Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[Br:5][C:6]1[CH:11]=[C:10]([C:12]2[C:21]3[C:22]4[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=4[S:24][C:20]=3[C:19]([Br:29])=[C:18]3[C:13]=2[CH:14]=[CH:15][CH:16]=[CH:17]3)[CH:9]=[C:8]([Br:30])[C:7]=1[OH:31].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:5][C:6]1[CH:11]=[C:10]([C:12]2[C:21]3[C:22]4[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=4[S:24][C:20]=3[C:19]([Br:29])=[C:18]3[C:13]=2[CH:14]=[CH:15][CH:16]=[CH:17]3)[CH:9]=[C:8]([Br:30])[C:7]=1[O:31][CH2:2][C:3]#[N:4]
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCOc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Reaction time: 2.5 h
Yield: 96.1 %

Procedure:
Bromoacetonitrile (0.25 mL, 3.56 mmol) was added to a room temperature, stirred suspension of 2,6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-phenol (1.0 g, 1.78 mmol) and potassium carbonate (0.615 g, 4.45 mmol) in DMF (5 mL). After 2.5 h, the reaction mixture was added to water, filtered, washed with water and triturated with petroleum ether. The solid was dried in vacuo at 80° C. to provide the title compound as a white solid (1.03 g, 96%): NMR (DMSO-d6); δ8.29 (d, J=8 Hz, 1 H), 8.08 (d, J=8 Hz, 1 H), 7.92 (s, 2 H), 7.80 (ddd, J=8, 7, 1 Hz, 1 H), 7.65-7.51 (m, 3 H), 7.27 (ddd, J=8, 7, 1 Hz, 1 H), 6.68 (d, J=8 Hz, 1 H), 5.36 (s, 2 H); MS (+FAB): [M+], 3 bromine isotope pattern, 599, 601, 603, 605; Anal. Calc. for C24H12Br3NOS: C, 47.87, H, 2.01, N, 2.33. Found: C, 47.83, H, 1.92, N, 2.32.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH2:7])=[S:6])[CH2:3][CH2:2]1.[C:8](#[N:12])[CH2:9][C:10]#[N:11]>>[CH:1]1([N:4]2[C:10]([NH2:11])=[CH:9][C:8]([NH2:12])=[N:7][C:5]2=[S:6])[CH2:3][CH2:2]1
Reactant: NC(=S)NC1CC1
Reactant: N#CCC#N
Product: Nc1cc(N)n(C2CC2)c(=S)n1
Yield: 38 %

Procedure:
N-cyclopropylthiourea (6.2 g) and malononitrile (6.6 g) were reacted in the same method as described in Preparation 12 to give the pale yellow above-indicated compound(3.7 g).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.N([O-])=O.[Na+].[I-:25].[Na+].C([O-])(=O)C.[Na+]>O.C(O)(=O)C>[I:25][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: Nc1ccc(-c2cccnc2)cc1
Agent: CC(=O)[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Ic1ccc(-c2cccnc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1.7 g (10 mmol) of 3-(4-aminophenyl)pyridine [F. S. Tanaka et al., J. Agric. Food Chem. 30, 957 (1982)], 17 ml of glacial acetic acid and 1.5 ml of trifluoroacetic acid was cooled in ice-water. Sodium nitrite, 0.8 g (11.4 mmol) was added in portions. After stirring for 15 minutes in ice-water and 15 minutes without cooling, 5 g of sodium iodide and 3 g of sodium acetate was added slowly with water cooling. The reaction mixture was diluted with 30 ml of water and stirred for 30 minutes. It was then partitioned between methylene chloride and 10% aqueous sodium carbonate solution. The organic phase was dried and evaporated and the residue was chromatographed over 20 g of silica gel using 10% (V/V) of ethyl acetate in methylene chloride. Crystallization from hexane yielded off-white crystals with m.p. 112°-115°.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1.[C:15]([Si:19]([CH3:22])([CH3:21])Cl)([CH3:18])([CH3:17])[CH3:16]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Si:19]([O:1][CH2:2][C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:22])[CH3:21]
Reactant: COC(=O)COc1ccc(CO)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)COc1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Reaction time: 5 h
Yield: 99.5 %

Procedure:
To a solution of 4.00 g (20.4 mmol) of the product of Step A dissolved in 30 mL of CH2Cl2 was added 5.00 g (40.8 mmol) of 4-dimethylaminopyridine and 3.69 g (24.5 mmol) of tert-butyldimethylchlorosilane and the mixture was stirred under N2 for 5 hours. The reaction mixture was then filtered and the filtrate was diluted with ethyl acetate. The solution was washed with water, 1N HCl, saturated NaHCO3, dried (MgSO4), filtered and evaporated. Drying in vacuo afforded 6.30 g (99%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]([OH:24])=O)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[NH:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]([N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)=[O:24])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: C1COCCN1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(=O)O)n2)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(=O)N3CCOCC3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.7 %

Procedure:
To a solution containing {3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-acetic acid (prepared in example 3, 100 mg, 0.22 mmol) in methylene chloride (2 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (121 μL, 0.24 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (28 μL, 0.24 mmol) was added to the solution. After 1 h, morpholine (21 μL, 0.24 mmol) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with saturated aqueous ammonium chloride solution, the organic phase was concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-morpholin-4-yl-2-oxo-ethyl)-1H-pyrazol-3-yl]-propionamide (71 mg, 62%) as a white solid: ESI-LRMS m/e calcd for C24H31ClN4O5S [M+] 522.17, found 523.4 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.05-1.18 (m, 2H, CH2), 1.41-1.95 (m, 8H, 4×CH2), 2.15-2.24 (m, 1H, CH), 3.26 (s, 3H, SO2CH3), 3.46 (m, 2H, NCH2), 3.55 (t, J=7.5 Hz, 1H, CH),), 3.58-3.70 (m, 6H, 2×OCH2 and NCH2), 4.81 (s, 2H, NCH2), 6.71 (m, 1H, Ar), 7.34 (m, 1H, Ar), 7.42 (m, 1H, Ar), 7.56 (m, 1H, Ar), 8.04 (d, Jo=8.1 Hz, 1H, Ar), 8.10 (s, 1H, NH).
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]Br.[O:8]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[Na+].[Na+]>CO>[O:8]([C:15]1[CH:16]=[CH:17][C:18]([N:19]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[CH:20][CH:21]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: BrCCNCCBr
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: c1ccc(Oc2ccc(N3CCNCC3)cc2)cc1

Procedure:
To a solution of 62.4 parts of bis-(β-bromoethyl)amine dihybromide in 160 parts of methanol there were added 37 parts of para-phenoxyaniline. The mixture was refluxed for 10 hours. 10.6 parts of Na2CO3 were then added and the reaction mixture was refluxed for a further 10 hours. After cooling, the precipitate was filtered off, washed with 80 parts of methanol and dried.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:4]([OH:5])[C:3]=1[OH:10].[CH3:11]S(C)=O.ClCCl.[OH-].[Na+]>O>[CH3:1][C:2]1[C:3]2[O:10][CH2:11][O:5][C:4]=2[CH:6]=[C:7]([CH3:9])[CH:8]=1
Reactant: Cc1cc(C)c(O)c(O)c1
Reactant: CS(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C)c2c(c1)OCO2
Yield: 93 %

Procedure:
3,5-Dimethylcatechol (13.8 g) in a vigorously stirred mixture of dimethylsulphoxide (150 ml), dichloromethane (10 g) and sodium hydroxide (8.3 g) under nitrogen atmosphere was heated over an oil bath (120°-130° C.) for 2 hours. The mixture was poured into water (600 ml) and extracted (×4) with ether. The ethereal solution was dried and evaporated to afford 3,5-dimethyl-l,2-(methylenedioxy)benzene (14.0 g, 93%) as an oil.
Reaction SMILES: Cl[C:2]1[CH2:6][CH2:5][CH2:4][N:3]=1.[CH3:7][C:8]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[C:11]([CH3:18])[C:9]=1[NH2:10]>>[CH3:7][C:8]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[C:11]([CH3:18])[C:9]=1[NH:10][C:2]1[CH2:6][CH2:5][CH2:4][N:3]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1N
Reactant: ClC1=NCCC1
Product: Cc1cc([N+](=O)[O-])cc(C)c1NC1=NCCC1

Procedure:
A mixture of 2-chloro-1-pyrroline, prepared as in Example 1, and 19.9 g (0.12 mole) of the aniline product of Example 6 were heated at reflux overnight, according to the general method of Example 8. The title compound was isolated and used for subsequent reactions without further purification. Structure assignment was supported by nmr and infrared spectra.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH:16]([CH3:18])[CH3:17])[CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:4][N:3]=1.Cl[C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][N:28]=1)C(O)=O.[CH:29]([N:32]1CCNCC1)(C)[CH3:30]>>[CH:16]([N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:32][CH2:29][CH2:30][N:28]3[CH2:20][CH2:21][CH2:22][CH2:26][CH2:27]3)[CH:7]=2)=[O:9])[CH2:11][CH2:12]1)([CH3:18])[CH3:17]
Reactant: CC(C)N1CCN(C(=O)c2ccnc(Cl)c2)CC1
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: CC(C)N1CCNCC1
Product: CC(C)N1CCN(C(=O)c2ccnc(NCCN3CCCCC3)c2)CC1

Procedure:
(2-Chloro-pyridin-4-yl)-(4-isopropyl-piperazin-1-yl)-methanone. The title compound was prepared in a manner similar to that described in Step A of Example 9 using 2-chloro-isonicotinic acid and 1-isopropyl-piperazine.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH:2]([CH:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][C@H:22]2[CH2:27][CH2:26][C@H:25]([C:28]3[CH:33]=[CH:32][C:31]([CH2:34][N:35]([CH3:37])[CH3:36])=[CH:30][CH:29]=3)[CH2:24][CH2:23]2)=[O:20])=[CH:14][CH:13]=1.C(OCC)C>C(O)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][C@H:22]2[CH2:23][CH2:24][C@H:25]([C:28]3[CH:29]=[CH:30][C:31]([CH2:34][N:35]([CH3:36])[CH3:37])=[CH:32][CH:33]=3)[CH2:26][CH2:27]2)=[O:20])=[CH:14][CH:13]=1.[C:6]([CH:4]([CH:2]([C:1]([O-:10])=[O:9])[OH:3])[OH:5])([O-:8])=[O:7]
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: CN(C)Cc1ccc([C@H]2CC[C@H](OC(=O)Cc3ccc(Cl)cc3)CC2)cc1
Agent: CN(C)Cc1ccc([C@H]2CC[C@H](OC(=O)Cc3ccc(Cl)cc3)CC2)cc1
Solvent: CCOCC
Solvent: CCO
Product: O=C([O-])C(O)C(O)C(=O)[O-]
Reaction time: 8 h

Procedure:
First 0.15 g (0.001 mol) of anhydrous tartaric acid and then 0.39 g (0.001 mol) of trans-O-(4-chlorophenylacetyl)-4-(4-dimethylaminomethylphenyl)-cyclohexanol are dissolved in 7 ml of absolute ethanol. Diethyl ether is then added to the clear solution until it becomes slightly cloudy and it is then left to stand for 8 hours at +4° C. The crystalline product precipitated is suction filtered, washed with diethyl ether and dried.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([OH:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1)N.[CH3:13][CH:14]([C:23](=O)[CH3:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]>C(O)(=O)C>[CH3:24][C:23]1[C:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])([CH3:13])[C:8]2[C:3](=[CH:4][CH:5]=[C:6]([S:9]([OH:12])(=[O:11])=[O:10])[CH:7]=2)[N:1]=1
Reactant: CC(=O)C(C)CCCCCC(=O)O
Reactant: NNc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Product: CC1=Nc2ccc(S(=O)(=O)O)cc2C1(C)CCCCCC(=O)O

Procedure:
4-Hydrazinobenzenesulfonic acid (1.88 g, 10 mmol), 7-methyl-8-oxononanoic acid (2.8 g, 15 mmol) and glacial acetic acid (10 ml) were mixed and heated under reflux for 6 hrs. The solvent was then evaporated under vacuum and the residue triturated with diethyl ether until a solid was obtained. This was dried under vacuum to give crude product, 3.4 g (100%). This was purified by preparative HPLC as required (RPC18. Water+0.1% TFA→MeCN+0.1% TFA gradient). UV/Vis (Water+0.1% TFA): 274, 229, 204 nm. 1H-nmr (D2O) δ 0.6-0.9 (2H, broad m), 1.10-1.25 (2H, broad m), 1.35-1.50 (2H, m), 1.60 (3H, s), 2.10-2.40 (2H, broad m+2H, t), 7.77 (1H, d), 7.97 (1H, dd) and 8.06 (1H, d)
Reaction SMILES: [H-].[Na+].CN(C=O)C.[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[NH:19][C:18](=[O:20])[CH2:17][C:16](=[O:21])[N:15]([CH3:22])[C:14]=2[CH:23]=1.[CH2:24](I)[CH3:25]>O>[CH2:24]([N:19]1[C:18](=[O:20])[CH2:17][C:16](=[O:21])[N:15]([CH3:22])[C:14]2[CH:23]=[C:10]([O:9][CH3:8])[CH:11]=[CH:12][C:13]1=2)[CH3:25]
Reactant: COc1ccc2c(c1)N(C)C(=O)CC(=O)N2
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1C(=O)CC(=O)N(C)c2cc(OC)ccc21
Temperature: 0 °C
Yield: 76.7 %

Procedure:
Sodium hydride (60% in oil, 44 mg) was suspended in of DMF (8 ml), and was cooled to 0° C. in an ice water bath. 8-Methoxy-1-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (220 mg) was added thereto at the same temperature, and the mixture was stirred at 0° C. for an hour. Ethyl iodide (187 mg) was added thereto, and the mixture was stirred at room temperature overnight. Water was added to the reaction liquid, followed by extraction by ethyl acetate. The organic layer was dried over sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=4:1→1:1). The purified product was condensed to dryness to give the title compound (190.2 mg) as a yellow solid.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].Br[CH:9]([OH:11])[CH3:10].[CH3:12][Si:13]([CH:16]([NH2:21])[Si:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:14].C(N(CC)CC)C>ClCCl>[CH3:12][Si:13]([CH:16]([NH:21][S:2]([N:5]1[CH2:10][CH2:9][O:11][C:6]1=[O:7])(=[O:4])=[O:3])[Si:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:14]
Reactant: C[Si](C)(C)C(N)[Si](C)(C)C
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(O)Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)C(NS(=O)(=O)N1CCOC1=O)[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 65 %

Procedure:
To 2.18 ml of chlorosulfonyl isocyanate in 10 ml of dichloromethane is added dropwise, at 0° C., a solution of 1.77 ml of bromoethanol in 10 ml of dichloromethane. The reaction medium is stirred for 10 minutes at 0° C. and then added dropwise to a solution of 4.38 grams of bis(trimethylsilyl)methylamine and 3.51 ml of triethylamine in 40 ml of dichloromethane at 0° C. After warming to 20° C. and stirring for 4 hours, the reaction mixture is cooled to 0° C. and 10.5 ml of triethylamine are then added dropwise. The reaction mixture is then stirred overnight at room temperature. It is then diluted with dichloromethane and washed 3 times with dilute hydrochloric acid. The organic phase is then washed once with saturated aqueous NaCl solution and then dried over sodium sulfate and concentrated under reduced pressure to give a white solid, 2-oxooxazolidine-3-sulfonic acid [bis(trimethylsilanyl)methyl]amide (65% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C:14]2=[O:26])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH3:27][N:28](C=O)C.C(OCC)(=O)C.N>[C-]#N.[Zn+2].[C-]#N.O>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][N:13]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:27]#[N:28])=[CH:3][CH:4]=2)[C:9]([O:11][CH3:12])=[O:10])[C:14](=[O:26])[CH2:15]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: COC(=O)C(c1ccc(Br)cc1)N1CCN(C(=O)OC(C)(C)C)CC1=O
Reactant: CN(C)C=O
Agent: N
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C(c1ccc(C#N)cc1)N1CCN(C(=O)OC(C)(C)C)CC1=O
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A mixture of methyl 2-(4-bromophenyl)-2-[4-(tert-butoxycarbonyl)-2-oxo-1-piperazinyl]acetate (1.28 g), zinc cyanide (211 mg), tetrakis (triphenylphosphine)palladium (139 mg) and DMF (10 ml) was stirred at 80° C. for 6 hours and cooled. To the reaction solution were added ethyl acetate, water and a little amount of ammonia solution. The organic layer was separated, washed with saturated brine, dried and concentrated, and the residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1) to give yellow syrup of methyl 2-[4-(tert-butoxycarbonyl)-2-oxo-1-piperazinyl]-2-(4-cyanophenyl)acetate (1.01 g).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH:6]([NH:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([OH:20])[N:19]=1)[C:14]([OH:16])=[O:15])([CH2:8][CH3:9])[CH3:7].[CH2:21](N(CC)CC)C>ClCCl>[CH3:21][O:15][C:14](=[O:16])[C:13]1[CH:17]=[C:18]([O:20][S:2]([CH3:1])(=[O:4])=[O:3])[N:19]=[C:11]([NH:10][CH:6]([CH2:8][CH3:9])[CH3:7])[CH:12]=1
Reactant: CCC(C)Nc1cc(C(=O)O)cc(O)n1
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CCC(C)Nc1cc(C(=O)OC)cc(OS(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.1 %

Procedure:
Add methanesulfonyl chloride (0.1 mL, 1.292 mmol) to a solution of 2-sec-butylamino-6-hydroxy-isonicotinic acid (242 mg, 1.016 mmol) and triethyl amine (0.25 mL, 1.793 mmol) in dichloromethane (15 mL) at 0° C. Stir at room temperature for 15 min, dilute with dichloromethane, wash with saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 15:85 ethyl acetate:hexanes) to give the title compound as a white solid (240 mg, 75%).
Reaction SMILES: CN(C)/[N:3]=[CH:4]/[C:5](=O)[C:6]([F:9])([F:8])[F:7].C([O-])(=O)C.[NH4+:16].[CH:17]1([C:20]2[C:21]([N:38]([CH2:43][CH2:44][CH:45]([CH3:47])[CH3:46])[S:39]([CH3:42])(=[O:41])=[O:40])=[CH:22][C:23]3[O:27][C:26]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)=[C:25]([CH:35]=O)[C:24]=3[CH:37]=2)[CH2:19][CH2:18]1.C(OCC)(=O)C.C(Cl)Cl>C(O)(=O)C.C(OCC)(=O)C>[CH:17]1([C:20]2[C:21]([N:38]([CH2:43][CH2:44][CH:45]([CH3:47])[CH3:46])[S:39]([CH3:42])(=[O:40])=[O:41])=[CH:22][C:23]3[O:27][C:26]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)=[C:25]([C:35]4[NH:3][CH:4]=[C:5]([C:6]([F:7])([F:8])[F:9])[N:16]=4)[C:24]=3[CH:37]=2)[CH2:19][CH2:18]1
Reactant: CC(C)CCN(c1cc2oc(-c3ccc(F)cc3)c(C=O)c2cc1C1CC1)S(C)(=O)=O
Reactant: CN(C)/N=C/C(=O)C(F)(F)F
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)CCN(c1cc2oc(-c3ccc(F)cc3)c(-c3nc(C(F)(F)F)c[nH]3)c2cc1C1CC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.2 %

Procedure:
To a mixture of (E)-3-(2,2-dimethylhydrazono)-1,1,1-trifluoropropan-2-one (9.48 mg, 0.056 mmol) and ammonium acetate (174 mg, 2.255 mmol) in acetic acid (450 μL) was added solid N-(5-cyclopropyl-2-(4-fluorophenyl)-3-formylbenzofuran-6-yl)-N-isopentylmethanesulfonamide (50 mg, 0.113 mmol, prepared as described in Kamitori Y, et al. J Organic Chemistry 1988; 53: 129-135) under nitrogen, and the mixture was stirred at room temperature for one hour. The mixture was heated at 80° C. for 18 hours. TLC (SiO2, 2% ethyl acetate/CH2Cl2) showed none of the trifluoroacylhydrazone reagent remaining, so additional (E)-3-(2,2-dimethylhydrazono)-1,1,1-trifluoropropan-2-one (9.48 mg, 0.056 mmol) was added and the mixture was continued to heat at 80° C. After 27 hours, additional (E)-3-(2,2-dimethylhydrazono)-1,1,1-trifluoropropan-2-one (9.48 mg, 0.056 mmol) was added and the mixture was heated overnight at 80° C. LCMS after a total of 42 hours showed ˜1:1 starting material to product ratio. The amber-brown colored reaction was cooled to room temperature, and ethyl acetate (50 mL) was added. The mixture was washed with saturated aqueous NaHCO3 (25 mL), the organic phase was dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation. The residue was purified by SiO2 flash chromatography (Alltech Extract-Clean™ column, 10 g bed) eluting with a step gradient of 2% to 3% ethyl acetate in CH2Cl2 to afford the title compound as a light yellow solid (7.2 mg, 0.013 mmol, 11%). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.53-0.61 (m, 1H), 0.80-0.90 (m, 1H), 0.83 (t, J=6.18 Hz, 6H), 0.97-1.02 (m, 2H), 1.22-1.31 (m, 1H), 1.34-1.44 (m, 1H), 1.54-1.69 (m, 1H), 2.35-2.44 (m, 1H), 3.14 (s, 3H), 3.61-3.79 (m, 2H), 7.09 (s, 1H), 7.35 (t, J=8.93 Hz, 2H), 7.90 (s, 1H), 7.92 (dd, J=8.47, 5.72 Hz, 2H), 8.01 (s, 1H), 13.13 (s, 1H); MS (ESI+) m/z 550 (M+H)+, 1099 (2M+H)+; MS (ESI−) m/z 548 (M−H)−, 1097 (2M−H)−.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1([CH3:15])[O:8][C:7]2[CH:9]=[C:10]([NH2:14])[C:11]([NH2:13])=[CH:12][C:6]=2[O:5]1.[OH-].[K+].C(O[C:21]([S-])=[S:22])C.[K+].C(O)(=O)C>C(O)(C)C.O>[CH3:3][C:4]1([CH3:15])[O:5][C:6]2=[CH:12][C:11]3[NH:13][C:21]([SH:22])=[N:14][C:10]=3[CH:9]=[C:7]2[O:8]1
Reactant: CCOC(=S)[S-]
Reactant: CC1(C)Oc2cc(N)c(N)cc2O1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC1(C)Oc2cc3nc(S)[nH]c3cc2O1
Yield: 78.1 %

Procedure:
To 18.8 g of 2,2-dimethyl-1,3-benzodioxole-5,6-diamine dihydrochloride in 250 ml of isopropanol were added first a solution of 8.6 g of potassium hydroxide in 25 ml of water and then 13.7 g of potassium ethylxanthate, and the mixture was left to boil at reflux overnight. The mixture was diluted with 250 ml of water, neutralized with glacial acetic acid and suction filtered. There were obtained 12.9 g (78.2% of theory) of 2,2-dimethyl-5H-1,3-dioxolo(4,5-f)benzimidazole-6-thiol with a melting point above 300° C.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].ClC(OCC(C)C)=O.CN1CCOCC1.[CH3:20][N:21]1[C:35]2[C:36]3[C:23]([CH2:24][C@@H:25]4[C@@H:30]([C:31]=3[CH:32]=[CH:33][CH:34]=2)[CH2:29][C@@H:28]([CH2:37][NH:38][NH2:39])[CH2:27][N:26]4[CH3:40])=[CH:22]1>C(#N)C>[CH3:20][N:21]1[C:35]2[C:36]3[C:23]([CH2:24][C@@H:25]4[C@@H:30]([C:31]=3[CH:32]=[CH:33][CH:34]=2)[CH2:29][C@@H:28]([CH2:37][NH:38][NH:39][C:1](=[O:4])[CH3:2])[CH2:27][N:26]4[CH3:40])=[CH:22]1
Reactant: CN1C[C@H](CNN)C[C@@H]2c3cccc4c3c(cn4C)C[C@H]21
Reactant: CC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CC(=O)NNC[C@@H]1C[C@@H]2c3cccc4c3c(cn4C)C[C@H]2N(C)C1
Temperature: -15 °C
Yield: 59.1 %

Procedure:
0.6 g of acetic acid are dissolved in 25 ml of acetonitrile with stirring. The solution is cooled to -15° C., and 1.39 ml of isobutyl chloroformate and 1.1 ml of N-methyl-morpholine are added. After 5 minutes of stirring a solution of 2.8 g of 1,6-dimethyl-8β-hydrazinomethyl-ergoline in 10 ml of acetonitrile is added to the mixture. The mixture is slowly (within 30 minutes) warmed to room temperature, stirred at room temperature for 2 hours, then evaporated in vacuo. The residue is dissolved in 200 ml of chloroform, and 100 ml of water are added. The pH of the aqueous phase is adjusted to 8 with 10% aqueous ammonia, and the mixture is shaken. The organic phase is separated, and the aqueous phase is extracted thrice with 100 ml of chloroform. The chloroform fractions are combined and evaporated to dryness in vacuo. The residue is subjected to column chromatography in order to remove the occasional impurities. 60 g of silica gel are used as adsorbent, and the column is eluted with a 30:0.3:9 mixture of chloroform, water and methanol. The effluent is analyzed by thin layer chromatography. The fractions containing a substance with an Rf value of 0.75 are combined, evaporated in vacuo, and the residue is crystallized from alcohol. 1.9 g (60.4%) of 1,6-dimethyl-8β-[(N'-acetyl-hydrazino)-methyl]-ergoline are obtained; m.p.: 190°-192° C., [α]D20 =-29.7° (c=1, in 96% ethanol).