Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCC1C=CC(C#N)=CC=1.Br[CH2:12][CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1.[CH2:23]([NH:30][C:31]([C:33]1[S:37][C:36]([N:38]2[CH2:42][CH2:41][NH:40][C:39]2=[O:43])=[N:35][C:34]=1[CH3:44])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[NH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([CH2:13][CH2:12][N:40]2[CH2:41][CH2:42][N:38]([C:36]3[S:37][C:33]([C:31]([NH:30][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:32])=[C:34]([CH3:44])[N:35]=3)[C:39]2=[O:43])=[CH:15]1
Reactant: Cc1nc(N2CCNC2=O)sc1C(=O)NCc1ccccc1
Reactant: BrCCc1c[nH]c2ccccc12
Agent: N#Cc1ccc(CCl)cc1
Product: Cc1nc(N2CCN(CCc3c[nH]c4ccccc34)C2=O)sc1C(=O)NCc1ccccc1
Yield: 22 %

Procedure:
Following the procedure as described in Example 23, making variations as required to replace 4-(chloromethyl)benzonitrile with 3-(2-bromoethyl)-1H-indole to react with N-benzyl-4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxamide, the title compound was obtained as a colorless solid in 22% yield: mp 215-217° C. (dichloromethane/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.50 (t, J=6.0 Hz, 1H), 7.57 (d, J=6.0 Hz, 1H), 7.36-7.20 (m, 7H), 7.10-6.96 (m, 2H), 4.38 (d, J=6.0 Hz, 2H), 3.96 (t, J=9.0 Hz, 2H), 3.61-3.51 (m, 4H), 2.95 (t, J=9.0 Hz, 2H), 2.47 (s, 3H); MS (ES+) m/z 460.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[C:23](S(C)(=O)=O)[N:22]=[CH:21][N:20]=3)=[CH:14][CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].[NH2:33][CH2:34][CH2:35][OH:36]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[C:23]([NH:33][CH2:34][CH2:35][OH:36])[N:22]=[CH:21][N:20]=3)=[CH:14][CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30]
Reactant: CS(=O)(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ncn1
Reactant: NCCO
Solvent: ClCCl
Product: O=C(Nc1ccc(Oc2cc(NCCO)ncn2)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 110 °C
Yield: 53.4 %

Procedure:
A solution of 1-(4-chloro-3-trifluoromethyl-phenyl)-3-[4-(6-methanesulfonyl-pyrimidin-4-yloxy)-phenyl]-urea (100 mg, 0.2 mmol) in dichloromethane (1 ml) and 2-aminoethanol (124 μl, 2.0 mmol) is sealed in a reaction tube and heated in the microwave at 110° C. for 15 minutes. The reaction mixture is evaporated and purified by preparative HPLC to yield 50 mg (52%) of a white powder.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:22][CH2:21][C:13]3[N:14]=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[S:16][C:12]=3[C:11]2=O)=O)=[CH:4][CH:3]=1.Cl.[Cl:25][C:26]1[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:27]=1[NH:35][NH2:36]>C(O)(=O)C>[Cl:25][C:26]1[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:27]=1[N:35]1[C:11]2[C:12]3[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][C:13]=3[CH2:21][CH2:22][C:10]=2[C:8]([C:5]2[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[N:36]1
Reactant: CC(=O)Nc1nc2c(s1)C(=O)C(C(=O)c1ccc(C)nc1)CC2
Reactant: NNc1ccc([N+](=O)[O-])cc1Cl
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)Nc1nc2c(s1)-c1c(c(-c3ccc(C)nc3)nn1-c1ccc([N+](=O)[O-])cc1Cl)CC2
Temperature: 60 °C
Yield: 72.9 %

Procedure:
A suspension of 5.0 g (15.2 mmol) N-[6-(6-methyl-pyridine-3-carbonyl)-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl]-acetamide (A-23) and 3.74 g (16.7 mmol) (2-chloro-4-nitro-phenyl)-hydrazine hydrochloride in 100 mL glacial acetic acid is stirred at 60° C. After stirring for 24 h at 60° C. the solvent is evaporated, the residue taken up in 200 mL of ACN and stirred for 20 min. The solid is filtered off and dried at 40° C. yielding 5.33 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=O)([O-:11])=[O:10]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[CH:15][C:14]2[CH:17]=[CH:18][CH:19]=[C:12]([N+:9]([O-:11])=[O:10])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: Nc1ccc(Cl)cc1
Solvent: CCO
Product: O=[N+]([O-])c1cccc(C=Nc2ccc(Cl)cc2)c1
Temperature: 25 °C
Yield: 92.1 %

Procedure:
A mixture of 4-chloro-phenylamine (6.4 g, 50 mmol) and 3-nitro-benzaldehyde (8.31 g, 55 mmol) in ethanol (100 mL) was prepared. The reaction mixture was heated to reflux for 3 h. Then the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford (4-chloro-phenyl)-(3-nitro-benzylidene)-amine (12 g, 92%) as a light yellow oil: LC/MS m/e calcd for C13H9ClN2O2 (M+H)+: 261.68, observed: 261.0.
Reaction SMILES: N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][N:21]=1.FC(F)(F)C(O)=O>C(OCC)C>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][NH:21]1
Reactant: COc1ccccc1C1=NCCc2ccccc21
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: COc1ccccc1C1NCCc2ccccc21
Temperature: 5 °C
Yield: 81.6 %

Procedure:
Under an argon atmosphere, a 1.0 M borane-THF complex solution (110 mL) was added to a mixture of (1R,2S)-1-amino-2-indanol (8.17 g) and diethyl ether (200 mL) under stirring at an internal temperature of 5° C. or lower. The mixture was further stirred at room temperature for 1.5 hours. The mixture was cooled to an internal temperature of 4° C. 1-(2-methoxyphenyl)-3,4-dihydroisoquinoline (10 g) was gradually added to the mixture at an internal temperature of 5° C. or lower, followed by stirring at the same temperature for 30 minutes. The mixture was stirred at room temperature for 3 days. Trifluoroacetic acid (61 mL) was added to the reaction mixture to decompose an excess of reagent, further followed by heating under reflux for 3 hours. After cooling, diethyl ether was evaporated under reduced pressure and the mixture was heated under reflux for 10 minutes. The residue was diluted with chloroform and extracted with concentrated aqueous ammonia to be alkaline. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform-EtOH-aqueous ammonia) to obtain 1-(2-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (8.23 g).
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[C:23]([C:25]#[N:26])[CH:22]=[C:21]([Cl:27])[CH:20]=2)=[O:16])[CH2:11][CH2:10]1)=O)(C)(C)C.Cl>CCOC(C)=O.O1CCOCC1>[NH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[C:23]([C:25]#[N:26])[CH:22]=[C:21]([Cl:27])[CH:20]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2cc(Cl)cc(C#N)c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: N#Cc1cc(Cl)cc(COC(=O)N2CCC(N)CC2)c1
Reaction time: 20 h

Procedure:
To a solution of 3-chloro-5-cyanobenzyl 4-((tert-butoxycarbonyl)amino)piperidine-1-carboxylate (1.846 g, 4.69 mmol) in EtOAc (30 ml) at RT under nitrogen was added 4M HCl in Dioxane (11.72 ml, 46.9 mmol) and the suspension stirred for 20 hours. After 3 hours a further 5 ml of 4M HCl in Dioxan was added. The solid was filtered off and dried to afford the title product as the hydrochloride salt;
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].[Br:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Br>CN(C)C=O.C(OCC)(=O)C>[Br:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: BrCc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)CCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCc1ccc(OCc2cccc(Br)c2)cc1
Temperature: 0 °C
Yield: 77.6 %

Procedure:
To a solution (100 mL) of tert-butyl 3-(4-hydroxyphenyl)propanoate (5.5 g, 24.7 mmol) in N,N-dimethylformamide was added 60% sodium hydride (1.09 g, 27.2 mmol) with stirring at 0° C., and the mixture was stirred at the same temperature for 15 min. Then, 3-bromobenzylbromide (6.55 g, 25.91 mmol) was added to this mixture with stirring at 0° C., and the mixture was stirred at room temperature for 12 hrs. The reaction mixture was diluted with ethyl acetate, and washed with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (7.5 g, yield 78%) as a colorless powder.
Reaction SMILES: [O:1]1[C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[O:4][CH2:3][CH2:2]1)[C:11](O)=[N:10][CH:9]=[CH:8]3.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:11]1[C:12]2[C:7](=[C:6]3[O:1][CH2:2][CH2:3][O:4][C:5]3=[CH:14][CH:13]=2)[CH:8]=[CH:9][N:10]=1
Reactant: Oc1nccc2c3c(ccc12)OCCO3
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nccc2c3c(ccc12)OCCO3

Procedure:
A solution of 2,3-dihydro-[1,4]dioxino[2,3-f]isoquinolin-7-ol (5 g, 24.61 mmol) in POCl3 (50 mL) was refluxed for 14 h. After Concentration, the residue was taken into the mixture of DCM and 4N NaOH solution. The organic phase was collected and dried over sodium sulfate, filtered, then concentrated under vacuum. The crude material was purified by silica gel chromatography using 20% EtOAc/Hexanes as eluent to give 4 g of the desired product 7-chloro-2,3-dihydro-[1,4]dioxino[2,3-f]isoquinoline as a solid. 1H NMR (400 Hz, CDCl3) δ ppm 4.42 (m, 4H), 7.24 (d, J=9.05 Hz, 1H), 7.77 (d, J=5.87 Hz, 1H), 7.84 (d, J=9.05 Hz, 1H), 8.18 (d, J=5.87 Hz, 1H); MS: (M+H)+ 222.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH2:5]Br.[Br:14][C:15]1[C:20]([F:21])=[CH:19][C:18]([OH:22])=[C:17]([F:23])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:14][C:15]1[CH:16]=[C:17]([F:23])[C:18]([O:22][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([C:10]([F:13])([F:12])[F:11])=[C:2]([Cl:1])[CH:3]=2)=[CH:19][C:20]=1[F:21]
Reactant: Oc1cc(F)c(Br)cc1F
Reactant: FC(F)(F)c1ccc(CBr)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1cc(OCc2ccc(C(F)(F)F)c(Cl)c2)c(F)cc1Br
Temperature: 25 °C
Yield: 98.5 %

Procedure:
To solution of 3-chloro-4-(trifluoromethyl)benzyl bromide (300 mg, 1.097 mmol) in acetone (15 mL) was added 4-bromo-2,5-difluorophenol (1.097 mmol) followed by potassium carbonate (303 mg, 2.194 mmol). The reaction mixture was heated at reflux for 3.5 hours and then allowed to cool to room temperature. The solvent was removed under reduced pressure to yield a white solid, which was partitioned with water/EtOAc mixture (1:1, 50 mL). The organic layer was separated and the aqueous was extracted with EtOAc (3×30 mL). The combined organics were washed with brine (50 mL), dried over sodium sulphate, filtered and concentrated in vacuo to give the title compound as a white solid (434 mg, 99%).
Reaction SMILES: O[CH:2]=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[OH:27]>>[OH:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[NH:20][CH:2]=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccccc1O
Reactant: O=C1C(=CO)C(c2ccccc2)Oc2ccccc21
Product: O=C1C(=CNc2ccccc2O)C(c2ccccc2)Oc2ccccc21

Procedure:
As in example 18 but starting from 5 g 3-hydroxymethylideneflavanone and 2.16 g o-aminophenol. Pure 3-(N-2-hydroxyphenyl)aminomethylidene-flavanone is obtained as yellow crystals; m.p. 226°-228° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:29][NH2:30].[I-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:30][CH2:29][C:25]2[S:24][CH:28]=[CH:27][CH:26]=2)[CH:16]=1
Reactant: NCc1cccs1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CNCc2cccs2)c1
Yield: 73.7 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-3-((thiophen-2-ylmethylamino)methyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.050 g; 0.144 mmol), thiophen-2-ylmethanamine (0.051 mL; 0.5 mmol), and sodium iodide (0.015 g; 0.1 mmol) in THF (3 mL), under a microwave irradiation at 150° C. for 10 minutes. Flash chromatography on silica gel (eluent 0 to 10% methanol in dichloromethane) furnished 0.045 g (73%) of the title compound as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[S:30])[NH:13][C:14]2[CH:27]=[C:26]([Cl:28])[C:17]([O:18][CH2:19][CH2:20]OS(C)(=O)=O)=[C:16]([Cl:29])[CH:15]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:31][NH:32][CH3:33]>O1CCCC1.C(OCC)(=O)C>[Cl:28][C:26]1[CH:27]=[C:14]([NH:13][C:12](=[S:30])[NH:11][C:8]2[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)[CH:15]=[C:16]([Cl:29])[C:17]=1[O:18][CH2:19][CH2:20][N:32]([CH3:33])[CH3:31]
Reactant: CNC
Reactant: CC(=O)Nc1ccc(NC(=S)Nc2cc(Cl)c(OCCOS(C)(=O)=O)c(Cl)c2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(NC(=S)Nc2cc(Cl)c(OCCN(C)C)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a solution of methanesulfonic acid 2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichlorophenoxy}-ethyl ester (0.33 g) in tetrahydrofuran (6 mL) is added aqueous dimethyl-amine (8.8 M, 0.5 mL) and the mixture is stirred at room temperature for 5 days. The reaction mixture is then diluted with ethyl acetate, then washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure the residue is chromatographed over silica gel (pure methanol is used as the eluant). Pooled product containing fractions are evaporated under reduced pressure and the residue is recrystallized from acetonitrile to provide the desired product as a white powder.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[C:23]4[CH:24]=[N:25][C:26]([NH2:40])=[C:27]([O:28][C@@H:29]([C:31]5[C:36]([Cl:37])=[CH:35][CH:34]=[C:33]([F:38])[C:32]=5[Cl:39])[CH3:30])[C:22]=4[O:21][C:20]=3Br)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:42][N:43](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[NH2:40][C:26]1[N:25]=[CH:24][C:23]2[C:19]([C:17]3[CH:16]=[N:15][N:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:18]=3)=[C:20]([C:42]#[N:43])[O:21][C:22]=2[C:27]=1[O:28][C@@H:29]([C:31]1[C:36]([Cl:37])=[CH:35][CH:34]=[C:33]([F:38])[C:32]=1[Cl:39])[CH3:30]
Reactant: C[C@@H](Oc1c(N)ncc2c(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)c(Br)oc12)c1c(Cl)ccc(F)c1Cl
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: C[C@@H](Oc1c(N)ncc2c(-c3cnn(C4CCNCC4)c3)c(C#N)oc12)c1c(Cl)ccc(F)c1Cl
Temperature: 150 °C
Reaction time: 4 h

Procedure:
A mixture of [4-(4-{6-amino-2-bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-furo[3,2-c]pyridin-3-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (20.0 mg, 0.0299 mmol), zinc cyanide (4.2 mg, 0.036 mmol) and Pd(PPh3)4 (3 mg, 0.003 mmol) in DMF (1 mL) was degassed and refilled with nitrogen (3×). The reaction was heated at 150° C. using a microwave reactor for 2 min. The solution was passed through a PL-Thiol SPE cartridge to remove metals. The material was then dissolved in dioxane and EtOH, charged with 4M HCl in Dioxane (0.2 mL) and stirred at rt for 4 h. The solution was concentrated in vacuo, redissolved in DMF (0.5 mL) and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.93 (d, J=6.8 Hz, 3H), 2.30-2.40 (m, 4H), 3.18-3.26 (m, 2H), 3.59 (d, J=13.4 Hz, 2H), 4.64-4.71 (m, 1H), 6.43 (q, J=6.8 Hz, 1H), 7.21-7.27 (m, 1H), 7.42 (dd, J=9.0, 4.9 Hz, 1H), 8.11 (s, 1H), 8.33-8.39 (m, 2H). MS (ES+): m/z 515.06/517.07 (100/68) [MH+]. HPLC: tR=2.78 min (ZQ2, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[N:4][N:5]([CH2:8][C:9]([OH:11])=O)[C:6]=1[CH3:7].C(N(CC)CC)C.[C:23]([O:27][C:28]([N:30]1[CH2:37][CH:36]2[CH:32]([CH2:33][NH:34][CH2:35]2)[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CN(C=O)C>[C:23]([O:27][C:28]([N:30]1[CH2:31][CH:32]2[CH:36]([CH2:35][N:34]([C:9](=[O:11])[CH2:8][N:5]3[C:6]([CH3:7])=[C:2]([Cl:1])[C:3]([C:12]([F:15])([F:14])[F:13])=[N:4]3)[CH2:33]2)[CH2:37]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CC2CN(C(=O)OC(C)(C)C)CC2C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
A solution of (4-Chloro-5-methyl-3-trifluoromethylpyrazol-1-yl)acetic acid (97 mg), triethylamine (0.2 mL) and compound 5 (76 mg) in DMF (2 mL) was stirred at 0° C. and 1-propanephosphonic acid cyclic anhydride (0.55 mL, 50% in EtOAc) was added dropwise. The reaction mixture was stirred another 30 min at 0° C. and directly purified by preparative HPLC to provide the title compound 6 as a pale yellow oil (146 mg, 93%). LCMS: Rf: 4.495 min, M+H+: 459.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]2=4)[N:14]([CH3:23])[CH:13]=3)[N:9]([CH3:24])[CH2:8]1)=[O:5])[CH3:2].F[B-](F)(F)F.[CH3:32][S+:33](C)SC.F[B-](F)(F)F.[H+].C(=O)(O)[O-]>C1COCC1.C(Cl)Cl>[CH2:25]([N:3]([CH2:1][CH3:2])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]2=4)[N:14]([CH3:23])[C:13]=3[S:33][CH3:32])[N:9]([CH3:24])[CH2:8]1)=[O:5])[CH3:26]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4c3c(cn4C)C[C@H]2N(C)C1
Reactant: CS[S+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [H+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4c3c(c(SC)n4C)C[C@H]2N(C)C1
Reaction time: 0.5 h

Procedure:
A solution is prepared from 354 mg of 1,1-diethyl-3-(1,6-dimethyl-8α-ergolinyl)urea (1 mmol) in 20 ml of THF and, at room temperature under nitrogen, 392 mg of dimethylmethylthiosulfonium tetrafluoroborate (2 mmol) and 0.24 ml of 50% strength tetrafluoroboric acid are added thereto. After 30 minutes of agitation at room temperature, the mixture is distributed between methylene chloride and bicarbonate solution, the organic phases are combined, dried with sodium sulfate, and evaporated. The crude product is chromatographed with methylene chloride on silica gel yielding, after crystallization, 276 mg (69% of theory). [α]D =+11° (0.5% in chloroform).
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([NH2:5])=[S:4].CO[CH:14](OC)[CH2:15]Cl>C1(C)C=CC=CC=1>[CH3:1][N:2]([C:3]1[S:4][CH:14]=[CH:15][N:5]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(CCl)OC
Reactant: CN(C(N)=S)c1ccccc1
Solvent: Cc1ccccc1
Product: CN(c1ccccc1)c1nccs1

Procedure:
A solution of 10 g (60 mmol) of N-methyl-N-phenylthiourea in 100 mL of toluene was treated with 7.2 mL (63 mmol) of chloroacetaldehyde dimethylacetal and heated at reflux for 12 h. The solvent was removed in vacuo and the residue purified by flash chromatography eluting with a linear gradient of 30% EtOAc in hexane to 80% EtOAc in hexane to deliver the title compound. MS (M+H)+ 191.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:10])=[CH:5][CH:4]=1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C>C(#N)C>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH:11]2[CH2:16][CH2:15][N:14]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:13][CH2:12]2)=[O:10])=[CH:5][CH:4]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: CCOC(=O)CBr
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Yield: 84.3 %

Procedure:
To a solution of (4-fluorophenyl)(piperidin-4-yl)methanone hydrochloride (51.8 g, 213 mmol) in acetonitrile (400 mL) was added ethyl 2-bromoacetate (38.2 mL, 345 mmol) and triethylamine (70 mL, 506 mmol). The mixture was heated at reflux for 5 h, the solvent was evaporated under reduced pressure and purified via flash column chromatography (ethyl acetate:hexane, 10:90 to 100:0) to provide product (52.7 g, 85% yield). 1H NMR (400 MHz, CDC3) δ 7.98 (dd, J=8.5, 5.5 Hz, 2H), 7.16 (t, J=8.5 Hz, 2H), 4.22 (q, J=7.2 Hz, 2H), 3.16-3.27 (m, 1H), 3.03 (d, J=11.5 Hz, 2H), 2.43 (td, J=11.2, 3.3 Hz, 2H), 1.81-2.09 (m, 4H), 1.51-1.73 (m, 2H), 1.30 (t, J=7.3 Hz, 3H). MS m/z 294.4 (M+1), retention time=1.94 min.
Reaction SMILES: CC([O-])(C)C.[K+].[Cl:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[C:9]=1[C:10]([OH:12])=[O:11].Cl[N:19]1[N:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[NH:20]1.Cl>CN(C)C=O.O>[Cl:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][N:19]2[N:20]=[C:21]([O:27][CH3:28])[CH:22]=[C:23]([O:25][CH3:26])[NH:24]2)[C:9]=1[C:10]([OH:12])=[O:11]
Reactant: COC1=CC(OC)=NN(Cl)N1
Reactant: O=C(O)c1c(O)cccc1Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1=CC(OC)=NN(Oc2cccc(Cl)c2C(=O)O)N1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
At 25° C., 20.2 g of potassium tert-butylate is added in portions to 15.5 g of 2-chloro-6-hydroxybenzoic acid in 50 ml of dimethylformamide. Subsequently, 15.7 g of 2-chloro-4,6-dimethoxytriazine is added. The mixture is stirred for 12 hours at 25° C. and poured into cold water, and the resulting mixture is acidified with hydrochloric acid. Extraction is then carried out with ethyl acetate, and the extract is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is stirred with a small amount of diethyl ether, followed by filtration. The residue is dried under reduced pressure (m.p. 128°-131° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+].C(OCC)C>CN(C=O)C>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([N:11]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:14])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(NS(=O)(=O)c2ccc(C)cc2)cc(OC)c1
Reactant: CCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCCCCN(c1cc(OC)cc(OC)c1)S(=O)(=O)c1ccc(C)cc1
Temperature: 120 °C
Yield: 96.3 %

Procedure:
A mixture of N-(3,5-Dimethoxy-phenyl)-4-methyl-benzenesulfonamide (15.0 g, 48.9 mmol), 1-bromoheptane (9.63 g, 53.8 mmol) and potassium carbonate (17.1 g, 124.2 mmol) in anhydrous DMF (100 mL) was stirred and heated at 120 ° C. for 4 h, and then cooled to room temperature and poured into ice-cold water (400 mL). Diethyl ether (400 mL) was added to extract the product. The ethereal solution was separated and washed with water, brine and dried with Na2SO4. Removal of solvent and drying reagent provided 19.50 g of light yellow liquid, which was treated with small amount of diethyl ether to give 19.10 g (96.4%) of the title compound as a white solid upon cooling.