Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([C:31]([N:33]4[CH2:38][CH2:37][N:36]([S:39]([CH3:42])(=[O:41])=[O:40])[CH2:35][CH2:34]4)=O)[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[N:10]=2)=CC=1.[CH2:54]([Mg]Br)[CH3:55].[OH-].[Na+].[C:60]([OH:66])([C:62]([F:65])([F:64])[F:63])=[O:61]>C1COCC1.S(O)(C(F)(F)F)(=O)=O.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[F:63][C:62]([F:65])([F:64])[C:60]([OH:66])=[O:61].[CH3:30][O:29][C:26]1[N:25]=[CH:24][C:23]([NH:22][C:21]2[C:16]([C:11]3[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([NH2:8])[N:10]=3)=[CH:17][C:18]([C:31]3([N:33]4[CH2:38][CH2:37][N:36]([S:39]([CH3:42])(=[O:40])=[O:41])[CH2:35][CH2:34]4)[CH2:55][CH2:54]3)=[CH:19][N:20]=2)=[CH:28][CH:27]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(=O)N4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc(OC)nc3)n2)cc1
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: CC[Mg+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1ccc(Nc2ncc(C3(N4CCN(S(C)(=O)=O)CC4)CC3)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 4.57 %

Procedure:
A solution of (5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)(4-(methylsulfonyl)piperazin-1-yl)methanone (0.163 g, 0.220 mmol) and titanium (IV) isopropoxide (0.194 mL, 0.661 mmol) in THF (2 mL) at 0° C. under nitrogen was treated dropwise with ethylmagnesium bromide (1.0 M solution in tert-butyl methyl ether; 1.322 mL, 1.322 mmol). The reaction was warmed to ambient temperature and an additional 3 equiv. EtMgBr was added. After 1 h, the reaction was quenched with ice and DCM, and was filtered through Celite® (diatomaceous earth) rinsing with copious amounts of DCM. The reaction was partitioned between water and DCM. The aqueous layer was extracted with DCM (3×) and the combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give an orange solid. The solid was taken up in TFA (1.5 mL) and 20 drops TfOH was added from a Pasteur pipette. The resulting mixture was sealed and heated at 80° C. for 1 h. The reaction was cooled in an ice bath and treated with ice and 10 N NaOH until basic. The reaction was partitioned between water and DCM. The aqueous layer was extracted with DCM (3×) and the combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. This material was dissolved in DMSO and purified by prep HPLC (5-50% MeCN/H2O with 0.1% TFA). Product-containing fractions were concentrated to give 4-(2-(6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)cyclopropyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine 2,2,2-trifluoroacetate (0.0063 g, 10.07 μmol, 4.57% yield) as an orange solid. m/z (ESI, +ve ion) 512 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.80 (s, 1H); 8.68 (d, J=2.3 Hz, 1H); 8.52 (d, J=2.5 Hz, 1H); 8.27 (d, J=2.2 Hz, 1H); 8.16 (dd, J=8.8, 2.7 Hz, 1H); 7.90 (br. s., 1H); 7.74 (br. s., 1H); 6.83 (d, J=8.8 Hz, 1H); 3.85 (s, 3H); 3.01-3.23 (m, 4H); 2.84 (s, 3H); 2.60-2.79 (m, 4H); 2.44 (s, 3H); 1.00-1.13 (m, 2H); 0.84-0.97 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][C:19]([C@H:22]2[C@H:27]([OH:28])[C@@H:26]([OH:29])[C@H:25]([OH:30])[C@@H:24]([S:31][CH3:32])[O:23]2)=[CH:18][C:3]=1[CH2:4][C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][CH2:11][CH2:12][C:13](O)=[O:14])=[CH:7][CH:6]=1.[NH2:33][C:34]1([C:39]([NH2:41])=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1[CH:21]=[CH:20][C:19]([C@H:22]2[C@H:27]([OH:28])[C@@H:26]([OH:29])[C@H:25]([OH:30])[C@@H:24]([S:31][CH3:32])[O:23]2)=[CH:18][C:3]=1[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][CH2:11][CH2:12][C:13]([NH:33][C:34]2([C:39]([NH2:41])=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:14])=[CH:16][CH:17]=1
Reactant: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(OCCCC(=O)O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: NC(=O)C1(N)CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(OCCCC(=O)NC4(C(N)=O)CCCC4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
4-(4-(2-methyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)phenoxy)butanoic acid (39, 46 mg, 0.10 mmol), 1-aminocyclopentanecarboxamide (26 mg, 0.20 mmol), HATU (57 mg, 0.15 mmol), and DIPEA (52 μL, 0.30 mmol) were combined in DMF (0.5 mL) and stirred overnight at room temperature. The reaction was diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine (with back extraction), dried over MgSO4, filtered, and concentrated under vacuum. The material was purified by prep HPLC (C18 30×100 mm column, 20-60% CH3CN/10 mM aqueous ammonium formate, 45 mL/min) and lyophilized to give 35 mg (61% yield) of amide 41 as a white solid. 1H NMR (400 MHz, MeOH-d4) δ ppm 7.10-7.19 (m, 3 H), 7.04 (d, J=8.6 Hz, 2 H), 6.81 (m, J=8.6 Hz, 2 H), 4.39 (d, J=9.3 Hz, 1 H), 4.12 (d, J=9.1 Hz, 1 H), 3.96 (t, J=6.2 Hz, 2 H), 3.92 (s, 2 H), 3.34-3.50 (m, 3 H), 2.41 (t, J=7.5 Hz, 2 H), 2.12-2.22 (m, 8 H), 2.04 (quin, J=6.9 Hz, 2 H), 1.93 (dt, J=12.8, 5.1 Hz, 2 H), 1.64-1.75 (m, 4H); MS (ES+) [M+H]+=573.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14](O)=[O:15])[C:11]3[CH:17]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[S:19][C:10]=3[C:9]=2[CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:4][CH:3]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH2:13][C:14]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:15])[C:11]3[CH:17]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[S:19][C:10]=3[C:9]=2[CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: COC(=O)c1cc2c(s1)c(C1CCCCC1)c(-c1ccc(Cl)cc1)n2CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1cc2c(s1)c(C1CCCCC1)c(-c1ccc(Cl)cc1)n2CC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
A solution (0.05 M) of [5-(4-chlorophenyl)-6-cyclohexyl-2-(methoxycarbonyl)-4H-thieno[3,2-b]pyrrol-4-yl]acetic acid in DMF at RT was treated with morpholine (2 eq.), DIEA (1.5 eq.) and HATU (2.5 eq.). The mixture was stirred at RT for 8 h, then it was diluted with DCM and washed sequentially with aqueous HCl (1 N), aqueous NaHCO3 (saturated solution) and dried. Evaporation of the solvent under reduced pressure gave a residue which was purified by RP-HPLC (Conditions: Waters X-TERRA MS C18, 10 micron, 19×150 mm; flow: 20 mL/min; Gradient: A: H2O+0.05% TFA; B: MeCN+0.05% TFA; 90% A isocratic for 2 min then linear to 10% A in 9 min) to afford the title compound (51%) as a solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=3)C(=O)[O:10][N:9]=2)=[N:5][O:6][N:7]=1.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C.C(Cl)Cl.CN(C1C=CN=CC=1)C.CN(C=O)C.CO>[C:22]1([S:28]([NH:1][CH2:2][C:3]2[C:4]([C:8]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=3)=[N:9][OH:10])=[N:5][O:6][N:7]=2)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NCc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: ClCCl
Solvent: CO
Product: O=S(=O)(NCc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 187.9 %

Procedure:
3-[4-(Aminomethyl)-1,2,5-oxadiazol-3-yl]-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (10 mg, 0.003 mmol) was dissolved in ACN (0.2 mL) and DCM (0.2 mL). Benzenesulfonyl chloride (11 mg, 0.064 mmol) DIPEA (12 mg, 0.096 mmol) and DMAP (0.4 mg, 0.003 mmol) were dissolved in DMF (1 mL). The reaction was stirred at rt for 6 hrs. The reaction was then diluted with MeOH and purified by preparative LCMS. The intermediate was stripped to dryness, redissolved in EtOH (1 mL) and 1 M of sodium hydroxide in water (0.06 mL) was added. The reaction was stirred at rt for 1 hr, quenched with acetic acid, diluted with MeOH and the crude residue was purified by preparative LCMS to afford the desired product (2.4 mg). MF═C16H13ClFN5O4S; LCMS calculated for C16H14ClFN5O4S(M+H)+: m/z=426.0.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:35])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]([C:17]3([C:20]4[CH:30]=[CH:29][C:23]5[O:24][C:25]([F:28])([F:27])[O:26][C:22]=5[CH:21]=4)[CH2:19][CH2:18]3)=[O:16])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:31]([CH3:34])([CH3:33])[CH3:32]>CO.C(N(CC)CC)C>[C:31]([C:6]1[N:5]([CH2:4][C@@H:3]([OH:35])[CH2:2][NH:1][C:25](=[O:26])[O:24][CH3:23])[C:13]2[C:8]([CH:7]=1)=[CH:9][C:10]([NH:14][C:15]([C:17]1([C:20]3[CH:30]=[CH:29][C:23]4[O:24][C:25]([F:28])([F:27])[O:26][C:22]=4[CH:21]=3)[CH2:19][CH2:18]1)=[O:16])=[CH:11][CH:12]=2)([CH3:32])([CH3:34])[CH3:33]
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2n1C[C@H](O)CN
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)NC[C@H](O)Cn1c(C(C)(C)C)cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc21
Reaction time: 0.5 h

Procedure:
To a stirred solution (R)—N-(1-(3-amino-2-hydroxypropyl)-2-tert-butyl-1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (0.10 g, 0.20 mmol) in methanol (1 mL) was added 2 drops of triethylamine and methylchloroformyl chloride (0.020 mL, 0.25 mmol). After 30 min, the reaction mixture was filtered and purified using reverse phase HPLC providing (S)-methyl 3-(2-tert-butyl-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclo-propanecarboxamido)-1H-indol-1-yl)-2-hydroxypropylcarbamate. The retention time on a three minute run is 1.40 min. LC/MS (M+1)=544.3. 1H NMR (400 MHz, CDCl3) δ 7.52 (d, 1H, J=2 Hz), 7.30 (dd, 1H, J=2, 8 Hz), 7.28 (m, 1H), 7.22 (d, 1H, J=8 Hz), 7.14 (d, 1H, J=8 Hz), 7.04 (br s, 1H), 6.97 (dd, 1H, J=2, 8 Hz), 6.24 (s, 1H), 5.19 (1H, br s), 4.31 (dd, 1H, J=6, 15 Hz), 4.28 (dd, 1H, J=11, 15 Hz), 4.18 (m, 1H), 3.70 (s, 3H), 3.40 (dd, 1H, J=3, 6 Hz), 3.36 (dd, 1H, J=3, 6 Hz), 3.26 (m, 1H), 1.74 (m, 2H), 1.40 (s, 9H), 1.11 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[OH:18][CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:18][CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:3]=1
Reactant: OCc1cccnc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(OCc2cccnc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 3-(hydroxymethyl)pyridine and DBU in DME. EI-MS m/e (%): 293 (M+, 54), 276 ([M—NH3]+, 36), 92 (100), 65 (44), 39 (23).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]([C:22]1[N:26]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:25]2[CH:35]=[CH:36][CH:37]=[CH:38][C:24]=2[N:23]=1)[CH2:10][CH2:11][CH2:12][N:13]([CH3:21])[C:14]([O:16]C(C)(C)C)=O.C(=O)([O-])[O-].[K+].[K+].[F:45][C:46]([F:69])([F:68])[C:47]1[CH:48]=[C:49]([CH:61]=[C:62]([C:64]([F:67])([F:66])[F:65])[CH:63]=1)[CH2:50][NH:51]C(=O)OC1C=CC=CC=1.[ClH:70].C(O)C>C(O)C.C(Cl)(Cl)Cl.O>[ClH:70].[CH3:8][N:9]([C:22]1[N:26]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:25]2[CH:35]=[CH:36][CH:37]=[CH:38][C:24]=2[N:23]=1)[CH2:10][CH2:11][CH2:12][N:13]([CH3:21])[C:14]([NH:51][CH2:50][C:49]1[CH:61]=[C:62]([C:64]([F:65])([F:66])[F:67])[CH:63]=[C:47]([C:46]([F:45])([F:68])[F:69])[CH:48]=1)=[O:16]
Reactant: O=C(NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Oc1ccccc1
Reactant: CN(CCCN(C)c1nc2ccccc2n1Cc1ccc(F)cc1)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: O
Product: CN(CCCN(C)c1nc2ccccc2n1Cc1ccc(F)cc1)C(=O)NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2 ml of trifluoroacetic acid was added to 1.3 g of N-methyl-N-(1-(4-fluorobenzyl)benzimidazol-2-yl)-N'-methyl-N'-t-butoxycarbonyl-1,3-propylenediamine, and the mixture was stirred at room temperature for one hour. Then, 50 ml of water and 50 ml of chloroform were added thereto, and potassium carbonate was added thereto until the mixture became basic. The organic layer was taken and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, to obtain 970 mg of a colorless oily substance. To 300 mg of this oily substance, 370 mg of phenyl N-(3,5-bis(trifluoromethyl)benzyl)carbamate was added, and the mixture was heated and stirred at 120° C. for two hours. After cooling, the obtained oily substance was purified by silica gel column chromatography (eluent: ethyl acetate/ethanol=9/1) to obtain 500 mg of a colorless oily substance. 250 mg of this oily substance was dissolved in 3 ml of ethanol, and 1 ml of 28% hydrochloric acid-ethanol was added thereto. The solvent was distilled off under reduced pressure, and the residue was crystallized from diethyl ether to obtain 280 mg of the above identified compound as colorless crystals. (m.p. 170.0-172.0° C.)
Reaction SMILES: Cl[C:2]1[CH:24]=[C:23](Cl)[CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[C:9](=[O:20])[NH:10][N:11]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:13]=1)=[O:7].O=C1C(C(O)=O)=CC(C2C=CN=CC=2)=NN1.C(Cl)(=O)C(Cl)=O.[F:48][C:49]([F:59])([F:58])C1C=CC(CN)=CC=1>C(N(CC)CC)C.CN(C)C=O.ClCCl>[O:20]=[C:9]1[C:8]([C:6]([NH:5][CH2:4][C:3]2[CH:21]=[CH:22][C:23]([C:49]([F:59])([F:58])[F:48])=[CH:24][CH:2]=2)=[O:7])=[CH:13][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[N:11][NH:10]1
Reactant: O=C(NCc1ccc(Cl)cc1Cl)c1cc(-c2ccncc2)n[nH]c1=O
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)c1cc(-c2ccncc2)n[nH]c1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1ccc(C(F)(F)F)cc1)c1cc(-c2ccncc2)n[nH]c1=O

Procedure:
Working as in example 2 for the preparation of N-(2,4-dichlorobenzyl)-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxamide, but starting with 0.3 g of 3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxylic acid, 10 cm3 of dichloromethane, 0.02 cm3 of dimethylformamide, 0.12 cm3 of oxalyl chloride, 0.21 cm3 of 4-(trifluoromethyl)benzylamine and 0.19 cm3 of triethylamine, 0.22 g of 3-oxo-6-pyridin-4-yl-N-[4-(trifluoromethyl)benzyl]-2,3-dihydropyridazine-4-carboxamide-was obtained in the form of a cream-colored solid melting at 227° C.
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:24]=[CH:23][CH:22]=[CH:21][C:7]=2[CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C:11]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:10]2=[O:20])[N:3]=[CH:4][CH:5]=1.C(N(C(C)C)CC)(C)C.Cl[C:35]1[CH:44]=[N:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:36]=1>C(#N)C>[N:1]1[N:2]([C:6]2[CH:24]=[CH:23][CH:22]=[CH:21][C:7]=2[CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C:11]3([CH2:15][CH2:16][N:17]([C:35]4[CH:44]=[N:43][C:42]5[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=5)[N:36]=4)[CH2:18][CH2:19]3)[C:10]2=[O:20])[N:3]=[CH:4][CH:5]=1
Reactant: O=C1N(Cc2ccccc2-n2nccn2)CCCC12CCNCC2
Reactant: Clc1cnc2ccccc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1N(Cc2ccccc2-n2nccn2)CCCC12CCN(c1cnc3ccccc3n1)CC2
Temperature: 120 °C
Yield: 66 %

Procedure:
To a stirred solution of 2-(2-(2H-1,2,3-triazol-2-yl)benzyl)-2,9-diazaspiro[5.5]undecan-1-one (TFA salt) (200 mg, 0.354 mmol, contains 2.0 moleq. TFA) and diisopropylethylamine (0.64 mL, 3.61 mmol) in acetonitrile (1 mL) was added 2-chloroquinoxaline [1448-87-9] (121 mg, 0.72 mmol). The mixture was heated at 120° C. for 40 min under microwave conditions. The reaction mixture was cooled to rt and concentrated under reduced pressure. The crude mixture was purified by flash-column chromatography over silicagel (eluent: gradient 10%-100% ethyl acetate/heptane) to yield the title compound (106 mg, 65%). [1H NMR (400 MHz, DMSO-d6) ♀ ppm 8.81 (s, 1H), 8.11 (s, 2H), 7.80 (d, 1H), 7.59-7.63 (m, 1H), 7.56-7.59 (m, 2H), 7.44-7.55 (m, 2H), 7.33-7.40 (m, 1H), 7.24-7.29 (m, 1H), 4.54 (br. s, 2H), 4.19-4.29 (m, 2H), 3.39-3.49 (m, 2H), 3.13 (t, 2H), 1.99-2.10 (m, 2H), 1.84-1.92 (m, 2H), 1.73-1.83 (m, 2H), 1.54-1.65 (m, 2H); LCMS RtA=1.16, [M+H]+=454.4].
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1.Cl.[O:17]([CH2:21][CH3:22])[C:18]([S-:20])=[S:19].[K+].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:21]([O:17][C:18]([S:20][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1)=[S:19])[CH3:22]
Reactant: CCOC(=S)[S-]
Reactant: Nc1ccc(CC(=O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: O
Product: CCOC(=S)Sc1ccc(CC(=O)O)cc1
Temperature: 45 °C
Reaction time: 0.75 h
Yield: 73.1 %

Procedure:
A solution of sodium nitrite (18.4 g, 0.267 mol) in water (133 mL) was added dropwise to a suspension of 2-(4-aminophenyl)acetic acid (40.3 g, 0.267 mol) in water (133 mL) and conc. HCl (54 mL, 0.65 mol) at 0° C. After addition, the reaction mixture was stirred at the same temperature for 45 min. The solution of the cold diazonium salt was then added dropwise to a mixture of potassium ethyl xanthate (49.3 g, 0.31 mol), water (80 mL) and aqueous sodium carbonate solution (200 mL, 2 M) at rt. After addition, the mixture was allowed to warm to 45° C. and stirred at this temperature until gas evolution ceased (about 3 h to overnight). The mixture was cooled to rt and adjusted to pH=1 with conc. HCl. The aqueous layer was extracted with ethyl acetate (3×300 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude 2-(4-((ethoxycarbonothioyl)thio)phenyl)acetic acid (50 g, 73%) as a dark red liquid, which was used for next step directly without further purification. 1H NMR (purified by pre-TLC, CDCl3 300 MHz): δ 7.40 (d, J=7.5 Hz, 2H), 7.28 (d, J=7.8 Hz, 2H), 4.54 (q, J=6.9 Hz, 2H), 3.63 (s, 2H), 1.26 (t, J=6.9 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:16]([CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:15][O:14][N:13]=2)=O)[CH:5]=[CH:6][C:7]=1[F:8].P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:32][OH:33]>C1C=CC=CC=1.CCO.CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:16]([CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:15][O:14][N:13]=2)=[N:32][OH:33])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NO
Reactant: O=C(Nc1ccc(F)c(Cl)c1)c1nonc1CCCN1CCOCC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CO
Solvent: c1ccccc1
Solvent: CCO
Product: ON=C(Nc1ccc(F)c(Cl)c1)c1nonc1CCCN1CCOCC1
Reaction time: 1 h
Yield: 50 %

Procedure:
N-(3-Chloro-4-fluorophenyl)-4-(3-morpholin-4-ylpropyl)-1,2,5-oxadiazole-3-carboxamide (10.0 mg, 27.1 μmol) was suspended in benzene (0.4 mL) under a nitrogen atmosphere and phosphorus pentachloride (6.2 mg, 29.8 μmol) was added and the solution was heated at reflux for 2.5 h. The reaction was then stripped to dryness in vacuo. The reaction was dissolved in EtOH (0.3 mL) and hydroxylamine (40 μL, 0.7 mmol) (50% solution in water) was added to the reaction. After stirring for 1 h, the reaction solution was diluted with MeOH and purified with preparative LCMS to give product (5.2 mg, 50%). LCMS for C16H20ClFN5O3(M+H)+: m/z=384.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][N:19]([C:22](=[O:24])C)[CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:25]=1.[CH2:26]([N:28](CC)CC)C.CN=C=O>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][N:19]([C:22]([NH:28][CH3:26])=[O:24])[CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:25]=1
Reactant: CC(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Reactant: CCN(CC)CC
Agent: CN=C=O
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Temperature: 25 °C

Procedure:
To a mixture of 2.03g (6.53 mmole) of 8-chloro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine and 1.0 mL of triethylamine in 30 mL of dry THF at -10° C. and under a nitrogen atmosphere was added dropwise over 10 minutes 0.40 mL (6.78 mmole) of methylisocyanate. The mixture was slowly warmed to room temperature. After 4 hours it was poured in water and extracted 3× with CH2Cl2. The organic portions were combined, dried over MgSO4, filtered and concentrated in vacuo to afford a product which was recrystallized from CH2Cl2 /ethyl acetate/hexanes to give 1.70 g of the title compound as white crystals. (m.p. 194.5°-196° C.).
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[C:5]([NH:17][CH3:18])=[C:6]([C:14]([NH2:16])=[O:15])[S:7][C:8]=1[C:9]1[CH:10]=[N:11][NH:12][CH:13]=1.C([O-])(O)=O.[Na+].[C:24]1(=O)[CH2:28][CH2:27][CH2:26][CH2:25]1.CC1C=CC(S(O)(=O)=O)=CC=1.[O-]S([O-])(=O)=O.[Mg+2]>CN(C=O)C.CCOC(C)=O>[Br:3][C:4]1[C:5]2[N:17]([CH3:18])[C:24]3([CH2:28][CH2:27][CH2:26][CH2:25]3)[NH:16][C:14](=[O:15])[C:6]=2[S:7][C:8]=1[C:9]1[CH:10]=[N:11][NH:12][CH:13]=1
Reactant: CNc1c(C(N)=O)sc(-c2cn[nH]c2)c1Br
Reactant: O=C1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1c2c(sc(-c3cn[nH]c3)c2Br)C(=O)NC12CCCC2
Yield: 42.5 %

Procedure:
A mixture of 4-bromo-3-(methylamino)-5-(1H-pyrazol-4-yl)thiophene-2-carboxamide dihydrochloride (90 mg, 0.267 mmol), saturated aqueous NaHCO3 (50 mL) and EtOAc (50 mL) was shaken well. The organic layer was collected, dried over MgSO4, filtered and concentrated under reduced pressure. This residue was mixed with cyclopentanone (2.00 mL, 22.6 mmol), PTSA (5.1 mg, 0.027 mmol), MgSO4 (64.2 mg, 0.533 mmol) and DMF (2 mL). This mixture was stirred at 80° C. for 4 h. The mixture was poured into saturated aqueous NaHCO3 and extracted with 3:1 EtOAc/THF (100 mL), and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc) to afford a white solid. This solid was triturated with EtOAc, and the precipitate was collected by filtration to afford the title compound (41.7 mg, 43%) as a white solid:
Reaction SMILES: [C:1]([NH:4][C:5]1[C:19]2=[C:20]3[C:8]([NH:9][CH:10]=[C:11]3[CH2:12][C@@H:13]3[C:18]2=[CH:17][C@H:16]([NH:21][C:22](=[O:28])[N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH2:15][N:14]3[CH3:29])=[CH:7][CH:6]=1)(=O)[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.Cl.N.C(O)(=O)C(C(C(O)=O)O)O>O1CCOCC1.C1(C)C=CC=CC=1.O>[CH2:1]([NH:4][C:5]1[C:19]2=[C:20]3[C:8]([NH:9][CH:10]=[C:11]3[CH2:12][C@@H:13]3[C:18]2=[CH:17][C@H:16]([NH:21][C:22](=[O:28])[N:23]([CH2:24][CH3:25])[CH2:26][CH3:27])[CH2:15][N:14]3[CH3:29])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCN(CC)C(=O)N[C@H]1C=C2c3c(NC(C)=O)ccc4[nH]cc(c34)C[C@H]2N(C)C1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: N
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCNc1ccc2[nH]cc3c2c1C1=C[C@H](NC(=O)N(CC)CC)CN(C)[C@@H]1C3
Temperature: 100 °C
Yield: 70 %

Procedure:
200 mg of 3-(12-acetylamino-9,10-didehydro-6-methyl-8α-ergolinyl)-1,1-diethylurea is dissolved in 10 ml of dioxane, combined with 2 ml of 20% diisobutyl aluminum hydride solution in toluene, and heated to 100° C. for 7 hours. The mixture is allowed to cool, then, under cooling, first water, thereafter 2N hydrochloric acid are added thereto, and the solution is rendered alkaline with dilute ammonia, after adding about 1 g of tartaric acid. The mixture is extracted by shaking with methylene chloride, the organic phase is dried and evaporated. The residue is charomatographed as disclosed in Example 7, thus producing 135 mg of 3-(9,10-didehydro-12-ethylamino-6-methyl-8α-ergolinyl)-1,1-diethylurea.