Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:29]/[O:30][C:31]2([C:34]([O:36][CH:37]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])[CH2:33][CH2:32]2)/[C:15]([NH:17][C@@H:18]2[C:21](=[O:22])[NH:20][C@@H:19]2[CH2:23]OS(C)(=O)=O)=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Na+].[I-].[N-:52]=[N+:53]=[N-:54].[Na+]>CN(C=O)C>[N:52]([CH2:23][C@@H:19]1[C@H:18]([NH:17][C:15](=[O:16])/[C:14](=[N:29]\[O:30][C:31]2([C:34]([O:36][CH:37]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])[CH2:32][CH2:33]2)/[C:12]2[N:13]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[S:10][CH:11]=2)[C:21](=[O:22])[NH:20]1)=[N+:53]=[N-:54]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2COS(C)(=O)=O)cs1
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2CN=[N+]=[N-])cs1
Temperature: 60 °C
Reaction time: 6 h
Yield: 57.3 %

Procedure:
To a solution of benzhydryl 1-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((2S,3S)-2-(((methylsulfonyl)oxy)methyl)-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylate (1.3 g, 1.82 mmol) in DMF (20 ml) was added NaI (0.82 g, 5.5 mmol) and sodium azide (0.83 g, 12.8 mmol). After stirring at 60° C. for 6 h, the reaction mixture was quenched with ice cold water and extracted with EtOAc. Combined organic layers were washed with water, brine, dried over anhydrous Na2SO4, concentrated in vacuo. The crude residue was purified via silica gel chromatography (EtOAc-heptane) to afford the title compound (689 mg, 57%). LCMS: R=1.02 min, m/z=661.1 (M+1), Method 2m_acidic.
Reaction SMILES: [CH2:1]([NH:9][C:10]([C@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]1)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(N(CC)CC)C.[C:25](Cl)(=[O:33])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:1]([NH:9][C:10]([C@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1[C:25](=[O:33])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCNC(=O)[C@H]1CCCCN1
Reactant: CCCCCCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCNC(=O)[C@H]1CCCCN1C(=O)CCCCCCC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(R)-(+)-2-piperidinecarboxylic acid n-octyl amide (23) (100 mg; 0.416 mmol) is dissolved in methylene chloride (3 mL) at ambient temperature. Triethylamine (63 mg; 0.624 mmol) is added and the solution cooled in an ice-bath. Octanoyl chloride (74 mg; 0.458 mmol) is added dropwise via syringe. The solution is stirred for 15 minutes and then allowed to warm to ambient temperature. After stirring for an additional 4.5 hours, the solution is poured onto saturated sodium bicarbonate solution and extracted with methylene chloride (20 mL). The methylene chloride extract is washed with water, dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified via silica gel chromatography using a gradient elution (0%→40% ethyl acetate in hexanes) affording the desired product (28) as an oil. ISMS: MH+367.4
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[K+].[K+].[C:10]([CH2:12][O:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[CH:21][CH:20]=[CH:19]2)#[N:11]>O.C(O)C>[N:22]1[C:23]2[C:18](=[CH:17][CH:16]=[CH:15][C:14]=2[O:13][CH2:12][C:10](=[N:2][OH:3])[NH2:11])[CH:19]=[CH:20][CH:21]=1
Reactant: NO
Reactant: N#CCOc1cccc2cccnc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: NC(COc1cccc2cccnc12)=NO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 6.4 g of hydroxylamine hydrochloride in 10 ml of water and 6.4 g of potassium carbonate in 10 ml of water is added dropwise at room temperature, within 15 minutes, to 15.8 g of 8-(cyanomethoxy)-quinoline in 100 ml of ethanol, in the course of which the reaction mixture warms up to 30° C. After 3 hours' stirring at room temperature, the reaction mixture is diluted with 250 ml of water; it is subsequently filtered, and the residue is washed with water and dried. There is thus obtained 2-(8-quinolinoxy)-acetamide oxime in the form of light-brown powder, m.p. 201-204° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:11])[C:7]=1[C:8](O)=[O:9].S(Cl)([Cl:14])=O.CN(C)C=O>ClCCCl>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:11])[C:7]=1[C:8]([Cl:14])=[O:9]
Reactant: O=C(O)c1c(Cl)cncc1Cl
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1c(Cl)cncc1Cl

Procedure:
Thus obtained 3,5-dichloropyridine-4-carboxylic acid (384 mg, 2 mmol) was dispersed in 1,2-dichloroethane (30 mL) to prepare a slurry, added with thionyl chloride (0.44 mL, 5 mmol), further added with dimethylformamide (0.3 mL), and the mixture was refluxed under heating for 1 hour. The solvent was evaporated under reduced pressure to thereby obtain a crude product of 3,5-dichloropyridine-4-carbonylchloride. 3-(4-aminophenyl)-2-{3-[(2,2-dimethyl propionyl)isobutylamino]-4-methoxyphenyl}propionic acid ethyl ester (2.04 g, 4.5 mmol) obtained in Example 38 was then dissolved in 1,2-dichloroethane (30 mL), and added with pyridine (0.57 mL, 7 mmol). To the mixture, the 1, 2-dichloroethane solution (10 mL) of 3,5-dichloro pyridine-4-carbonylchloride obtained in the above was added, and the mixture was stirred for 1 hour. The reaction solution was treated with water (15 mL), extracted with chloroform, dried over anhydrous sodium sulfate, evaporated under reduced pressure so as to remove the solvent, and the resultant residue was purified through silica gel column chromatography (hexane:ethyl acetate (v/v)=3:2) to thereby obtain 3-[4-(3,5-dichloropyridine-4-carbonylamino) phenyl]-2-{3-[(2,2-dimethylpropionyl)isobutylamino]-4-methoxyphenyl}propionic acid ethyl ester (yield: 2.77 g, yield ratio: 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][S:28]2(=[O:33])=[O:32])[CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([C:20]2[CH:21]=[N:22][CH:23]=[C:24]([CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][S:28]3(=[O:32])=[O:33])[CH:25]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC1(C)OB(c2ccc(C#N)c(Cl)c2)OC1(C)C
Reactant: O=S1(=O)CCCN1Cc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1ccc(-c2cncc(CN3CCCS3(=O)=O)c2)cc1Cl
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To 2-chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile (217 mg, 0.824 mmol) in DMF (4 mL) were added 3-bromo-5-(1,1-dioxo-isothiazolidin-2-ylmethyl)-pyridine (200 mg, 0.687 mmol) and 2M aqueous sodium carbonate (0.687 mL, 1.374 mmol). The reaction mixture was flushed and evacuated with N2 thrice followed by the addition of PdCl2(dppf).CH2Cl2 adduct (28.0 mg, 0.034 mmol). The reaction mixture was stirred at 100° C. for 1 hour. The reaction was cooled to room temperature, diluted with ethyl acetate and washed with water thrice. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo. The crude was dissolved in DMF (5 mL) and purified using Xbridge C18 eluting with a 10 to 100% ACN-water to afford 2-chloro-4-[5-(1,1-dioxo-isothiazolidin-2-ylmethyl)-pyridin-3-yl]-benzonitrile as a white solid. HRMS: (ESI) m/z 348.0575 [(M+H)+ Calcd for C16H14ClN3O2S 348.0573]. 1H NMR (400 MHz, MeOD) δ ppm 2.33-2.47 (m, 2H), 3.24-3.33 (m, 4H), 4.37 (s, 2H), 7.87 (dd, J=8.2, 1.6 Hz, 1H), 7.97 (d, J=8.1 Hz, 1H), 8.06 (d, J=1.5 Hz, 1H), 8.22 (t, J=2.1 Hz, 1H), 8.68 (d, J=2.0 Hz, 1H), 8.87 (d, J=2.3 Hz, 1H).
Reaction SMILES: C1COCC1.C(O)C.C[O:10][C:11](=O)[C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([NH:22][C:23](=[O:32])[CH2:24][S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:13]=1.[BH4-].[Na+]>C(OCC)(=O)C>[OH:10][CH2:11][C:12]1[CH:13]=[C:14]([NH:22][C:23](=[O:32])[CH2:24][S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1
Reactant: COC(=O)c1cc(NC(=O)CSc2ccccc2)cc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(CSc1ccccc1)Nc1cc(CO)cc(C(F)(F)F)c1
Temperature: 65 °C
Reaction time: 2 h
Yield: 54.3 %

Procedure:
To a THF/ethanol (10:1) solution of 3-(2-Phenylsulfanyl-acetylamino)-5-trifluoromethyl-benzoic acid methyl ester (252 mg, 0.68 mmol) was added sodium borohydride (46 mg, 1.4 mmol), and the mixture was stirred at 65° C. for 2 hours. The reaction mixture was left overnight. The mixture was diluted with ethyl acetate, washed with 1 N HCl (2×) and brine. The organic layer was dried over MgSO4, filtered and stripped. The crude product was purified by flash chromatography on silica gel eluted with hexane/ethyl acetate (4:1) to give 126 mg of N-(3-Hydroxymethyl-5-trifluoromethyl-phenyl)-2-phenylsulfanyl-acetamide in 54% yield.
Reaction SMILES: [C:1]1([C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22](=[NH:24])[NH2:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][C:42]=1[N+:51]([O-:53])=[O:52]>ClCCl>[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([S:47]([NH:24][C:22]([C:19]2[CH:20]=[CH:21][C:16]([N:13]3[CH2:14][CH2:15][N:10]([CH2:9][CH:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:11][CH2:12]3)=[CH:17][CH:18]=2)=[NH:23])(=[O:49])=[O:48])=[CH:43][C:42]=1[N+:51]([O-:53])=[O:52]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: N=C(N)c1ccc(N2CCN(CC=C(c3ccccc3)c3ccccc3)CC2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N=C(NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(N2CCN(CC=C(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.7 %

Procedure:
A suspension of EXAMPLE 12B (0.421 g, 0.897 mmol) and diisopropylethylamine (0.50 mL) in dichloromethane (5 mL) was treated with 4-chloro-3-nitrobenzenesulfonyl chloride (0.252 g, 0.99 mmol), stirred at room temperature for 24 hours and concentrated. The resulting residue was purified by silica gel chromatography eluting with a gradient from 0%-10% methanol/dichloromethane to give the desired product (0.33 g, 60%). MS (ESI) m/e 614 (M−H)−.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10].N1CCCCC1>CCO>[CH2:15]([O:14][C:12](=[O:13])/[C:11](/[C:9]#[N:10])=[CH:1]/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:16]
Reactant: CCOC(=O)CC#N
Reactant: O=Cc1ccccc1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)/C(C#N)=C/c1ccccc1
Reaction time: 8 h
Yield: 48.3 %

Procedure:
A mixture of benzaldehyde (0.6 mol, 63.7 g), ethyl cyanoacetate (0.6 mol, 67.8 g) and piperidine (1 mL) in EtOH (60 mL) was stirred overnight. The clear solution was then placed in an ice-water bath to initiate the crystallization. The crystalline material was filtered, washed with EtOH and dried in a vacuum oven at 50° C. to give 58.27 g of (E)-2-cyano-3-phenyl-acrylic acid ethyl ester. The mother liquors and the washings were concentrated under reduced pressure; the residue was cooled in an ice-water bath to produce more crystalline product. This material was collected by filtration and washed with hexane, and a mixture EtOH/hexane (1/4), it was then dried in a vacuum oven at 63° C. to give 38.01 g of (E)-2-cyano-3-phenyl-acrylic acid ethyl ester (80% combined yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:18]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[C:5]([CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:6]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN1CCC(c2c[nH]c3ccc(Cl)cc23)CC1
Reactant: O=C(Cl)c1ccccc1
Product: CN1CCC(c2cn(C(=O)c3ccccc3)c3ccc(Cl)cc23)CC1

Procedure:
(23.0 mg, 65%); from 5-chloro-3-(1-methyl-4-piperidinyl)-1H-indole (Example 5e, 25 mg, 0.10 mmol) and benzoyl chloride (21.1 mg, 0.15 mmol), HRMS-FAB+ for C21H21N2OCl, calculated MH+ : 353.14206; found: 353.14033.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].CCCCCCC.[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1>>[CH3:1][CH:2]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)[CH:3]=[CH2:4]
Reactant: C=CC=C
Reactant: Cc1ccc(C)cc1
Solvent: CCCCCCC
Product: C=CC(C)Cc1ccc(C)cc1
Temperature: 170 °C
Yield: 8 %

Procedure:
7 g of this catalyst was packed into a quartz reaction tube having an inside diameter of 15 mm in a current of argon. The reaction temperature was maintained at 170°C., and a gaseous mixture consisting of p-xylene, butadiene, n-heptane as a diluent, and nitrogen gas in a molar ratio of 1:5:10:5 was passed through the catalyst layer. The contact time of p-xylene was 24 seconds. The conversion of p-xylene was 43%, and the intended 3-methyl-4-(p-tolyl) butene was obtained in a yield of 8%.
Reaction SMILES: [CH:1]([C@:3]12[CH2:47][CH2:46][C@@H:45]([C:48]([CH3:50])=[CH2:49])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:44])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH2:43][C:27]4([CH2:30][C:29]([C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38])([C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])[CH2:28]4)[CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1)=O.C(O)(=O)C.[NH2:55][CH2:56][CH2:57][CH2:58][N:59]1[CH2:64][CH2:63][S:62](=[O:66])(=[O:65])[CH2:61][CH2:60]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C([O-])(O)=O.[Na+]>[O:65]=[S:62]1(=[O:66])[CH2:61][CH2:60][N:59]([CH2:58][CH2:57][CH2:56][NH:55][CH2:1][C@:3]23[CH2:47][CH2:46][C@@H:45]([C:48]([CH3:50])=[CH2:49])[C@@H:4]2[C@@H:5]2[C@@:18]([CH3:21])([CH2:19][CH2:20]3)[C@@:17]3([CH3:22])[C@@H:8]([C@:9]4([CH3:44])[C@@H:14]([CH2:15][CH2:16]3)[C:13]([CH3:23])([CH3:24])[C:12]([C:25]3[CH2:43][C:27]5([CH2:30][C:29]([C:31]([O:33][CH:34]([CH3:35])[CH3:36])=[O:32])([C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38])[CH2:28]5)[CH:26]=3)=[CH:11][CH2:10]4)[CH2:7][CH2:6]2)[CH2:64][CH2:63]1
Reactant: NCCCN1CCS(=O)(=O)CC1
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7(C6)CC(C(=O)OC(C)C)(C(=O)OC(C)C)C7)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: C=C(C)[C@@H]1CC[C@]2(CNCCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7(C6)CC(C(=O)OC(C)C)(C(=O)OC(C)C)C7)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
To a solution of diisopropyl 6-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)spiro[3.3]hept-5-ene-2,2-dicarboxylate (100 mg, 0.146 mmol) from Step 3 in DCE (2 mL) was added acetic acid (0.017 mL, 0.291 mmol) and 4-(3-aminopropyl)thiomorpholine 1,1-dioxide (56.0 mg, 0.291 mmol). The mixture was stirred at RT for 2 h, then to the mixture was added sodium triacetoxyborohydride (154 mg, 0.728 mmol) and it was stirred for 24 hours. The mixture was diluted with 7 mL of sat. NaHCO3 and extracted with dichloromethane (3×7 mL). The organic layers were combined and dried with Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified over a silica gel column eluted with mixture of ethyl acetate and hexanes. The fractions containing the expected product were combined to give the title compound as a white solid (90 mg, 71.6% yield). MS: m/e 863.9 (M+H)+, 3.03 min (method 2). 1H NMR (400 MHz, CHLOROFORM-d) δ 5.85 (s, 1H), 5.54-5.43 (m, 1H), 5.14-4.96 (m, 2H), 4.68 (d, J=2.0 Hz, 1H), 4.57 (s, 1H), 3.12-2.90 (m, 9H), 2.83-2.63 (m, 7H), 2.63-2.50 (m, 4H), 2.42 (td, J=11.0, 5.8 Hz, 1H), 2.28-2.17 (m, 1H), 2.13-2.03 (m, 1H), 1.98-1.29 (m, 17H), 1.27-1.18 (m, 16H), 1.13 (s, 3H), 1.09-1.00 (m, 10H), 0.97 (s, 3H), 0.84-0.75 (m, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:5]=1)([O-])=O.C(Cl)Cl>CO.[C].[Pd]>[N:10]1([C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][N:7]=2)[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: O=[N+]([O-])c1ccnc(N2CCCC2)c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Nc1ccnc(N2CCCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
4-Nitro-2-(pyrrolidin-1-yl)pyridine (560 mg, 2.90 mmol) was dissolved in methanol (21 mL) and methylene chloride (8.3 mL) and the solution was added with palladium carbon (50% aqueous, 560 mg), followed by stirring at room temperature for 1 hour under hydrogen atmosphere. After filtering off the insoluble matter of the reaction mixture, the solvent was evaporated under reduced pressure to obtain 2-(pyrrolidin-1-yl)pyridin-4-ylamine (474 mg, 91%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:17])[CH2:15]Cl)=[C:9]([OH:18])[CH:8]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:19])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]2[NH:13][C:14](=[O:17])[CH2:15][O:18][C:9]=2[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(NC(=O)CCl)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc2c(c1)OCC(=O)N2
Temperature: 50 °C

Procedure:
To a stirred solution of 11-4 (4.28 g, 15.0 mmol) in DMF (50 mL) was added K2CO3 (4.50 g, 32.6 mmol). The resulting suspension was heated to 50° C. for 12 h., after which time the reaction was concentrated. The residue was partitioned between saturated NaHCO3 and EtOAc and extracted twice with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), and concentrated. Flash chromatography (silica gel; 25:75 EtOAc/hexanes) yielded 11-5 as a beige solid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:17][C@H:16]2[C@@H:6]([CH2:7][C:8]3[C:18]4[C:11](=[CH:12][CH:13]=[CH:14][C:15]2=4)[NH:10][CH:9]=3)[N:5]([CH3:19])[CH2:4]1.[C:20]([O:24][CH3:25])(=[O:23])[CH:21]=[CH2:22]>CO>[CH3:19][N:5]1[C@H:6]2[C@@H:16]([C:15]3[CH:14]=[CH:13][CH:12]=[C:11]4[C:18]=3[C:8]([CH2:7]2)=[CH:9][NH:10]4)[CH2:17][C@@H:3]([CH2:2][NH:1][CH2:22][CH2:21][C:20]([O:24][CH3:25])=[O:23])[CH2:4]1
Reactant: CN1C[C@H](CN)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reactant: C=CC(=O)OC
Solvent: CO
Product: COC(=O)CCNC[C@@H]1C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1

Procedure:
A mixture of 5.1 g of 8β-aminomethyl-6-methyl-ergoline and 1.8 ml of methyl acrylate in 100 ml of methanol was refluxed for four hours. The solvent was evaporated off under reduced pressure, and the residue was crystallized from diethyl ether to give 6 g of 6-methyl-8β-[N-(2-methoxycarbonylethyl)-aminomethyl]-ergoline (II: R1 =R2 =R3 =R7 =R8 =H, R4 =CH3, n=1, A=CH2 --CHR6, R6 =H, B=COOCH3) melting at 130°-132° C. To a solution of 2.86 g of potassium cyanate in 30 ml of water, a solution of 6 g of 6-methyl-8β-[N-(2-methoxycarbonylethyl)-aminomethyl]-ergoline in 120 ml of water and 35 ml of 1N hydrochloric acid was added. This reaction mixture was heated for four hours at 80° C. and allowed to stand overnight at room temperature. The solid separated out and was filtered off and recrystallized from ethanol to give 4.5 g of the title compound melting at 330° C. with decomposition.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9](OC)=[O:10])[N:4]=1.O.[NH2:16][NH2:17]>CCO>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([NH:16][NH2:17])=[O:10])[N:4]=1
Reactant: COC(=O)c1nccc(C(F)(F)F)n1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1nccc(C(F)(F)F)n1
Reaction time: 1 h
Yield: 86.1 %

Procedure:
To a solution of methyl 4-(trifluoromethyl)pyrimidine-2-carboxylate (500 mg, 2.4 mmol) in EtOH (12 mL) was added hydrazine monohydrate (0.24 mL, 4.9 mmol). After 1 h, the reaction was concentrated to afford the desired product as a white solid (426 mg, 85%). 1H NMR (400 MHz, CDCl3) δ 9.22 (d, J=5.0 Hz, 1H), 9.05 (s, 1H), 7.83 (d, J=5.0 Hz, 1H), 4.25 (br s, 2H).
Reaction SMILES: O.[OH-].[Li+].O.[CH3:5][N:6]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:23]C)=[O:22])[CH:16]=1)[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10]>O1CCOCC1>[C:21]([C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][N:6]([CH3:5])[C:7](=[O:13])[O:8][C:9]([CH3:11])([CH3:12])[CH3:10])([OH:23])=[O:22]
Reactant: COC(=O)c1cccc(CN(C)C(=O)OC(C)(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CN(Cc1cccc(C(=O)O)c1)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
Lithium hydroxide monohydrate (420 mg, 10 mmol) and water (15 ml) were added to a solution of tert-butyl N-methyl-N-(3-(methyloxycarbonyl)benzyl)carbamate (1.6 g, 5.6 mmol) in dioxan (20 ml) and the mixture was stirred for 2 h. The dioxan was removed in vacuo and the residue was taken up in 0.3N potassium hydrogen sulphate. The mixture was extracted with ethyl acetate and the organic phase was washed with water and brine, dried and reduced to afford tert-butyl N-(3-carboxybenzyl)-N-methylcarbamate (1.4 g, 95%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:20])([CH3:19])[CH2:9][NH:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][N:12]=2)=[CH:4][CH:3]=1.C([O-])([O-])=[O:22].[K+].[K+].OO>CS(C)=O.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:20])([CH3:19])[CH2:9][NH:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]([NH2:16])=[O:22])=[CH:13][N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(CNc1ccc(C#N)cn1)c1ccc(F)cc1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(CNc1ccc(C(N)=O)cn1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
To a cooled (0° C.) suspension of 6-(2-(4-fluorophenyl)-2-methylpropylamino)nicotinonitrile (75 mg, 0.28 mmol, 1.0 equiv) and K2CO3 (50 mg, 0.36 mmol, 1.3 equiv) in DMSO (1 mL) was added aq. H2O2 (250 uL, 30% by wt., 2.6 mmol, 9 equiv) by syringe. The reaction was allowed to warm to RT and stirred for 30 minutes. The resulting mixture was diluted with EtOAc and washed three times with satd. aq. LiCl and once with brine. The resulting solution was dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography (2%-10% MeOH/DCM) provided the title compound as an off-white foam (54 mg, 77%), (m/z [M+H]=288.1).