Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[N:3]=1
Reactant: COc1cccnc1Br
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COc1ccc([N+](=O)[O-])nc1Br
Temperature: 60 °C

Procedure:
To a 500 mL round bottomed flask fitted with a Teflon stir bar and a thermometer was added 90 mL of concentrated sulphuric acid and 37.6 g of 2-bromo-3-methoxypyridine (200 mmol). The flask was warmed in an oil bath to 60° C. Added slowly over 1h 16.5 mL (350 mmol) of fuming nitric acid (90%, d=1.50). Maintain the temperature between 60 and 70° during the addition. Stir at 60° for 3h after the addition was complete, then at room temperature overnight. By TLC (70/30 hex/EtOAc) is consumed. The product mixture was poured into 600 mL of ice/water, from which the product precipitated. This material was filtered, washed with 3×200 mL of cold water and then 100 mL of saturated sodium bicarbonate. After drying in the filter funnel in a stream of air, the remaining water was removed under reduced pressure, to give 16.5 g of a solid. H NMR (400 MHz, CDCl3): δ 8.27(d, J=8 Hz,1H); 6.32(d, J=8 Hz,1H); 4.06(s, 3H).
Reaction SMILES: NC1C=C([N+]([O-])=O)C=CC=1C.OS(O)(=O)=O.C=O.[OH-].[Na+].[CH3:21][NH:22][C:23]1[CH:28]=[C:27]([N+:29]([O-])=O)[CH:26]=[CH:25][C:24]=1[CH3:32]>O.[Pd]>[CH3:21][NH:22][C:23]1[CH:28]=[C:27]([NH2:29])[CH:26]=[CH:25][C:24]=1[CH3:32]
Reactant: CNc1cc([N+](=O)[O-])ccc1C
Agent: [Pd]
Agent: C=O
Agent: Cc1ccc([N+](=O)[O-])cc1N
Solvent: O
Product: CNc1cc(N)ccc1C
Reaction time: 0.5 h

Procedure:
15.4 g. (0.1M) of 2-amino-4-nitrotoluene was dissolved in 100 ml. 96% H2SO4 at room temperature with stirring and 50 ml. of a 36% solution of formaldehyde in H2O was added. The mixture was stirred for 30 minutes and poured on ice, neutralized with NaOH, filtered and washed. There was obtained 16.1 g. of 2-methylamino-4-nitrotoluene; m.p. 107°-108° (Gnehm/Blume. Ann. 304, 100, gives 107.5° C). 8.3 g. of the above compound was reduced catalytically with Pd as catalyst and the free amine produced was reacted with HCl to form 10 g. of the dihydrochloride (the free amine is liquid). ##STR9##
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([O:10][C@H:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19](Cl)[C:14]=3[C@H:13]([CH3:21])[CH2:12]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:24]([N:31]1[CH2:36][CH2:35][C:34]2([C:44]3[C:39](=[CH:40][CH:41]=[C:42]([Cl:54])[C:43]=3[CH2:45][NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])[NH:38][CH2:37]2)[CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([O:10][C@H:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([N:38]4[C:39]5[C:44](=[C:43]([CH2:45][NH:46][C:47]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:53])[C:42]([Cl:54])=[CH:41][CH:40]=5)[C:34]5([CH2:35][CH2:36][N:31]([CH2:24][C:25]6[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=6)[CH2:32][CH2:33]5)[CH2:37]4)[C:14]=3[C@H:13]([CH3:21])[CH2:12]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)NCc1c(Cl)ccc2c1C1(CCN(Cc3ccccc3)CC1)CN2
Reactant: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(Cl)c21
Product: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(N3CC4(CCN(Cc5ccccc5)CC4)c4c3ccc(Cl)c4CNC(=O)OC(C)(C)C)c21

Procedure:
(5R,7R)-4-(1′-benzyl-4-((tert-butoxycarbonylamino)methyl)-5-chlorospiro[indoline-3,4′-piperidine]-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate was prepared by the procedures described in Example 1, Step 8, substituting (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine with (5R,7R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate, and substituting tert-butyl 5-chlorospiro[indoline-3,4′-piperidine]-1′-carboxylate with tert-butyl (1′-benzyl-5-chlorospiro[indoline-3,4′-piperidine]-4-yl)methylcarbamate. LCMS (APCI+) m/z 739, 741 [M+H]+; Rt=4.53 min.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[C@@H:5]([NH2:14])[CH2:6][C:7]([F:13])([F:12])[CH2:8][CH:9]([CH3:11])[CH3:10].C(NC(C)C)(C)C.[N:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>ClCCl>[CH3:2][O:3][C:4](=[O:15])[C@@H:5]([NH:14][C:29]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:30])[CH2:6][C:7]([F:13])([F:12])[CH2:8][CH:9]([CH3:10])[CH3:11]
Reactant: O=C(Cl)N1CCOCC1
Reactant: COC(=O)[C@@H](N)CC(F)(F)CC(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: COC(=O)[C@H](CC(F)(F)CC(C)C)NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 65.9 %

Procedure:
To a mixture of (S)-2-amino-4,4-difluoro-6-methyl-heptanoic acid methyl ester hydrochloride (238 mg, 0.97 mmol) and diisopropyl amine (2.42 mmol, 313 mg) in dry dichloromethane (5 mL) under N2 is added drop wise morpholine carbonyl chloride (1.45 mmol, 218 mg). The mixture is stirred at room temperature for 23 h, then diluted with dichloromethane (25 mL) and washed with dilute HCl (30 mL), and saturated NaHCO3 (30 mL). The organic layers are dried over magnesium sulfate and concentrated in vacuum. Purification over 12 g silica gel, eluting with EtOAc:Heptane (1:1, then 2:1) affords (S)-4,4-Difluoro-6-methyl-2-[(morpholine-4-carbonyl)-amino]-heptanoic acid methyl ester (206 mg, 66%).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@@H:10]([OH:25])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:33]([Si:37]([CH3:40])([CH3:39])Cl)([CH3:36])([CH3:35])[CH3:34].N1C=CN=C1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C1COCC1.CO>[C:1]([NH:8][C@@H:9]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C@@H:10]([O:25][Si:37]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:40])[CH3:39])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1cccc(C[C@H](C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(C[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)c1

Procedure:
In analogy with Example 44e), 1.3 g of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(3-methoxyphenyl)methyl]hexanoic acid in 13 ml of DMF are silylated with 1.987 g of tert-butyldimethylchlorosilane and 1.646 g of imidazole. The silyl ester group in the crude product is detached at RT in 2 h in a mixture consisting of 38.94 ml of methanol, 13.34 ml of THF, 13.34 ml of water and 2.35 g of potassium carbonate. Chromatography on silica gel (eluents: E, D and C) yields the pure title compound. TLC Rf (D)=0.06. FAB-MS (M+H)+ =558.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([C:8]2[CH:25]=[CH:24][C:11]([CH2:12][N:13]3[C:17]4[C:18]([Cl:23])=[N:19][NH:20][C:21](=[O:22])[C:16]=4[CH:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:28](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:25]=[CH:24][C:11]([CH2:12][N:13]3[C:17]4[C:18]([Cl:23])=[N:19][N:20]([CH3:28])[C:21](=[O:22])[C:16]=4[CH:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:26][CH:27]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cn2ccc3c(=O)[nH]nc(Cl)c32)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: Cn1nc(Cl)c2c(ccn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.6 %

Procedure:
In DMF (15 ml) was dissolved 1-[4-(4-chlorobenzoyl)benzyl]-7-chloropyrrolo [2,3-d]pyridazin-4(5H)-one (352 mg) followed by addition of potassium carbonate (858 mg). Then, methyl iodide (0.06 ml) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (30 ml) and extracted with ethyl acetate (200 ml). The organic layer was washed with water (100 ml) 3 times and saturated aqueous NaCl solution once and dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration, the solvent was distilled off under reduced pressure and the resulting crystals were rinsed with hexane to provide 290 mg (yield 80%) of the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]#[CH:12])[CH:6]=[CH:7][CH:8]=1.[F:13][C:14]([F:27])([F:26])[C:15]1[CH:16]=[C:17](I)[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1.C1C=CC=CC=1>CN(C)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]Cl>[CH3:1][NH:2][C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]#[C:12][C:17]2[CH:18]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:20]=[C:15]([C:14]([F:13])([F:27])[F:26])[CH:16]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: C#CC#Cc1cccc(NC)c1
Reactant: FC(F)(F)c1cc(I)cc(C(F)(F)F)c1
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Agent: CN(C)C
Solvent: c1ccccc1
Product: CNc1cccc(C#CC#Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 13 h
Yield: 76.7 %

Procedure:
320 mg of the thus-obtained 1-[3-(N-methylamino)phenyl]-1,3-butadiyne and 700 mg of 3,5-bis(trifluoromethyl) iodobenzene were dissolved in 30 ml of trimethylamine in an atmosphere of argon, and 14 mg of bis(triphenylphosphine)palladium (II) chloride and 4 mg of copper (I) chloride were then rapidly added to the reaction mixture. After the solution had been stirred at room temperature for 13 hours, 50 ml of benzene were added thereto, and the solvent was then evaporated. The residue was neutralized by 1N hydrochloric acid and subjected to extraction with 50 ml of benzene three times. The organic layer was then dried over magnesium sulfate, and the solvent was evaporated. The residue was then purified by silica-gel chromatography using a mixture of hexane and benzene as an eluent to obtain 580 mg of 1-[3-(N-methylamino)phenyl]-4-[3,5-bis(trifluoromethyl)phenyl]-1,3-butadiyne. This compound was a yellowish green crystal having a melting point of from 75° to 76° C.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.C([Mg]Br)C.CON(C)[C:15]([C:17]1[CH:21]=[CH:20][S:19][CH:18]=1)=[O:16].Cl>ClCCl.O>[CH3:7][N:6]1[C:2]([C:15]([C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)=[O:16])=[CH:3][N:4]=[CH:5]1
Reactant: CON(C)C(=O)c1ccsc1
Reactant: Cn1cncc1Br
Agent: CC[Mg]Br
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: Cn1cncc1C(=O)c1ccsc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
To a solution of 5-Bromo-1-methyl-imidazole (18.8 g, 117 mmol) in dichloromethane (50 mL) was added dropwise ethylmagnesium bromide (3 M in Et2O, 38.9 mL, 117 mmol). After stirring at room temperature for 30 min, the reaction mixture was cooled down to 0° C. with an ice-brine bath and N-methoxy-N-methylthiophene-3-carboxamide (20.0 g, 117 mmol) was added dropwise. The mixture was stirred for 3.5 h at room temperature. The mixture was worked-up by addition of water (400 mL), then acidified with aq. HCl (1 M) until pH=7. After extraction with dichloromethane (3×100 mL), the organic layers were washed with water (100 mL) then dried over MgSO4 and concentrated in vacuo. Purification of the residue on silica gel afforded (1-methyl-1H-imidazol-5-yl)(3-thienyl)methanone [11.6 g, yield 41%; HPLC/MS: m/z=193 (M+H); log P(HCOOH)=0.43].
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]([CH3:12])([CH3:11])[C:8]([CH3:10])=[CH:9][C:4]=2[CH:3]=1.CC(C)([O-])C.[Na+].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[SH:29]>C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29][C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]([CH3:12])([CH3:11])[C:8]([CH3:10])=[CH:9][C:4]=2[CH:3]=1
Reactant: CC1=Cc2cc(Br)ccc2OC1(C)C
Reactant: COc1ccccc1S
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccccc1Sc1ccc2c(c1)C=C(C)C(C)(C)O2
Yield: 68.8 %

Procedure:
6-Bromo-2,2,3-trimethyl-2H-benzo[b]pyran (9.6 g) (see Preparation 4) was dissolved in absolute ethanol (200 ml), then sodium tert-butoxide (11.0 g), 2-methoxybenzenethiol (5.3 g) and tetrakis(triphenylphosphine)palladium(O) (0.45 g) were added and the mixture heated under reflux under a nitrogen atmosphere for 24 hours. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane and washed with water. The organic layer was dried (anhydrous sodium sulphate), the solvent was removed under reduced pressure and the crude product was chromatographed first on silica using 1:1 hexane: dichloromethane as the eluent and then on silica using 24:1 hexane: ethyl acetate as the eluent to yield 6-(2-methoxyphenyl)thio-2,2,3-trimethyl-2H-benzo[b]pyran (8.12 g) as an oil.
Reaction SMILES: [C:1]([O:4][C:5]1([C:8]([OH:10])=O)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.Cl.[NH2:23][C:24]1[N:25]=[C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:34]=[CH:35][C:36]([CH3:49])=[C:37]([NH:39][C:40]([C:42]4[N:46]([CH3:47])[N:45]=[C:44]([CH3:48])[CH:43]=4)=[O:41])[CH:38]=3)=[N:28][N:27]2[CH:50]=1>CN(C)C=O.CN(C)C(=O)C>[C:1]([O:4][C:5]1([C:8]([NH:23][C:24]2[N:25]=[C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]4[CH:34]=[CH:35][C:36]([CH3:49])=[C:37]([NH:39][C:40]([C:42]5[N:46]([CH3:47])[N:45]=[C:44]([CH3:48])[CH:43]=5)=[O:41])[CH:38]=4)=[N:28][N:27]3[CH:50]=2)=[O:10])[CH2:6][CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1(C(=O)O)CC1
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2C)n(C)n1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)OC1(C(=O)Nc2cn3nc(Oc4ccc(C)c(NC(=O)c5cc(C)nn5C)c4)ccc3n2)CC1
Yield: 74.5 %

Procedure:
In the same manner as in Example 279 and using 1-acetoxycyclopropanecarboxylic acid (90 mg, 0.63 mmol), tetrahydrofuran (1.5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (54 μL, 0.63 mmol), N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide hydrochloride (200 mg, 0.48 mmol) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (180 mg, 74%) was obtained as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[C:22]([S:27]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH3:26]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:21]=[C:22]([S:27]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)(=[O:28])=[O:29])[CH:23]=[CH:24][C:25]=1[CH3:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)N2CCCCC2)cc1Br
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: Cc1ccc(S(=O)(=O)N2CCCCC2)cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 1-[(3-bromo-4-methylphenyl)sulfonyl]piperidine (Intermediate 139), the title compound was obtained as a yellow solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([F:14])[CH:8]=1)C.CC(C[AlH]CC(C)C)C.[Cl-].[NH4+].S([O-])([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1.C(OCC)C>[F:13][C:11]1[CH:12]=[C:7]([CH2:6][CH2:5][CH:4]=[O:3])[CH:8]=[C:9]([F:14])[CH:10]=1
Reactant: CCOC(=O)CCc1cc(F)cc(F)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=CCCc1cc(F)cc(F)c1
Temperature: -58 °C
Yield: 98.7 %

Procedure:
The above 3-(3,5-difluorophenyl)propionic ethyl ester 53.0 g (247 mmol) was dissolved in toluene 500 ml and cooled to −58° C. under stirring, and a 1.01 M of toluene solution 255 ml (258 mmol) of DIBAL was added dropwise, and the mixture was stirred at −55° C. for 15 minutes. At the same temperature, a saturated ammonium chloride aqueous solution 200 ml was added dropwise to the reactant, and the mixture was heated to room temperature and stirred for 30 minutes. Diethyl ether 100 ml was added to the reactant, and the mixture was stirred at room temperature for one hour, and magnesium sulfate was added, and the suspension was filtered with cerite. The filtrate was washed with water, the organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 3(3,5-difluorophenyl)propanal 41.5 g. The yield was 98.8% from 3-(3,5-difluorophenyl)propionic acid ethyl ester.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[S:9][CH:10]=1)C.[Li+].[OH-].Cl.[Na+].[Cl-]>C1COCC1.CCOC(C)=O.CO>[OH:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:8]1[S:9][CH:10]=[C:6]([CH2:5][C:4]([OH:18])=[O:3])[N:7]=1
Reactant: CCOC(=O)Cc1csc(-c2ccccc2O)n1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cc1csc(-c2ccccc2O)n1
Yield: 99.1 %

Procedure:
A stirred solution of 4a (824 mg, 3.13 mmol) in THF (5 mL)/MeOH (5 mL) was treated with 2N LiOH (4 mL), the resultant mixture was stirred at ambient temperature under nitrogen for 30 min. The mixture was treated with 5N HCl (2 mL), followed by adding EtOAc (50 mL) and solid NaCl to saturate the aq. layer. The organic layer was separated, washed with brine (20 mL×2), dried over MgSO4, filtered, and concentrated in vacuo to give a solid residue. After recrystallization from acetone/hexane, 5a (730 mg, 99%) was obtained as a white solid. mp 173.0°-174.0° C.; IR (KBr) 3250-2400 (br), 3108, 1696, 1223 cm-1 ; 1H NMR (DMSO-d6) δ3.76 (2H, s, CH2), 6.89 (1H, t, J=7.8 Hz, Ar), 6.96 (1H, d, J=7.8 Hz, Ar), 7.26 (1H, t, J=7.8 Hz, Ar), 7.45 (1H, s), 7.92 (1H, d, J=7.8 Hz, Ar), 11.33 (1H, s, OH), 12.42 (1H, br s, CO2H); FABMS m/z 235 (M+), 236 (M+ +1); Anal. Calcd for C11H9NO3S: C, 56.16; H, 3.86; N, 5.95. Found: C, 56.30; H, 3.85; N, 6.10.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][CH2:11][CH3:12])[C:6]([C:13]([OH:15])=O)=[CH:5][N:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:29][NH2:30].O>C1COCC1>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][CH2:11][CH3:12])[C:6]([C:13]([NH:29][NH2:30])=[O:15])=[CH:5][N:4]=1
Reactant: NN
Reactant: CCCNc1nc(SC)ncc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: CCCNc1nc(SC)ncc1C(=O)NN
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84 %

Procedure:
2-Methylthio-4-n-propylaminopyrimidine-5-carboxylic acid (22.6 g) obtained in Step 1 was dissolved in THF (360 mL), then carbonyldiimidazole (16.9 g) was added thereto, followed by stirring at room temperature for 1.5 hours. Then, a THF (100 mL) solution of hydrazine monohydrate (14.5 mL) was added dropwise to the reaction mixture over 30 minutes, followed by stirring at room temperature for 2.5 hours. After completion of the reaction was confirmed by thin-layer chromatography, water was added to the reaction mixture. Precipitated crystals were collected by filtration and the resulting crystals were washed with water and dried thoroughly under reduced pressure to give 2-methylthio-4-n-propylaminopyrimidine-5-carbohydrazide (20.1 g, yield 84%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH:7]([C:9]([OH:11])=[O:10])[NH2:8].C(=O)([O-])[O-].[K+].[K+].[C:18](Cl)([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].C(OCC)(=O)C.C(O)(=O)C.C(#N)C.O>O.O1CCOCC1>[CH2:21]([O:20][C:18]([NH:8][CH:7]([C:9]([OH:11])=[O:10])[CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC(Cc1cccs1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(NC(Cc1cccs1)C(=O)O)OCc1ccccc1
Reaction time: 1 h
Yield: 97.9 %

Procedure:
To a mixture of 3.0 g (16.9 mmol) of β-thienyl-D,L-alanine in 75 mL of water and 60 mL of dioxane, was added 5.6 g (40.6 mmol) of anhydrous potassium carbonate, followed by 2.85 mL (20 mmol) of carbobenzyloxychloride. The resulting mixture was stirred rapidly for approximately one hour. When the reaction was substantially complete, as indicated by thin layer chromatography (21/7/7/9, ethyl acetate/acetic acid/acetonitrile/water), the reaction mixture was concentrated. The resultant layers were separated and the aqueous layer was washed with 75 mL of diethyl ether and then layered with 150 mL of methylene chloride. The resultant mixture was acidified with rapid stirring to pH=2.0 using 5N hydrochloric acid. The layers were then separated, and the organic layer was dried sodium sulfate (Na2SO4), filtered and concentrated to provide 5.05 g of desired compound (98%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[CH2:6](N)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O1CCCC1.C(OCC)(=O)C>[CH2:6]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCCCO
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCCCNCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.8 %

Procedure:
3-amino-1-propanol (150 g) was dissolved in tetrahydrofuran (200 mL), followed by the addition of benzylamine(23.8 g). The mixture was stirred at room temperature for 1 hour. Subsequently, the reaction mixture was diluted with ethyl acetate, was sequentially washed with water and a saturated aqueous solution of sodium chloride, and was then dried over anhydrous sodium sulfate. The solvent was removed to obtain 3-(benzylamino)-1-propanol (20.1 g, 61%).
Reaction SMILES: O1CCCC1.[CH2:6]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18](Cl)=[N:19][OH:20])=[CH:13][CH:12]=1)[CH2:7][CH2:8][CH3:9].[C:22]([C:24]1[C:25]([NH2:30])=[N:26][CH:27]=[CH:28][CH:29]=1)#[CH:23].C(N(CC)CC)C>O>[CH2:6]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[CH:23]=[C:22]([C:24]3[C:25]([NH2:30])=[N:26][CH:27]=[CH:28][CH:29]=3)[O:20][N:19]=2)=[CH:13][CH:12]=1)[CH2:7][CH2:8][CH3:9]
Reactant: C#Cc1cccnc1N
Reactant: CCCCOc1ccc(CC(Cl)=NO)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCCCOc1ccc(Cc2cc(-c3cccnc3N)on2)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 21.1 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-butoxy-phenyl)-acetohydroximoyl chloride (150 mg, 0.619 mmol) described in Manufacturing Example 67-1-4 and 3-ethynyl-pyridin-2-ylamine (47 mg, 0.395 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (216 μL, 1.55 mmol) at room temperature, which was stirred for 2 hours at 50° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was devaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=4:1-2:1) to obtain the title compound (27 mg, 14%).
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C@@H:4]([CH2:18][NH:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:3]1.[O-:26][C:27]#[N:28].[K+].[OH-].[Na+]>O.Cl>[CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C@@H:4]([CH2:18][N:19]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:27](=[O:26])[NH2:28])[CH2:3]1
Reactant: COC(=O)CCNC[C@@H]1C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: COC(=O)CCN(C[C@@H]1C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1)C(N)=O
Temperature: 60 °C
Yield: 67.9 %

Procedure:
A mixture of 8.5 g of 6-methyl-8β-[N-(2-methoxycarbonyl-ethyl)aminomethyl]-ergoline (II: R1 =R2 =R3 =H, R4 =CH3, n=1, A=CH2 --CHR6, R6 =H, B=COOCH3 ; prepared as described in Example 1) and 2.86 g of potassium cyanate in 120 ml of water and 35 ml of 1N hydrochloric acid was heated at 60° C. for one hour. The solution was then neutralized with 1N sodium hydroxide and extracted with chloroform. The organic layer was evaporated off, and the residue was purified by column chromatography on silica gel, to give 6.5 g of the title compound. Rf in ethyl acetate:dimethylformamide:n-butanol:pyridine (4:3:3:1 by volume)=0.45; MS (F.D.): 384 (M+), 352 (M+ --CH3OH).