Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][N:17]2[C@H:11]([C:12](=O)[NH:13][C:14]3[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=3[C:16]2=[O:19])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.[Cl-].[NH4+]>O1CCCC1>[Si:1]([O:8][C@H:9]1[CH2:18][N:17]2[C@H:11]([CH2:12][NH:13][C:14]3[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=3[C:16]2=[O:19])[CH2:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H]2C(=O)Nc3ccccc3C(=O)N2C1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H]2CNc3ccccc3C(=O)N2C1
Temperature: 50 °C
Reaction time: 1 h
Yield: 55.4 %

Procedure:
A solution of (2R,11aS)-2-(tert-butyldimethylsilyloxy)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5,11-dione (34.6 g) in tetrahydrofuran (100 ml) was dropwise added to a suspension of lithium aluminum hydride (4.2 g) in tetrahydrofuran (200 ml) at 0° C. over 15 minutes in a nitrogen gas atmosphere, followed by stirring at room temperature for one hour and at 50° C. for one hour. After ice-cooling the reaction solution, 30 ml of ethyl acetate and 8 ml of a saturated aqueous ammonium chloride solution were added to the reaction solution, the mixture was stirred for 30 minutes and the precipitates separated out were filtered off. The filtrate was dried, concentrated under reduced pressure and the resulting residue was recrystallized from ethyl acetate to give 18.4 g (yield 55.3%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][O:5][C@H:4]([CH2:8][OH:9])[CH2:3]1.[H-].[Na+].[N+](C1C=CC([O:21][C:22]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:26][CH2:25]2)=O)=CC=1)([O-])=O>C1COCC1>[F:36][C:33]1[CH:32]=[CH:31][C:30]([N:27]2[CH2:26][CH2:25][N:24]([C:22]([O:9][CH2:8][C@H:4]3[O:5][CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]3)=[O:21])[CH2:29][CH2:28]2)=[CH:35][CH:34]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccc(F)cc2)CC1
Reactant: CN1CCO[C@H](CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCO[C@H](COC(=O)N2CCN(c3ccc(F)cc3)CC2)C1
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
(S)-(4-Methyl-morpholin-2-yl)-methanol (Intermediate 10; 100 mg, 0.76 mmol) was added to a suspension of NaH (60% dispersion in oil; 90.0 mg, 2.28 mmol) in anhydrous THF (7 mL) and stirred under nitrogen for 30 min. 4-(4-Fluorophenyl)-piperazine-1-carboxylic acid 4-nitrophenyl ester (Intermediate 6; 314 mg, 0.91 mmol) was added and the reaction mixture was stirred at room temperature for 48 h. The reaction mixture was filtered through celite and the solid washed with THF (10 mL). The filtrates were combined and the solvent removed in vacuo. The residue was purified by column chromatography (normal phase silica, 5 g Isolute-Si column, gradient 1-5% MeOH in DCM) and the solvents were removed in vacuo to give [(2S)-4-methylmorpholin-2-yl]methyl 4-(4-fluorophenyl)-piperazine-1-carboxylate (130 mg, 51%) as a light brown solid.
Reaction SMILES: Cl.[CH:2]12[CH2:12][CH:6]([CH2:7][CH:8]([CH2:10][OH:11])[CH2:9]1)[CH2:5][NH:4][CH2:3]2.[F:13][C:14]([F:28])([F:27])[C:15]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:16]=1[CH:17]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C1COCC1>[F:13][C:14]([F:27])([F:28])[C:15]1[CH:22]=[C:21]([C:23]([F:26])([F:24])[F:25])[CH:20]=[CH:19][C:16]=1[CH2:17][N:4]1[CH2:3][CH:2]2[CH2:12][CH:6]([CH2:7][CH:8]([CH2:10][OH:11])[CH2:9]2)[CH2:5]1
Reactant: O=Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: OCC1CC2CNCC(C1)C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: OCC1CC2CC(C1)CN(Cc1ccc(C(F)(F)F)cc1C(F)(F)F)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-azabicyclo[3.3.1]non-7-ylmethanol hydrochloride (2.54 g) in THF (66.2 mL) was added 2,4-bis(trifluoromethyl)benzaldehyde (2.82 mL). The reaction mixture was stirred at room temperature for 1 hr, and sodium triacetoxyborohydride (5.62 g) was added. The mixture was further stirred at room temperature for 30 min and poured into 0.1M aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.64 g).
Reaction SMILES: Cl[C:2]1[NH:3][C:4](=[O:12])[C:5]2[CH:10]=[CH:9][N:8]([CH3:11])[C:6]=2[N:7]=1.Cl.[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.C(N(CC)C(C)C)(C)C>C(O)C>[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:22][CH2:23][N:24]([C:2]3[NH:3][C:4](=[O:12])[C:5]4[CH:10]=[CH:9][N:8]([CH3:11])[C:6]=4[N:7]=3)[CH2:25][CH2:26]2)=[CH:17][CH:16]=1
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: Cn1ccc2c(=O)[nH]c(Cl)nc21
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccc2c(=O)[nH]c(N3CCC(c4ccc(F)cc4)CC3)nc21
Temperature: 140 °C
Yield: 104.6 %

Procedure:
A microwave reaction vial was charged with 2-chloro-7-methyl-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one (Intermediate A) (25 mg, 0.13 mmol), 4-(4-fluorophenyl)piperidine hydrochloride (35.2 mg, 0.16 mmol), and N,N-diisopropylethylamine (52.8 mg, 0.41 mmol) in ethanol (1.5 mL). The vial was sealed and then heated in the microwave at 140° C. for 15 min. At this time, the resulting mixture was concentrated in vacuo. Flash chromatography (20/1 methylene chloride/methanol) afforded 2-[4-(4-fluoro-phenyl)-piperidin-1-yl]-7-methyl-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one (44.4 mg, 36%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.5-1.7 (m, 2H) 1.8 (d, J=11.55 Hz, 2H) 2.8 (br. s., 1H) 2.9 (t, J=12.05 Hz, 2H) 3.5 (s, 3H) 4.5 (d, J=13.05 Hz, 2H) 6.2 (d, J=3.51 Hz, 1H) 6.7 (d, J=3.26 Hz, 1H) 7.1 (t, J=8.78 Hz, 2H) 7.3 (dd, J=8.53, 5.52 Hz, 2H) 10.7 (s, 1H). LC-MS calcd. for C18H20FN4O [(M+H)+] 327, obsd. 327.0.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]3[N:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O-:25])=[O:24])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[CH:8]=[C:7]([O:26][C@@H:27]([C@@H:29]3[CH2:33][C:32](=[O:34])[N:31]([C@@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=4)[CH3:36])[CH2:30]3)[CH3:28])[C:6]=12.[Br-].[CH:46]1([Zn+])[CH2:48][CH2:47]1>[Cl-].[NH4+]>[CH:46]1([C:2]2[CH:3]=[N:4][N:5]3[CH:10]=[C:9]([C:11]4[N:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:9]([CH3:11])([CH3:10])[CH3:8])=[O:24])[CH2:19][CH2:18]5)=[CH:13][CH:12]=4)[CH:8]=[C:7]([O:26][C@@H:27]([C@@H:29]4[CH2:33][C:32](=[O:34])[N:31]([C@@H:35]([C:37]5[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=5)[CH3:36])[CH2:30]4)[CH3:28])[C:6]=23)[CH2:48][CH2:47]1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(-c4ccc(N5CCN(C(=O)[O-])CC5)cn4)cn4ncc(I)c34)CC2=O)cc1
Reactant: [Zn+]C1CC1
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cn4)cn4ncc(C5CC5)c34)CC2=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an appropriate sized microwave vial, 4-(6-(3-iodo-4-((R)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)pyridin-3-yl)piperazine-1-carboxylate 6.48 (35 mg, 0.046 mmol) and [(2-dicyclohexylphosphino-2′,6′-bis(N,N-dimethylamino)-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (3.7 mg, 0.0046 mmol) were added. After evacuating and backfilling with nitrogen, THF (1.0 mL) was added followed by cyclopropylzinc bromide (0.55 mL, 0.27 mmol, 0.5M solution in THF). The mixture was stirred at room temperature for 15 min. The reaction was diluted with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford tert-butyl 4-(6-(3-cyclopropyl-4-((R)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)pyridin-3-yl)piperazine-1-carboxylate 6.49.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:12]([N:14]1[C:18](=[O:19])[C:17](=[C:20]2[N:24]([CH3:25])[C:23]3[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=3[S:21]2)[S:16][CH2+:15]1SC)[CH3:13].[NH2:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[N:39]=[CH:38][CH:37]=[CH:36]2>>[CH2:12]([N:14]1[C:18](=[O:19])[C:17](=[C:20]2[N:24]([CH3:25])[C:23]3[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=3[S:21]2)[S:16][C:15]1=[N:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[N:39]=[CH:38][CH:37]=[CH:36]2)[CH3:13]
Reactant: Nc1ccc2ncccc2c1
Reactant: CCN1C(=O)C(=C2Sc3ccccc3N2C)S[CH2+]1SC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCN1C(=O)C(=C2Sc3ccccc3N2C)SC1=Nc1ccc2ncccc2c1

Procedure:
The title compound was prepared from 3-ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate and 6-aminoquinoline in a manner similar to that described in Example 1. 1H-NMR (CDCl3): δ 8.85 (1H, dd), 8.11 (1H, d), 8.10 (1H, d), 7.51 (1H, dd) 7.46 (1H, dd), 7.40 (1H, d), 7.38 (1H, dd), 7.32 (1H, m), 7.16 (1H, m), 7.01 (1H, d), 4.10 (2H, q), 3.70 (3H, s), 1.41 (3H, t); MS(ESI): 419 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N+:18]([O-:20])=[O:19])=[C:11]([O:16][CH3:17])[CH:12]=[C:13](F)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=[O:23].[OH-].[Na+].Cl>O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([OH:23])[CH:12]=[C:11]([O:16][CH3:17])[C:10]=1[N+:18]([O-:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(F)cc(OCc2ccccc2)c1[N+](=O)[O-]
Reactant: CS(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(O)cc(OCc2ccccc2)c1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of 3-benzyloxy-5-fluoro-2-nitroanisole(0.75 g), dimethylsulphoxide(5 mL) and 5N aqueous sodium hydroxide(2 mL) was stirred at 70° C. for 3 h. The mixture was diluted with water and acidified with concentrated hydrochloric acid, extracted with ethyl acetate and the extract was washed with water dried and evaporated to dryness to give the product (0.71 g), (m/e274, MH−).
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][O:9][C:10]([CH:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:23][S:24](O)(=[O:26])=[O:25]>C(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([CH:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([S:24]([Cl:23])(=[O:26])=[O:25])[CH:19]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:21][CH:22]=1)([O-:3])=[O:2]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)C1CCc2ccccc21
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)C1CCc2ccc(S(=O)(=O)Cl)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.2 %

Procedure:
To a solution of indan-1-carboxylic acid 4-nitro-benzyl ester (2.3 g, 8.1 mmol) in anhydrous CHCl3 (13 mL) at −20° C. was added chlorosulfonic acid (2.8 g, 24.0 mmol) over a period of 10 minutes. The mixture was warmed to ambient temperature and stirred for 16 h. The reaction mixture was combined with ice-water and the resulting layer was extracted with CH2Cl2. The CH2Cl2 layer was washed with brine and was dried over anhydrous Na2SO4. The crude product was purified using flash silica chromatography (0-30% EtOAc/Hex) to yield 0.84 g (27%) of 6-chlorosulfonyl-indan-1-carboxylic acid 4-nitro-benzyl ester.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:23][C:24]([F:36])([F:35])[O:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>>[F:18][C:17]1[C:12]2[N:13]([C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:28]4[CH:29]=[CH:30][CH:31]=[C:26]([O:25][C:24]([F:23])([F:35])[F:36])[CH:27]=4)[CH:3]=3)=[CH:10][N:11]=2)[CH:14]=[CH:15][C:16]=1[C:19]([OH:22])([CH3:21])[CH3:20]
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4cccc(OC(F)(F)F)c4)c3)cnc2c1F
Yield: 3 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo [1,2-α]pyridin-7-yl]-propan-2-ol and 3-trifluoromethoxybenzeneboronic acid were coupled in the same way as in Example 30 to give 2-[8-fluoro-3-(2-fluoro-3′-trifluoromethoxybiphenyl-5-yl)imidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (4 mg, 3%): m/z (ES+) 449 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=[CH:18][C:13]=2[N:12]([CH3:22])[C:11](=[O:23])[CH:10]([CH3:24])[N:9]=1>Cl>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]2[N:12]([CH3:22])[C:11](=[O:23])[CH:10]([CH3:24])[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C:14]=2[CH:15]=1
Reactant: CC1N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc2N(C)C1=O
Agent: Cl
Product: CC1N=C(c2ccccc2F)c2cc(N)ccc2N(C)C1=O
Reaction time: 0.25 h

Procedure:
85 g (0.26 M) of rac-5-(o-fluorophenyl)-1,3-dihydro-1,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one are dissolved in 700 ml of concentrated hydrochloric acid and treated slowly with 180 g of stannous chloride. After about 15 minutes, the mixture is cooled with ice and then concentrated on a rotary evaporator. The residue is dissolved in ice-water, slowly made alkaline with 200 g of sodium carbonate in 1 liter of water and extracted several times with methylene chloride. The organic solution is dried over sodium sulphate, filtered and concentrated. The residue is crystallised from ethyl acetate and there is obtained rac-7-amino-5-(o-fluorophenyl)-1,3-dihydro-1,3-dimethyl-2H-1,4-benzodiazepin-2-one which melts at 178°-180° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7][C:6]([Si](C)(C)C)=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[Si](C)(C)c1[nH]c2c([N+](=O)[O-])cc(Cl)cc2c1-c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(Cl)cc2c(-c3ccccc3)c[nH]c12
Yield: 101.2 %

Procedure:
5-Chloro-7-nitro-3-phenyl-2-trimethylsilyl-1H-indole (1.5 g, 4.35 mmol) obtained in Step 2 was dissolved in tetrahydrofurane (30 mL), and 1 M tetrabutylammoniumfluoride solution (5.2 mL, 5.2 mmol) was added in drops at 0° C. At the end of reaction, the resulting mixture was diluted with water and extracted with ethylacetate. The extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The solvent was removed under reduced pressure and the residue was separated using column chromatography to give 5-chloro-3-phenyl-7-nitro-1H-indole (1.2 g, Yield 100%).
Reaction SMILES: [O-]CC.[Na+].[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([O:13]CC)=O.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]#[N:25])=[CH:19][CH:18]=1.Cl>C(O)C.O>[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([OH:13])=[C:23]([C:24]#[N:25])[C:20]1[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1ccccn1
Reactant: N#CCc1ccc(F)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CC(=C(O)c1ccccn1)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a solution of 40.8 g (0.60 mol) of sodium ethoxide in 200 ml absolute ethanol was added a mixture of 60.5 g (0.40 mol) of ethyl picolinate and 54.1 g (0.40 mol) of 4-fluorophenylacetonitrile. The solution was refluxed 10 minutes, then cooled to ambient temperature. The solids were dissolved by the addition of 330 ml of water. Then, 50 ml 12N hydrochloric acid was added dropwise. The solid was collected by filtration, washed with water, and dried overnight (30° C. in vacuo) to give 1-(2-pyridinyl)-2-cyano-2-(4-fluorophenyl)-ethen-1-ol. This compound was dissolved in 250 ml 48% hydrobormic acid and refluxed for 17 hours. Upon cooling, aqueous ammonium hydroxide was added until the reaction mixture was basic. The aqueous solution was extracted three times with chloroform. The combined organic extracts were washed with water, dried (MgSO4), and concentrated. The resulting solid was chromatographed on silica gel with ether-petroleum ether (1:3) as eluant, and recrystallized from 2-propanol-hexane to give the title Formula (X) compound, m.p. 56.58° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.C1(CN)CCCCC1.[O:18]=[C:19]1[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:39][C:40]1[CH:48]=[CH:47][CH:46]=[CH:45][C:41]=1[C:42](O)=[O:43].O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:42](=[O:43])[C:41]1[CH:45]=[CH:46][CH:47]=[CH:48][C:40]=1[CH2:39][N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:19]1=[O:18]
Reactant: COc1ccccc1N
Reactant: O=C(O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: COc1ccccc1NC(=O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using o-anisidine to replace cyclohexanemethylamine, and 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-(2-methoxyphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (84%) as a colorless solid: mp 172-174° C.; 1H NMR (300 MHz, DMSO-d6) δ9.66 (s, 1H), 7.78 (d, J=7.6 Hz, 1H), 7.60 (d, J=7.0 Hz, 1H), 7.49-7.32 (m, 2H), 7.24-6.86 (m, 8H), 6.52 (s, 1H), 6.40 (s, 1H), 5.19-5.00 (m, 2H), 4.86 (d, J=9.4 Hz, 1H), 4.70 (d, J=9.4 Hz, 1H), 3.79 (s, 3H), 2.93 (t, J=8.7 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ177.9, 167.6, 161.6, 161.2, 152.1, 142.8, 136.5, 134.4, 132.6, 130.8, 129.1, 128.2, 127.8, 127.1, 126.8, 126.5, 124.9, 124.1, 123.6, 120.9, 120.7, 120.4, 119.6, 112.0, 109.7, 92.9, 80.4, 72.6, 57.4, 56.2, 41.4, 28.8; MS (ES+) m/z 519.2 (M+1).
Reaction SMILES: Br[C:2]1[C:3]([C:17]([F:20])([F:19])[F:18])=[N:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)[C:6]=1[CH3:7].[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:7][C:6]1[N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)[N:4]=[C:3]([C:17]([F:20])([F:19])[F:18])[C:2]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1c(Br)c(C(F)(F)F)nn1-c1ccc(CCO)cc1
Product: Cc1c(-c2ccccc2)c(C(F)(F)F)nn1-c1ccc(CCO)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 12 from 2-{4-[4-bromo-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}ethanol (step 2) and phenylboronic acid: MS (ESI) m/z 346 [M+H]+, 1H-NMR (CDCl3) δ 7.44-7.32 (9H, m), 3.89-3.83 (2H, m), 2.94-2.89 (2H, m), 2.33 (3H, s), 2:32 (3H, s)
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[CH3:5][CH:6]([CH3:10])[CH2:7][CH2:8]N>>[CH3:5][CH:6]([CH3:10])[CH2:7][CH2:8][NH:1][C:2]([NH:4][CH2:8][CH2:7][CH:6]([CH3:10])[CH3:5])=[O:3]
Reactant: NC(N)=O
Reactant: CC(C)CCN
Product: CC(C)CCNC(=O)NCCC(C)C
Temperature: 25 °C
Yield: 64.5 %

Procedure:
Heated was a mixture of urea 0.601 g (10.0 mmol) and 3-methylbutylamine 5.0 mL (ca. 6 equivalents) at 150° C. for 24 hours attaching with a reflux cooler and during which time added more 3-methylbutylamine 2.5 mL. Removed was the excess amine under the reduced pressure and allowed to cool to room temperature to give a colorless solid. Purification by recrystallization from ethyl ether gave N,N′-bis(3-methylbutyl)urea 1.29 g as white plates (64.5% yield).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C)C=O>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:4]=1[C:5]([Cl:18])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(F)cc1C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(F)cc1C(F)(F)F

Procedure:
A suspension of 2-trifluoromethyl-4-fluorobenzoic acid (16.85 g, 81 mmol) in dichloromethane (150 mL) containing a few drops of dimethylformamide was treated dropwise under nitrogen with oxalyl chloride (8.5 mL, 97.4 mmol). After the gas evolution subsided, the reaction mixture was refluxed for an additional 10 minutes, and then evaporated to dryness in vacuo. The crude acid chloride was used as such in the next step.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[C:13]([O:15]C)=[O:14]>CO.O>[NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH:2]1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[C:13]([OH:15])=[O:14]
Reactant: COC(=O)c1cnccc1-c1cnccn1
Solvent: CO
Solvent: O
Product: O=C(O)c1cnccc1C1CNCCN1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 4-(2-pyrazinyl)-3-pyridinecarboxylate (400 mg; may be prepared as described in Intermediate 19) in methanol (20 mL) and water (3 mL) LiOH was added (44.5 mg). The reaction mixture was stirred at 80° C. for 2 h. The reaction mixture was filtered to remove the inorganic salts and evaporated in vacuo. The residue was dissolved in MeOH (20 ml), Pd/C (300 mg) was added and the reaction mixture was placed under hydrogen at 3 bar for 2 days. The reaction was monitored by LCMS which showed complete conversion of starting material. Then the catalyst was filtered by means of a celite plug and the filter was washed with MeOH. Then the solvent was evaporated in vacuo and the residue dissolved in 25 ml of MeOH to give a solution of the title compound, used directly in subsequent reactions.
Reaction SMILES: [CH3:1][N:2]1[C@@H:7]2[CH2:8][C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][C:16]=4[CH:6]2[CH2:5][C@@H:4]([CH2:18][C:19]#[N:20])[CH2:3]1)[NH:11][CH:10]=3.B(F)(F)F.CCOCC.C1C[C@H]2[C@@H](CC3C4C(=CC=CC2=4)NC=3)NC1.S(Cl)([Cl:49])(=O)=O>[OH-].[NH4+].C(Cl)Cl.C(#N)C>[CH3:1][N:2]1[C@@H:7]2[CH2:8][C:9]3[C:17]4[C:16](=[CH:15][CH:14]=[CH:13][C:12]=4[NH:11][C:10]=3[Cl:49])[C@H:6]2[CH2:5][C@@H:4]([CH2:18][C:19]#[N:20])[CH2:3]1
Reactant: O=S(=O)(Cl)Cl
Reactant: CN1C[C@H](CC#N)CC2c3cccc4[nH]cc(c34)C[C@H]21
Agent: FB(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: ClCCl
Solvent: CCOCC
Product: CN1C[C@H](CC#N)C[C@@H]2c3cccc4[nH]c(Cl)c(c34)C[C@H]21
Yield: 72 %

Procedure:
810 mg. of D-6-methyl-8-cyanomethylergoline were suspended in 50 ml. acetonitrile and the suspension cooled to -5° to 0° C. 1.25 ml. of boron trifluoride etherate were added thus solubilizing the ergoline. Next, a solution of 0.27 ml. of sulfuryl chloride in 20 ml. of methylene dichloride was added in dropwise fashion. The reaction mixture was stirred and cooled for 30 minutes, then diluted with ammonium hydroxide. The diluted solution was extracted with a chloroform-isopropanol 3:1 solvent mixture. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried and the solvent evaporated. The residue comprising lergotrile formed in the above chlorination procedure was chromatographed over fluorosil using chloroform containing 2 percent methanol as the eluant; 660 mg. of lergotrile were obtained melting at 268°-271° C. (with decomposition), 72 percent yield.