Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:22]=[CH:21][C:15]([O:16][CH2:17][C:18]([OH:20])=O)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:24][C@H:25]([C:30]([NH:32][C@@H:33]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C@H:34]([OH:49])[C:35]([N:37]1[CH2:48][CH2:47][CH2:46][C@H:38]1[C:39]([NH:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:36])=[O:31])[CH2:26][C:27](=[O:29])[NH2:28].C(OC(N[C@H](C(N[C@@H](CC1C=CC=CC=1)[C@H](O)C(N1CCC[C@H]1C(NC(C)(C)C)=O)=O)=O)CC(=O)N)=O)(C)(C)C.Cl>O1CCOCC1>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]([NH:24][C@H:25]([C:30]([NH:32][C@@H:33]([CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C@H:34]([OH:49])[C:35]([N:37]2[CH2:48][CH2:47][CH2:46][C@H:38]2[C:39]([NH:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:36])=[O:31])[CH2:26][C:27](=[O:29])[NH2:28])=[O:20])=[CH:21][CH:22]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)COc1ccc(NC(=O)OCc2ccccc2)cc1
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Agent: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)COc1ccc(NC(=O)OCc2ccccc2)cc1
Yield: 73.4 %

Procedure:
Following a procedure similar to that described in Example 14, but using 99.8 mg (0.33 mmol) of 4-(benzyloxycarbonylamino)phenoxyacetic acid (prepared as described in Preparation 15) and 150 mg (0.30 mmol) of 1-[(2S,3S)-3-(L-asparaginylamino)-2-hydroxy-4-phenylbutyryl]-N-t-butyl-L-prolinamide hydrochloride {prepared by treating 1-[(2S,3S)-3-(N2 -t-butoxycarbonyl-L-asparaginyl)amino-2-hydroxy-4-phenylbutyryl]-N-t-butyl-L-prolinamide, the compound prepared as described in Example 15, with a 4N solution of hydrogen chloride in dioxane), 164 mg of the title compound were obtained as a white powder, melting at 103°-105° C.
Reaction SMILES: Br[CH2:2][CH2:3][S:4]([O-:7])(=[O:6])=[O:5].[Na+].[NH2:9][C:10]([NH2:12])=[S:11]>>[CH2:3]([S:4]([O-:7])(=[O:6])=[O:5])[CH3:2].[NH2+:9]=[C:10]([NH2:12])[SH:11]
Reactant: O=S(=O)([O-])CCBr
Reactant: NC(N)=S
Agent: [Na+]
Product: CCS(=O)(=O)[O-]
Product: NC(=[NH2+])S

Procedure:
Sodium 2-bromoethane sulfonate is allowed to react under carefully controlled conditions with thiourea to yield 2-S thiouronium-ethan sulfonate. This compound is then recrystallized from an aqueous solution as a hard-white-crystalline solid.
Reaction SMILES: C(C1CC(C)(C)CCC1(O[SiH3])[C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15](=[O:23])[NH:16][C:17]2=[O:22])(C)(C)C.C([SiH]([CH2:31][CH3:32])CC)C.[CH3:33][CH:34]([CH3:46])[CH2:35][CH:36]=[C:37]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH:38]=[O:39].[Bi](Br)(Br)Br>C(#N)C>[CH3:33][CH:34]([CH3:46])[CH2:35][CH:36]=[C:37]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:38][O:39][C@H:32]1[CH2:31][CH2:15][C@H:14]([N:16]2[C:15](=[O:23])[C:14]3[C:18](=[CH:19][CH:20]=[CH:21][CH:13]=3)[C:17]2=[O:22])[CH2:13][CH2:21]1
Reactant: CC[SiH](CC)CC
Reactant: CC1(C)CCC(O[SiH3])(c2cccc3c2C(=O)NC3=O)C(C(C)(C)C)C1
Reactant: CC(C)CC=C(C=O)c1ccccc1
Agent: Br[Bi](Br)Br
Solvent: CC#N
Product: CC(C)CC=C(CO[C@H]1CC[C@H](N2C(=O)c3ccccc3C2=O)CC1)c1ccccc1
Reaction time: 1.3 h

Procedure:
To a stirred mixture of 1 g of trans-2-(4-(tert-butyl-dimethyl-silyloxy-cyclohexyl)-isoindole-1,3-dione, 20 mL of anhydrous acetonitrile, 0.8 mL of triethylsilane and 0.6 g of 5-methyl-2-phenyl-2-hexenal (commercial, predominantly trans was added ) 0.08 g of bismuth tribromide. After stirring for 1.3 h, the reaction was quenched with 10 mL of saturated sodium bicarbonate and extracted with 3×25 mL portions of ethyl acetate. The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. Chromatography over silica gel eluting with a gradient of 1%-20% ethyl acetate in hexane gave first 0.30 g of saturated product, trans-2-[4-(5-methyl-2-phenyl-hexyloxy)-cyclohexyl]-isoindole-1,3-dione, then 0.50 g of product as a resin: 1H NMR (400 MHz, CDCl3) 7.8 (m, 2H), 7.7 (m, 2H), 7.3-7.1 (m, 5H), 5.8 (t, 1H), 4.25 (s, 2H), 4.15 (m, 2H), 3.4 (m, 1H), 2.3 (m, 2H), 2.1 (d, 2H), 1.9 (t, 2H), 1.75 (d, 2H), 1.65 (, 1H), 1.35 (m, 2H), 1.3 (t, 2H), 0.9 (d, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[NH:16][CH2:15][CH2:14]2.Br[C:23]1[S:27][C:26]([S:28]([NH:31][CH2:32][CH3:33])(=[O:30])=[O:29])=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>CCCCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:23]2[S:27][C:26]([S:28]([NH:31][CH2:32][CH3:33])(=[O:30])=[O:29])=[CH:25][CH:24]=2)=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[NH:16][CH2:15][CH2:14]2
Reactant: Nc1ncc(B(O)O)cc1-c1ccc2c(c1)CCNC2=O
Reactant: CCNS(=O)(=O)c1ccc(Br)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: CCNS(=O)(=O)c1ccc(-c2cnc(N)c(-c3ccc4c(c3)CCNC4=O)c2)s1
Temperature: 140 °C

Procedure:
A mixture of (6-amino-5-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)boronic acid (291 mg, 1.02 mmol), 5-bromo-N-ethylthiophene-2-sulfonamide (278 mg, 1.02 mmol), and PdCl2(PPh3)2 (35 mg, 0.05 mmol) in n-BuOH (3 mL) was treated with 2.0 M aq. Na2CO3 solution (1 mL) then microwave heated at 140° C. for 6 min. The reaction was then filtered, and purified by HPLC to provide 5-(6-amino-5-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)-N-ethylthiophene-2-sulfonamide as a white solid after preparatory HPLC purification. 1H NMR (300 MHz, MeOH) δ ppm 8.31 (d, J=2.3 Hz, 1H), 8.07 (d, J=8.0 Hz, 1 H), 7.72 (d, J=2.3 Hz, 1H), 7.54 (dd, J=3.8, 2.1 Hz, 1H), 7.52 (d, J=1.7 Hz, 1H), 7.48 (s, 1 H), 7.34 (d, J=3.8 Hz, 1H), 3.57 (dd, J=13.4, 6.5 Hz, 1H), 2.93-3.15 (m, 2H), 1.85-2.03 (m, 3H), 1.13 (dd, J=14.5, 7.2 Hz, 3H); MS (EI) m/z: 429 [M+H]+.
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]([NH2:7])=[NH:6])[CH3:3].[C:8]([C:10]([CH2:19][CH:20]=[C:21]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[CH3:22])=[C:11](OCCCCC)[CH3:12])#[N:9].[C:30]([C:32]([CH2:41][CH2:42][C:43]([C:45]1[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=1)=[CH2:44])=[C:33](OCCCCC)[CH3:34])#[N:31].C[O-].[Na+]>C(O)C.CN(C)C(=O)C>[CH2:2]([NH:4][C:5]1[N:7]=[C:8]([NH2:9])[C:10]([CH:19]=[CH:20][CH:21]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH3:22])=[C:11]([CH3:12])[N:6]=1)[CH3:3].[CH2:2]([NH:4][C:5]1[N:7]=[C:30]([NH2:31])[C:32]([CH2:41][CH:42]=[C:43]([C:45]2[CH:46]=[CH:47][C:48]([Cl:51])=[CH:49][CH:50]=2)[CH3:44])=[C:33]([CH3:34])[N:6]=1)[CH3:3]
Reactant: C=C(CCC(C#N)=C(C)OCCCCC)c1ccc(Cl)cc1
Reactant: CCCCCOC(C)=C(C#N)CC=C(C)c1ccc(Cl)cc1
Reactant: CCNC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)N(C)C
Product: CCNc1nc(C)c(C=CC(C)c2ccc(Cl)cc2)c(N)n1
Product: CCNc1nc(C)c(CC=C(C)c2ccc(Cl)cc2)c(N)n1

Procedure:
These compounds are prepared in a manner analogous to that of Step E Of Example 1, using 4.8 grams (0.039 mole) of 1-ethylguanidine hydrochloride, 3.6 grams (0.011 mole) of a mixture of 3-cyano-2-pentoxy-6-(4-chlorophenyl)-2,5-heptadiene and 3-cyano-2-pentoxy-6-(4-chlorophenyl)-2,6-heptadiene (prepared in Steps A-D of Example 1), 2.3 grams (0.039 mole) of sodium methoxide, 20 mL Of N,N-dimethylacetamide, and 40 mL of ethanol. The crude reaction product is subjected to column chromatography, yielding the separated isomers, 2-ethylamino-4-amino-6-methyl-5-[3-(4-chlorophenyl)-1-butenyl]pyrimidine (Compound 47) and 2-ethylamino-4-amino-6-methyl-5-[3-(4-chlorophenyl)-2-butenyl]pyrimidine.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH3:34][O:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[NH:2]=[C:1]([N:41]1[CH2:42][CH2:43][N:38]([CH2:37][CH2:36][O:35][CH3:34])[CH2:39][CH2:40]1)[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COCCN1CCNCC1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Product: COCCN1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NCc4ccc(S(N)(=O)=O)cc4)cc3)c2)CC1
Yield: 41.5 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 2.2 equivalent of 1-(2-methoxyethyl)piperazine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [CH2:1]([N:8]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([C:23](F)(F)F)=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:27]S(O)(=O)=O.[OH2:32]>>[CH2:1]([N:8]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([C:23]([OH:27])=[O:32])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: O=S(=O)(O)O
Reactant: FC(F)(F)c1cccc2c(-c3ccccc3)n(Cc3ccccc3)nc12
Product: O=C(O)c1cccc2c(-c3ccccc3)n(Cc3ccccc3)nc12

Procedure:
2-Benzyl-3-phenyl-7-trifluoromethyl-2H-indazole (353 mg, 1 mmol), prepared similarly to that of Example 1, was treated with 3 ml of 70% aq H2SO4 at 90° C. for 4 hours. After cooling, 10 volumes of water were added and the product was extracted with dichloromethane. Flash column chromatography (SiO2, dichloromethane as an eluant) afforded 2-benzyl-3-phenyl-2H-indazole-7-carboxylic acid in 60% yleld. The 2-benzyl-3-phenyl-2H-indazole-7-carboxylic acid (1.64 g, 5 mmol) was dissolved in 20 ml of pyridine followed by addition of 1-(-3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.34 g, 7 mmol) and N,O-dimethyhydroxylamine hydrochloride (585 mg, 6 mmol). The reaction mixture was stirred at room temperature overnight. Pyridine was evaporated and the residue was shaken with 0.5M aq HCl and dichloromethane. The product was extracted with dichloromethane, and flash column chromatography (SiO2, dichloromethane as an eluant) afforded 2-benzyl-3-phenyl-2H-indazole-7-carboxylic acid methoxy-methyl-amide in 79% yleld.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:6]([O:5][CH3:1])=[O:7])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(OS(=O)(=O)C(F)(F)F)ccc2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2
Temperature: 70 °C
Reaction time: 8 h

Procedure:
In methanol (50 ml), 2-tert-butoxycarbonyl-6-trifluoromethanesulfonyloxy-1,2,3,4-tetrahydroisoquinoline (1.34 g) was dissolved, followed by the addition of triethylamine (0.73 ml), palladium (II) acetate (40 mg) and 1,3-(diphenylphosphino)propane (145 mg). Under a carbon monoxide gas stream, the resulting mixture was stirred overnight at 70° C. The reaction mixture was concentrated under reduce pressure and the residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=15:1), whereby the title compound (665 mg, 65%) was obtained.
Reaction SMILES: [Br:1][C:2]1([C:9](Cl)=[O:10])[CH:6]([Br:7])[C:5]([Br:8])=[CH:4][S:3]1.[NH2:12][C@H:13]([C:15]([OH:17])=[O:16])[CH3:14].[OH-].[Na+]>O1CCOCC1.O>[Br:1][C:2]1([C:9]([NH:12][C@H:13]([C:15]([OH:17])=[O:16])[CH3:14])=[O:10])[S:3][CH:4]=[C:5]([Br:8])[CH:6]1[Br:7]
Reactant: O=C(Cl)C1(Br)SC=C(Br)C1Br
Reactant: C[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](NC(=O)C1(Br)SC=C(Br)C1Br)C(=O)O
Yield: 60.4 %

Procedure:
15.3 g 2,3,4-tribromothiophene carboxylic acid chloride in 60 ml dioxane are reacted in a manner analogous to Example 89 with 34.56 g L-alanine and 3.20 g NaOH in 60 ml H2O. After workup, 10.5 g (60.1% of theory) N-(2',3',4'-tribromothenoyl)-L-alanine with a melting point of 175°-179° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:14]1[C:22]2[C:17](=[C:18]([CH2:23][S:24][CH3:25])[CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[CH2:10][CH2:11][C:12]#[N:13].ClCCl.ClC1C=CC=C(C(OO)=[O:37])C=1>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:14]1[C:22]2[C:17](=[C:18]([CH2:23][S:24]([CH3:25])=[O:37])[CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[CH2:10][CH2:11][C:12]#[N:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cccc2c(C(CCC#N)c3ccc(Cl)cc3Cl)c[nH]c12
Solvent: ClCCl
Solvent: CO
Product: CS(=O)Cc1cccc2c(C(CCC#N)c3ccc(Cl)cc3Cl)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
200 mg (0.51 mmol) of the compound from Example 41 were introduced into 30 ml of dichloromethane at 0° C., 127 mg (0.51 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT overnight. 2 ml of methanol were added, and the residue after concentration was taken up in dichloromethane, washed twice with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 99 mg (48% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:34])[C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH2:20][C:19]([C:25]4[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=4)([C:21]([F:24])([F:23])[F:22])[O:18][N:17]=3)=[CH:12][C:11]=2[CH3:33])=[N:6][CH:7]=1.[H-].[Na+].[H][H].Cl[C:40]([O:42][CH3:43])=[O:41]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:9](=[O:34])[C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH2:20][C:19]([C:25]4[CH:26]=[C:27]([Cl:32])[CH:28]=[C:29]([Cl:31])[CH:30]=4)([C:21]([F:23])([F:24])[F:22])[O:18][N:17]=3)=[CH:12][C:11]=2[CH3:33])[C:40](=[O:41])[O:42][CH3:43])=[N:6][CH:7]=1
Reactant: [H][H]
Reactant: COC(=O)Cl
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Nc1ccc(Cl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)N(C(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C)c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.1 %

Procedure:
In a solution of 0.30 g of N-(5-chloro-2-pyridyl)-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl benzoic acid amide in 3 mL of tetrahydrofuran, 0.037 g of 60% oily sodium hydride was added and stirred at room temperature for 10 minutes. After ceasing the generation of hydrogen gas, 0.080 g of methyl chloroformate was added under cooling with ice and with stirring, and continued to stir at the same temperature further for 10 minutes. After the completion of the reaction, the reaction mixture was poured in 10 mL of ice water, extracted with ethyl acetate (10 mL×1), the organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (2:3) to obtain 0.29 g of the aimed product as yellow resinous substance.
Reaction SMILES: [NH2:1][C:2]1[S:17][C:5]2[CH2:6][N:7]([C:10]([O:12][CH2:13][CH2:14][C:15]#[CH:16])=[O:11])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:18](=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25].N1C=CC=CC=1.[Br:33][CH:34]([CH3:38])[C:35](Br)=[O:36].O>O1CCOCC1>[Br:33][CH:34]([CH3:38])[C:35]([NH:1][C:2]1[S:17][C:5]2[CH2:6][N:7]([C:10]([O:12][CH2:13][CH2:14][C:15]#[CH:16])=[O:11])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:18](=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])=[O:36]
Reactant: C#CCCOC(=O)N1CCc2c(sc(N)c2C(=O)c2ccccc2Cl)C1
Reactant: CC(Br)C(=O)Br
Solvent: O
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: C#CCCOC(=O)N1CCc2c(sc(NC(=O)C(C)Br)c2C(=O)c2ccccc2Cl)C1
Yield: 65.4 %

Procedure:
1.35 g of 2-amino-3-(2-chlorobenzoyl)-6-(3-butynyloxycarbonyl)-4,5,6,7-tetrahydro-thieno[2,3-C]pyridine was dissolved in 20 ml of dioxane, to which 0.33 g of pyridine was added, followed by dropping at 0° C. 0.90 g of 2-bromopropionyl bromide. After completion of the reaction, the reaction mixture was charged into water, extracted with dichloromethane and dried with anhydrous magnesium sulfate, after which the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography (elution solvent: dichloromethane:hexane=1:1-1:0), thereby obtaining 1.19 g of the intended compound.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[CH:7]=[C:8]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)[CH:9]=[CH:10][C:11]=1[CH3:12]>C(Cl)(Cl)Cl>[CH3:5][C:6]1[CH:7]=[C:8]([CH2:13][CH2:14][CH2:15][C:16]([Cl:3])=[O:18])[CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: Cc1ccc(CCCC(=O)O)cc1C
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(CCCC(=O)Cl)cc1C

Procedure:
2.5 mL of thionyl chloride was added at room temperature to a 60 mL chloroform solution of 3.3 g of compound 1-1 obtained in Reference Example 1, and the system was refluxed under heating, for 10 hours. After the reaction, reduced-pressure solvent distillation was performed to obtain 4-(3,4-dimethylphenyl)butanoyl chloride.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:4]=1[N+:10]([O-])=O)[CH3:2].O.O.[Sn](Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C(OCC)(=O)C>[Br:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[C:4]([CH:5]=1)[NH2:10]
Reactant: CCc1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CCc1ccc(Br)cc1N
Temperature: 70 °C
Yield: 17.1 %

Procedure:
To a solution of 2-ethyl-5-bromo nitrobenzene (9.71 g, 230 mmol) in ethanol (125 ml) is added tin(II) chloride dihydrate (35.72 g, 225.71 mmol), followed by heating at 70° C. for 2 hours. After cooling to room temperature the solution is poured into crushed ice (1 liter) then diluted with ethyl acetate (200 ml). Solid sodium carbonate is cautiously added until pH 7 is achieved, at which stage the viscous mixture is filtered through diatomaceous earth (further washing with ethyl acetate/aqueous sodium carbonate) and the phases separated. After additional extraction of the aqueous phase, all organic phases are combined, dried over anhydrous magnesium sulfate then concentrated in vacuo. The crude oil is purified by flash column chromatography on silica gel (hexane/ethyl acetate 8:2 ratio) to afford 5-bromo-2-ethylaniline (7.89 g) as a brown oil.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].[OH-].[Na+]>O1CCCC1.O>[CH2:25]([O:24][C:22]([NH:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1)[C:3]([O:5][CH3:6])=[O:4])=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)C(N)c1cccc(OCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(NC(=O)OCc1ccccc1)c1cccc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55.5 %

Procedure:
To a solution of methyl 2-amino-2-(3-(benzyloxy)phenyl)acetate (1.09 g, 4 mmol) in a mixture of tetrahydrofuran and water (1:1, 90 mL) at 0° C. was added benzyl chloroformate (0.57 mL, 4 mmol) and aqueous sodium hydroxide (4 N, 1 mL, 4 mmol) simultaneously. The mixture was stirred at 0° C. for one hour. The ice bath was removed and the reaction mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo and ethyl acetate (100 mL) and water (30 mL) were added. The layers were separated and the aqueous phase re-extracted with ethyl acetate (2×50 mL). The combined organic fractions were dried over magnesium sulfate, filtered and the solvent removed in vacuo. The residue was purified by silica gel column chromatography, eluting with 0-40% ethyl acetate in iso-hexane to afford the title compound (900 mg, 56%) as a brown oil.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C@@H:11]2[CH2:25][C@H:24]3[C@@H:14]([CH2:15][C:16]4[C:26]5[C:19](=[CH:20][CH:21]=[CH:22][C:23]3=5)[N:18]([CH:27]([CH3:29])[CH3:28])[CH:17]=4)[N:13]([CH3:30])[CH2:12]2)=[O:10])[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39]>O1CCCC1>[C:38]([NH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]([C@@H:11]2[CH2:25][C@H:24]3[C@@H:14]([CH2:15][C:16]4[C:26]5[C:19](=[CH:20][CH:21]=[CH:22][C:23]3=5)[N:18]([CH:27]([CH3:28])[CH3:29])[CH:17]=4)[N:13]([CH3:30])[CH2:12]2)=[O:10])[CH2:6][CH2:7]1)(=[O:40])[CH3:39]
Reactant: CC(C)n1cc2c3c(cccc31)[C@H]1C[C@@H](C(=O)N[C@H]3CC[C@H](N)CC3)CN(C)[C@@H]1C2
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)[C@@H]2C[C@@H]3c4cccc5c4c(cn5C(C)C)C[C@H]3N(C)C2)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 620 mg of (8β)-N-(trans-4-aminocyclohexyl)-1-isopropyl-6-methylergoline-8-carboxamide in 100 ml of dry tetrahydrofuran were added 222 μl of triethylamine. The solution was cooled by means of an external ice bath and 118 μl of acetyl chloride were added in dropwise fashion. The mixture was stirred at room temperature under a nitrogen atmosphere for 2.5 hours. The reaction mixture was concentrated in vacuo and ethyl acetate, water, and 2N sodium hydroxide were added. The layers were separated and the aqueous layer extracted an additional three times with ethyl acetate and six times with methylene chloride. The combined organic layers were washed twice with water, once with a saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to provide 690 mg of a pale yellow solid. This material was crystallized from tetrahydrofuran/ethanol/hexanes to provide 259 mg of title product as a tan powder, m.p. >280° C. Analytical high pressure liquid chromatography indicated the material was 97.9% pure. NMR, MS
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[C:12]1[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][N:13]=1.O>CN(C=O)C>[I:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:12]2[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][N:13]=2)=[CH:6][CH:5]=1
Reactant: COc1ccnc(Cl)n1
Reactant: Oc1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccnc(Oc2ccc(I)cc2)n1
Temperature: 125 °C
Reaction time: 9 h
Yield: 95.1 %

Procedure:
Under an argon atmosphere, sodium hydride (108 mg) was added to a solution of 4-iodophenol (220 mg) and 2-chloro-4-methoxypyrimidine (168 mg) in anhydrous DMF (10 ml), and the resulting mixture was stirred at 125° C. for 9 hours. The reaction solution was cooled to room temperature and water was added thereto, followed by extracting the resulting mixture with ethyl acetate. Organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: hexane/ethyl acetate=5/1) to obtain 2-(4-iodophenoxy)-4-methoxypyrimidine (312 mg).