Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].Br[CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[C:15]([Cl:16])=[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[S:13][C:12]=2[CH:22]=1.CN(C)C=O>O1CCCC1>[Cl:16][C:15]1[C:11]2[CH:10]=[CH:9][C:8]([CH2:7][O:4][C:1]([CH3:2])=[O:3])=[CH:22][C:12]=2[S:13][C:14]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)c1sc2cc(CBr)ccc2c1Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc2cc(COC(C)=O)ccc2c1Cl
Temperature: 80 °C
Yield: 63 %

Procedure:
Sodium acetate (3.3 g, 40.5 mmol) was added to a stirred solution of ethyl 6-bromomethyl-3-chlorobenzo[b]thiophene-2-carboxylate (Preparation 10, 4.5 g, 13.5 mmol) in a mixture of anhydrous dimethylformamide (20 ml) and anhydrous tetrahydrofuran (10 ml), under a nitrogen atmosphere. The mixture was heated at 80° C. for 20 hours, then the mixture was partitioned between diethyl ether and water. The organic layer was separated and washed with more water, dried (magnesium sulfate), and evaporated under reduced pressure. The residue was flash chromatographed on silica gel using dichloromethane as eluant to give the title compound as a colourless gum (2.66 g).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][C:18]=4[O:27][CH3:28])=[N:11][C:10]=3[N:9]([CH2:29][CH3:30])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:31]1[CH2:37][CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([S:23]([N:31]5[CH2:37][CH2:36][CH2:35][NH:34][CH2:33][CH2:32]5)(=[O:25])=[O:24])=[CH:19][C:18]=4[O:27][CH3:28])=[N:11][C:10]=3[N:9]([CH2:29][CH3:30])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCn1nc(C2CCCCC2)c2c(=O)[nH]c(-c3ccc(S(=O)(=O)Cl)cc3OC)nc21
Reactant: C1CNCCNC1
Product: CCn1nc(C2CCCCC2)c2c(=O)[nH]c(-c3ccc(S(=O)(=O)N4CCCNCC4)cc3OC)nc21
Yield: 59 %

Procedure:
The same reaction procedure as in Example 49 was performed, except that the compound obtained in Example 206 was used in place of the compound obtained in Example 48, and homopiperazine was used in place of N-methylpiperazine. In this manner, 100 mg (59%) of the captioned compound was obtained.
Reaction SMILES: [F:1][C:2]1([F:16])[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:4]=2[O:3]1.[C:17]([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:16][C:2]1([F:1])[C:7](=[O:8])[N:6]([CH3:17])[C:5]2[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:4]=2[O:3]1
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2OC1(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)C(F)(F)Oc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C

Procedure:
To a stirred suspension of 2,2-difluoro-7-nitro-4H-1,4-benzoxazin-3-one (WO 99/40094,2.16 g, 9.38 mmol) in DMF (10 mL) is added K2CO3 (1.94 g, 14.07 mmol) followed by addition of Mel (0.87 mL, 14.07 mmol). The resulting solution is stirred over night at room temperature. To this reaction mixture is added water (50 mL), and the resulting solution is extracted with EtOAc (50 mL×3). The combined organic phases are washed with water (50 mL) and saline (50 mL), dried over Na2SO4 and concentrated under reduced pressure to give the title compound that is purified by passing through a short silica gel column with EtOAc (1.3 g, 57%), 1H NMR (300 MHz, DMSO) δ 8.25-8.17 (m, 2H), 7.62 (d, 1H), 3.47 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][N:4]=[C:5]([NH2:24])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[N:21][C:22]#[N:23])SC)[N:8]=1.[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31][NH2:32])[CH3:28]>CO>[F:1][C:2]([F:26])([F:25])[CH2:3][N:4]=[C:5]([NH2:24])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([NH:32][CH2:31][CH2:30][N:29]([CH2:33][CH3:34])[CH2:27][CH3:28])=[N:21][C:22]#[N:23])[N:8]=1
Reactant: CCN(CC)CCN
Reactant: CSC(=NC#N)NCCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Solvent: CO
Product: CCN(CC)CCNC(=NC#N)NCCCSc1nccc(NC(N)=NCC(F)(F)F)n1

Procedure:
A mixture of 4-[2-(2,2,2-trifluoroethyl)-guanidino]-2-[3-(3-cyano-2-methylisothioureido)propylthio]pyrimidine (0.2 g.), N,N-diethylethylenediamine (0.5 ml.) and methanol (2 ml.) was heated under reflux for 24 hours and then evaporated to dryness. Water was added to the residue, the mixture extracted with ethyl acetate and the ethyl acetate extract dried and evaporated to dryness. The residue was purified by preparative thin layer chromatography using ethyl acetate/methanol/ammonia 6:1:0.5 v/v/v as developing solvent to give 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[3-(2-cyano-3-[2-diethylaminoethyl]guanidino)propylthio]-pyrimidine (0.08 g.), characterised as the bis hydrogen maleate, m.p. 76°-80° after recrystallisation from acetone.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].CCN(CC)CC.[C:14]([C:16]1[CH:17]=[CH:18][C:19]([O:26][C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=2)=[C:20]([S:22](Cl)(=[O:24])=[O:23])[CH:21]=1)#[N:15]>C(Cl)Cl>[C:14]([C:16]1[CH:17]=[CH:18][C:19]([O:26][C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=2)=[C:20]([S:22]([NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])(=[O:23])=[O:24])[CH:21]=1)#[N:15]
Reactant: N#Cc1ccc(Oc2cc(Cl)cc(Cl)c2)c(S(=O)(=O)Cl)c1
Reactant: CN(C)CCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CCNS(=O)(=O)c1cc(C#N)ccc1Oc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
To a solution of N1,N1-dimethyl-ethane-1,2-diamine (74.0 mg, 0.84 mmol) and Et3N in dry CH2Cl2 (3 ml) was added the solution of 5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonylchloride (90%, 282 mg, 0.7 mmol) in dry CH2Cl2 (6 ml) dropwise. The resulting solution was stirred at room temperature for 1 hour. CH2Cl2 (60 ml) was added and the mixture was washed with water, brine, and dried over MgSO4. The solvent was evaporated, and the residue was purified by column chromatography (CH2Cl2/CH3OH=10:1) to give 5-cyano-2-(3,5-dichloro-phenoxy)-N-(2-dimethylamino-ethyl)-benzene-sulfonamide as white solid (220 mg, 75.9%): HPLC-MS (ESI): Calcd for C19H21Cl2N3O4S [M+H]+ 414, Found: 414
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:6]=2[N:7]=1.[CH:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:29]>O1CCOCC1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][S:12][C:8]2[C:6]3[N:7]=[C:2]([N:33]4[CH2:34][CH2:35][N:30]([CH:28]=[O:29])[CH2:31][CH2:32]4)[N:3]=[C:4]([N:21]4[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]4)[C:5]=3[N:11]=[CH:10][N:9]=2)=[CH:15][CH:16]=1
Reactant: O=S1CCN(c2nc(Cl)nc3c(SCc4ccc(F)cc4)ncnc23)CC1
Reactant: O=CN1CCNCC1
Solvent: C1COCCO1
Product: O=CN1CCN(c2nc(N3CCS(=O)CC3)c3ncnc(SCc4ccc(F)cc4)c3n2)CC1

Procedure:
This compound was prepared analogous to Example 93 from 2-chloro-8-(4-fluorobenzyl-thio)-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 192°-194° C.) and N-formyl-piperazine in dioxane.
Reaction SMILES: [H-].[Na+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[C:14]([C:21]3[NH:29][C:28]4[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=4[CH:22]=3)[CH:15]=[CH:16][CH:17]=2)[N:12]=1.CO>CN1C(=O)CCC1>[C:3]1([S:9][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[C:14]([C:21]4[NH:29][C:28]5[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=5[CH:22]=4)[CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CO
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(Sc5ccccc5)nc34)cc21
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 44.8 %

Procedure:
To NaH (60 wt % in mineral oil; 0.050 g, 1.259 mmol) in 1 mL NMP was added benzenethiol (0.129 ml, 1.259 mmol). After 10 min, a clear/colorless solution resulted. 2-(2-Chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 0.075 g, 0.252 mmol) was added as a solid and the reaction became orange. After 1 h, the reaction was sealed and heated to 70° C. for 1 h. The reaction was cooled and was partitioned between saturated aq. NaHCO3 and EtOAc. The organic layer was washed with saturated aq. NaHCO3 (3×) and saturated aq. NaCl (1×), and the organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (25 g column) using 0-50% 90/10 DCM/MeOH in DCM. The product-containing fractions were concentrated to afford a yellow solid. The material was treated with 1 mL MeOH, sonicated, and filtered, rinsing with MeOH, to give 2-(2-(phenylthio)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.042 g, 0.113 mmol, 45% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.18-11.45 (1H, m), 8.28 (1H, d, J=8.6 Hz), 8.09 (1H, dd, J=7.5, 1.5 Hz), 7.67-7.79 (3H, m), 7.48-7.61 (4H, m), 7.36 (1H, d, J=8.8 Hz), 7.05 (1H, d, J=2.3 Hz), 6.92-6.98 (1H, m), 3.33-3.42 (2H, m), 2.50-2.55 (2H, m). m/z (ESI, +ve) 371.9 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH2:15][C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])=[C:9]([CH:13]=1)[C:10](O)=[O:11])(=[O:4])=[O:3].FC(F)(F)C(O)=O.[F:30][C:31]([F:44])([F:43])[C:32]1[S:36][C:35]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[N:34][N:33]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH2:15][C:16]([F:22])([F:21])[C:17]([F:19])([F:20])[F:18])=[C:9]([C:10]([N:40]2[CH2:39][CH2:38][N:37]([C:35]3[S:36][C:32]([C:31]([F:43])([F:30])[F:44])=[N:33][N:34]=3)[CH2:42][CH2:41]2)=[O:11])[CH:13]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(OCC(F)(F)C(F)(F)F)c(C(=O)O)c1
Reactant: FC(F)(F)c1nnc(N2CCNCC2)s1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(OCC(F)(F)C(F)(F)F)c(C(=O)N2CCN(c3nnc(C(F)(F)F)s3)CC2)c1
Yield: 56 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-(2,2,3,3,3-pentafluoro-propoxy)-benzoic acid (Example A30) and 1-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-piperazine trifluoroacetate (Example 62(b)). The crude material was purified by chromatography (SiO2, methanol/dichloromethane) to yield the title compound as an off-white solid (yield 56%). MS (m/e): 569.3 (M+H+, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[B:8]([OH:10])[OH:9].[Br:11]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[B:8]([OH:10])[OH:9]
Reactant: Cc1ccccc1B(O)O
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: OB(O)c1ccccc1CBr
Temperature: 82 °C
Yield: 38.5 %

Procedure:
A suspension of 2-methylphenylboronic acid (10.65 g), N-bromosuccinimide (NBS, 16.86 g) and 2,2′-azobisisobutyronitrile (AIBN, 1.708 g) in carbon tetrachloride (1000 mL) was heated in an oil bath at 82° C. to reflux for 2 hours under anhydrous condition. Cooled the reaction mixture to room temperature and filtered off the solid. Extracted the filtrate with water (2×200 mL). The organic layer was separated, dried over MgSO4 and concentrated in vacuo to dryness. Redissolved the solid in methanol (100 mL) and added ethyl acetate (1000 mL) to it. The resultant precipitate was collected, washed with ethyl acetate (2×50 mL) and dried in the air. The filtrate was concentrated to a small volume and a second crop of solid was also collected. The combined solid was dried in an oven under high vacuum at 50° C. overnight. There was obtained 6.48 g (39%) of product.
Reaction SMILES: [OH:1][C:2]([CH3:14])([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].C1CCN2C(=NCCC2)CC1.[C:26](Cl)(=[O:28])[CH3:27].Cl>CN(C1C=CN=CC=1)C.ClCCl>[CH3:13][C:2]([O:1][C:26](=[O:28])[CH3:27])([CH3:14])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=[O:4]
Reactant: CSc1ccc(C(=O)C(C)(C)O)cc1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CSc1ccc(C(=O)C(C)(C)OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 41.1 %

Procedure:
To a 0° C. solution of 2-hydroxy-2-methyl-1-(4-(methylthio)phenyl)propan-1-one (150 g, example 1, Step 2), DBU (217 g) and DMAP (7 g) in dichloromethane (850 mL) was added acetyl chloride (112.2 g) dropwise and the mixture was stirred for 6 h. at 25° C. More DBU (32.5 g) was added and the mixture was stirred an additional 16 h. The reaction mixture was poured over 2N HCl (800 mL) and the organic layer was separated, washed with a saturated solution of NaHCO3, dried over MgSO4, filtered and the solvent was evaporated under vacuum. The residue was swished in Et2O, then 25% ethyl acetate in hexane, then filtered and dried giving 74 g of the title compound.
Reaction SMILES: [OH:1][C@@H:2]([CH3:11])[C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>ClCCl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:1][C@@H:2]([CH3:11])[C:3]([N:5]1[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)=[O:4]
Reactant: C1=COCCC1
Reactant: C[C@H](O)C(=O)N1CCOCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: C[C@H](OC1CCCCO1)C(=O)N1CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
A mixture of (S)-ethyl lactate (75 g) and morpholine (164 g) was heated at 80° C. for 64 hours. The reaction solution was concentrated and the residue was subjected to silica gel chromatography (eluent: hexane/ethyl acetate=4/1 to ethyl acetate) to give 4-[(S)-2-hydroxypropionyl]-morpholine (69.4 g) as a pale yellow oily substance. p-Toluenesulfonic acid monohydrate (0.82 g) was added to a solution of 4-[(S)-2-hydroxypropionyl]morpholine (69.4 g) in dichloromethane (300 ml), to which 3,4-dihydro-2H-pyran (40.3 g) was added dropwise at ice-bath temperature. The reaction solution was stirred at 0° C. for 30 minutes and washed with a 5% aqueous solution of sodium bicarbonate. After the organic layer was dried over anhydrous magnesium sulfate and concentrated, the residue was subjected to silica gel chromatography (eluent: hexane/ethyl acetate=8/1 to ethyl acetate) to give 4-[(2S)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine (89.1 g) as a pale yellow oily substance.
Reaction SMILES: [C:1]1([CH2:7][C:8]#N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][C:11]1([C:16]2[CH:21]=C[C:19]([N+:22]([O-])=[O:23])=[CH:18][CH:17]=2)[O:15][CH2:14][CH2:13][O:12]1.[OH-].[Na+]>CO>[CH3:10][C:11]1([C:16]2[CH:17]=[CH:18][C:19]3[C:8]([CH:21]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:23][N:22]=3)[O:12][CH2:13][CH2:14][O:15]1
Reactant: CC1(c2ccc([N+](=O)[O-])cc2)OCCO1
Reactant: N#CCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(c2ccc3noc(-c4ccccc4)c3c2)OCCO1
Reaction time: 16 h
Yield: 79.3 %

Procedure:
Phenylacetonitrile (0.84 g, 7.2 m mol) and 2-methyl-2-(4-nitrophenyl)-1,3-dioxolane (mp. 69°-71° C.) (1.50 g, 7.2 m mol) were added to a room temperature solution of sodium hydroxide (1.44 g, 36 m mol) in methanol (8 ml). A slight exotherm was noted and stirring was continued for 16 hrs. The mixture was filtered and the collected solid washed several times with water and once with cold methanol to yield a yellow powder (1.60 g) with mp. 137° C. (lit. mp. 137°-138° C., see J. Heterocyclic Chem. 11, 107 (1974)).
Reaction SMILES: C([Li])CCC.[CH3:6][CH:7]([CH3:22])[CH2:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:11]=[CH:10]1.CN([CH:26]=[O:27])C>O1CCCC1>[CH3:6][CH:7]([CH3:22])[CH2:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:11]=[C:10]1[CH:26]=[O:27]
Reactant: CC(C)Cn1cnc2cnc3ccccc3c21
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)Cn1c(C=O)nc2cnc3ccccc3c21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of n-butyllithium in hexanes (2.5 M, 45.5 mL, 1.15 equivalents) was added dropwise to a stirred, −78° C. solution of 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (prepared as described in Example 32 of U.S. Pat. No. 4,689,338, 25.64 g) in tetrahydrofuran (450 mL). The solution was stirred for 10 minutes, then DMF (20.1 mL, 2.3 equivalents) was added. The reaction mixture was allowed to warm to room temperature over 1 hour. The volatiles were removed under reduced pressure and the residue was portioned between ethyl acetate (400 mL) and brine (400 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield a brown solid that was purified by flash chromatography (silica gel, gradient elution with 0.5-1% methanol in dichloromethane) to provide 10.5 g of 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-carbaldehyde.
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[NH2:12][C@H:13]1[CH2:27][C@H:26]2[C@@H:16]([CH2:17][C:18]3[C:28]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]2=4)[NH:20][CH:19]=3)[N:15]([CH3:29])[CH2:14]1>C(Cl)(Cl)Cl.C(O)(C)C.[OH-].[Na+]>[CH2:4]([O:3][C:1]([NH:12][C@H:13]1[CH2:27][C@H:26]2[C@@H:16]([CH2:17][C:18]3[C:28]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]2=4)[NH:20][CH:19]=3)[N:15]([CH3:29])[CH2:14]1)=[O:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CN1C[C@@H](N)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: CN1C[C@@H](NC(=O)OCc2ccccc2)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10.5 ml (75 mM) carbobenzyloxychloride are added to a suspension of 18 g (74.7 mM) 8α-amino-6-methylergoline in 1000 ml chloroform, 150 ml isopropanol and 37 ml 2N (74 mM) sodium hydroxide at room temperature. The mixture is stirred for 2 hours at room temperature. After separation of the organic phase, this is dried, filtered and concentrated. The resultant crude product is filtered through silicagel with methylene chloride/methanol (99:1) giving the heading compound as a foam.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][N:16](C)P(=O)(N(C)C)N(C)C>>[C:15]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])#[N:16]
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: COC(=O)c1ccc(I)c([N+](=O)[O-])c1
Product: COC(=O)c1ccc(C#N)c([N+](=O)[O-])c1
Temperature: 100 °C
Yield: 80.4 %

Procedure:
5 g (0.016 mol) Methyl 4-iodo-3-nitrobenzoate (Compound IV-1), 1.77 g (0.02 mol) cuprous cyanide and 15 ml hexamethylphosphoric triamide were added into a reaction flask, and heated to 100° C. and reacted for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, then extracted with 100 ml ethyl acetate, and the organic layer was washed with water for three times, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness, separated by column chromatography to obtain methyl 4-cyano-3-nitrobenzoate (Compound II-8), 2.7 g (0.013 mol), yield 80.4%.
Reaction SMILES: [C:1]1([S:7]([C:10]([CH:19]2[CH2:31][C:22]3[NH:23][C:24]4[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][C:29]=4[C:21]=3[CH2:20]2)([F:18])[C:11]2[O:15][N:14]=[C:13]([CH2:16][NH2:17])[N:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[C:41](OC(=O)C)(=[O:43])[CH3:42]>C1COCC1>[C:1]1([S:7]([C:10]([CH:19]2[CH2:31][C:22]3[NH:23][C:24]4[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][C:29]=4[C:21]=3[CH2:20]2)([F:18])[C:11]2[O:15][N:14]=[C:13]([CH2:16][NH:17][C:41](=[O:43])[CH3:42])[N:12]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCc1noc(C(F)(C2Cc3[nH]c4ccc(Cl)cc4c3C2)S(=O)(=O)c2ccccc2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)NCc1noc(C(F)(C2Cc3[nH]c4ccc(Cl)cc4c3C2)S(=O)(=O)c2ccccc2)n1
Reaction time: 0.5 h
Yield: 48.5 %

Procedure:
To a stirred solution of 57 mg (0.123 mmol) of (RS,SR)-C-{5-[benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,2,4]oxadiazol-3-yl}-methylamine in 5 mL of THF, 20 μL (0.123 mmol, 1 eq) of Huenig base and 11.6 μL (0.123 mmol, 1 eq) of acetic anhydride were added at 0° C. After 30 min., the reaction mixture was quenched by addition of an aqueous solution of NaHCO3 and extracted with CH2Cl2. The combined organic phases were dried over Na2SO4, filtered and evaporated. Column chromatography on silica gel gave 30 mg (48%) of (RS,SR)-N-{5-[benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,2,4]oxadiazol-3-ylmethyl}-acetamide as a light yellow solid, MS: 503 (MH+).
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:18][CH2:19][C@:20]1([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([O:47][CH3:48])[CH:40]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:38])[C:26]2[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=2)[CH2:21]1)(=O)=O.C(#N)C>>[CH3:48][O:47][C:41]1[CH:40]=[C:39]([C@:20]2([CH2:19][CH2:18][N:10]3[CH2:11][CH2:12][CH:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)[CH2:24][CH2:23][N:22]([C:25](=[O:38])[C:26]3[CH:27]=[C:28]([O:36][CH3:37])[C:29]([O:34][CH3:35])=[C:30]([O:32][CH3:33])[CH:31]=3)[CH2:21]2)[CH:44]=[CH:43][C:42]=1[O:45][CH3:46]
Reactant: COc1ccc([C@@]2(CCOS(C)(=O)=O)CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)cc1OC
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: CC#N
Product: COc1ccc([C@]2(CCN3CCC(N4CCCCC4)CC3)CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)cc1OC

Procedure:
In 30 ml of acetonitrile (S)-3-(2-methanesulfonyloxyethyl)-3-(3,4-dimethoxyphenyl)-1-(3,4,5-trimethoxybenzoyl)pyrrolidine (3.17 g), prepared essentially as described, supra, is mixed with an equimolar amount of 4-(piperidin-1-yl)piperidine. The reaction mixture is then heated to reflux and refluxed for about ten hours. The mixture is then concentrated under vacuum and the residue is taken up in methylene chloride and washed with a 3N solution of hydrochloric acid, followed by a wash with brine. The organic fraction is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue precipitates from an acetone/diethyl ether mixture to give the desired title product.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[C:12]([C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][C:10]([C:18]([F:21])([F:20])[F:19])=[N:9]2)[N:3]=1.[CH3:22][N:23](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>[O:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[C:12]1[N:8]([C:4]2[N:3]=[C:2]([C:22]#[N:23])[CH:7]=[CH:6][CH:5]=2)[N:9]=[C:10]([C:18]([F:21])([F:20])[F:19])[CH:11]=1
Reactant: FC(F)(F)c1cc(-c2ccco2)n(-c2cccc(Cl)n2)n1
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: N#Cc1cccc(-n2nc(C(F)(F)F)cc2-c2ccco2)n1
Temperature: 95 °C
Reaction time: 8 h
Yield: 11.9 %

Procedure:
To a stirred solution of 45 (588 mg, 1.88 mmol) in DMF (12.5 mL) was added zinc cyanide (0.238 mL, 3.75 mmol) followed by Pd(PPh3)4 (217 mg, 0.187 mmol). The resulting suspension was allowed to stir at 95° C. overnight. The residue was purified via ISCO flash chromatography (5% to 35% EtOAc/Hexane; 40G column). The title product 46 (68 mg, 11.9% yield) was isolated as a colorless oil. LRMS (ESI): calc. 304.2; found 305.3 (MH)+.
Reaction SMILES: OS(O)(=O)=O.[C:6]([OH:14])(=[O:13])[CH:7]1[CH:12]=[CH:11][CH2:10][CH:9]=[CH:8]1.[CH3:15]O>O>[CH3:15][O:13][C:6]([CH:7]1[CH:12]=[CH:11][CH2:10][CH:9]=[CH:8]1)=[O:14]
Reactant: O=C(O)C1C=CCC=C1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)C1C=CCC=C1

Procedure:
Concentrated H2SO4 (1 ml) was added to a solution of 1,4-dihydrobenzoic acid (3 g, 23.97 mmol) in freshly dried methanol (10 ml). The reaction was heated to reflux in air for 1 h, cooled, poured into H2O (25 ml) and extracted with ether (3×50 ml). The combined ether layers were washed with 5% Na[HCO3] solution (50 ml) and saturated NaCl solution (50 ml) and dried over MgSO4. The ether was removed on the rotary evaporator to leave a colourless oil which was used without further purification.