamino)-1,3-dihydro-2H-imidazole-2-thione in 100 ml of absolute dichloromethane are treated with 1.47 g of trimethyloxonium tetrafluoroborate, the mixture is stirred at room temperature for 3 hours and the resulting precipitate is removed by filtration under suction. From the filtrate, there is precipitated by the addition of diethyl ether an additional portion of the desired product which, together with the first portion, is washed once with water, once with cold methanol and three times with diethyl ether and subsequently re-precipitated from acetonitrile/diethyl ether. There is obtained colorless 1,3-bis(benzylideneamino)-2-(methylthio)imidazolium tetrafluoroborate of melting point 215°-220° (decomposition).
Reaction SMILES: [CH:1]1([CH2:4][NH2:5])[CH2:3][CH2:2]1.[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH2:18][NH:19][C:20](=[O:34])[C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][N:30]=[C:29](Cl)[N:28]=4)=[CH:23][CH:22]=3)[CH:15]=2)[NH:10][CH:9]=1)#[N:7]>>[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH2:18][NH:19][C:20](=[O:34])[C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][N:30]=[C:29]([NH:5][CH2:4][CH:1]5[CH2:3][CH2:2]5)[N:28]=4)=[CH:23][CH:22]=3)[CH:15]=2)[NH:10][CH:9]=1)#[N:7]
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Reactant: NCC1CC1
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(NCC5CC5)n4)cc3)cc12

Procedure:
Using cyclopropylmethyl-amine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. 1H NMR (DMSO) δ 0.26 (m, 2H); 0.44 (m, 2H); 3.00 (bt, 2H, J=7 Hz); 3.25 (bs, 2H); 3.56 (m, 2H); 7.20 (m, 2H); 7.36 (bt, 1H); 7.50 (m, 2H); 7.94 (d, 2H, J=8 Hz); 8.29 (m, 3H); 8.38 (d, 1H, J=5 Hz); 8.69 (bt, 1H); 12.15 (bs, 1H). MS (ion spray) m/z 437 (M+H)+.