Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]5)=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:40]2[CH:41]=[N:42][N:43]([CH2:45][CH2:46]OS(C)(=O)=O)[CH:44]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:52][NH:53][CH3:54]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]5)=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:40]2[CH:41]=[N:42][N:43]([CH2:45][CH2:46][N:53]([CH3:54])[CH3:52])[CH:44]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CNC
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2cnn(CCOS(C)(=O)=O)c2)n1
Solvent: C1CCOC1
Product: CN(C)CCn1cc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)cn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 15 %

Procedure:
To a solution of Intermediate 108e (0.20 mmol) in THF (2 mL) was added dimethylamine (2M in MeOH, 0.8 mL, 1.6 mmol) and stirring at RT was continued for 48 h. The crude reaction mixture was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-10% [2M NH3 in MeOH] in DCM followed by MDAP (Method 7) purification, to give the title compound (20 mg, 15%). LCMS (Method 5): Rt 3.34 min, m/z 666 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.24 (9H, s), 1.54-1.65 (2H, m), 1.67-1.77 (4H, m), 1.81-2.13 (4H, m), 2.16 (6H, s), 2.67 (2H, t, J=6.5 Hz), 3.13 (4H, t, J=5.3 Hz), 4.20 (2H, t, J=6.5 Hz), 4.79-4.87 (1H, m), 5.55 (1H, t, J=4.5 Hz), 6.26 (1H, s), 7.11-7.19 (2H, m), 7.26-7.41 (4H, m), 7.58-7.64 (3H, m), 7.99-8.05 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[NH:6][C:7](=[O:27])[CH:8]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.B(Br)(Br)Br>ClC(Cl)C.ClCCl>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[NH:6][C:7](=[O:27])[CH:8]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(C2=NC(Cc3ccccc3Cl)C(=O)Nc3ccc(Cl)cc32)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: O=C1Nc2ccc(Cl)cc2C(c2ccc(O)cc2)=NC1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.9 %

Procedure:
(Z)-7-Chloro-3-(2-chlorobenzyl)-5-(4-methoxyphenyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (74 mg, 0.174 mmol) was dissolved in dichloroethane (1 mL) under nitrogen and BBr3 (1M in dichloromethane, 0.348 mL, 0.348 mmol) was added dropwise at room temperature (there was an immediate color change from colorless to orange). The reaction mixture was stirred at room temperature for approximately 5 hours. Two more equivalents of BBr3 in dichloromethane were added (0.348 mL, 0.348 mmol) and the mixture was left stirring for another approximately 18 hours. The reaction was carefully quenched with methanol (exothermic) then diluted with dichloromethane and washed twice with water then once with brine (the last wash gelled so some methanol was added to separate the layers). The organic layer was dried (MgSO4). Chromatography eluting with 20-40% ethyl acetate in hexanes gave some starting material plus (Z)-7-chloro-3-(2-chlorobenzyl)-5-(4-hydroxyphenyl)-1H-benzo[e][1,4]diazepin-2(3H)-one as a yellow solid (40 mg, 56%). 1H NMR (300 MHz, CDCl3) δ 3.59-3.89 (m, 3H), 6.30 (br s, 1H), 6.71 (d, J=8 Hz, 2H), 7.09-7.32 (m, 4H), 7.44 (dd, J=9, 2 Hz, 1H), 7.58 (d, J=7 Hz, 1H), 9.13 (s, 1H); ESI m/z 411.0.
Reaction SMILES: C([O-])(=O)C1C(=CC=CC=1)C([O-])=[O:5].[C:13]([C:15]1[CH:28]=[CH:27][C:26]2SC3C(=CC=CC=3)N(C[C@]([NH3+])(CCC)C3C=CC=CC=3)[C:17]=2[CH:16]=1)#[N:14].C([C:43]1[CH:56]=[CH:55][C:54]2[S:53][C:52]3[C:47](=[CH:48]C=CC=3)[N:46](C[C@@]([NH3+])(C3C=CC=CC=3)CCC)[C:45]=2[CH:44]=1)#N.[OH-].[K+].O>C(O)C>[OH:5][CH2:48][CH:47]([N:46]1[C:27]2[CH:28]=[C:15]([C:13]#[N:14])[CH:16]=[CH:17][C:26]=2[S:53][C:54]2[C:45]1=[CH:44][CH:43]=[CH:56][CH:55]=2)[CH3:52]
Reactant: O=C([O-])c1ccccc1C(=O)[O-]
Reactant: CCC[C@@]([NH3+])(CN1c2ccccc2Sc2ccc(C#N)cc21)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(CO)N1c2ccccc2Sc2ccc(C#N)cc21
Reaction time: 0.17 h
Yield: 127 %

Procedure:
(-)-2-(2-cyano-10-phenothiazinyl)-1-propyl 1-phenyl-(S)-ethylammonium phthalate (95.4 g) is added to a solution of 23.5 g of potassium hydroxide in 1150 cc ethanol under reflux and reflux is continued while stirring for 10 minutes. The reaction mixture is then poured into iced water (1 liter) and extracted with ethyl acetate (2 liters and then 500 cc). The combined organic phases are washed successively with a 0.1N aqueous solution of hydrochloric acid (2×500 cc), with a saturated aqueous solution of sodium bicarbonate (2×500 cc) and with a saturated aqueous solution of sodium chloride (500 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual yellow solid (44 g) is taken up in isopropyl ether (200 cc) under reflux and the product crystallizes whilst warm. The mixture is allowed to return to a temperature of about 20° C. and the solid is centrifuged, washed with isopropyl ether (20 cc) and dried under reduced pressure (5 mm Hg; 0.7 kPa) at 20° C. D series 10-(1-hydroxy-2-propyl)-2-phenothiazinecarbonitrile (36.5 g) is thus obtained in the form of yellow crystals which melt at 135° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][S:4][C:5]1[NH:10][C:9](=O)[CH:8]=[CH:7][N:6]=1.O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:9]1[CH:8]=[CH:7][N:6]=[C:5]([S:4][CH2:3][C:2]([F:13])([F:12])[F:1])[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ccnc(SCC(F)(F)F)[nH]1
Product: FC(F)(F)CSc1nccc(Cl)n1
Yield: 58.8 %

Procedure:
The solution of 2-(2,2,2-trifluoro-ethylsulfanyl)-3H-pyrimidin-4-one (25 g, crude) in POCl3 (250 mL) was stirred and refluxed for 5 hours. After most POCl3 was removed, the residue was dropped into ice and the pH was adjusted to 8-9, extracted with ethyl acetate, dried over MgSO4 and the crude material was purified by column chromatography on silica gel to give 4-chloro-2-(2,2,2-trifluoro-ethylsulfanyl)-pyrimidine (14.6 g, 58.8%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([NH:12][C:13](=[O:15])[CH3:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH-].[Na+]>>[CH3:1][C:2]1[CH:11]=[C:10]([NH:12][C:13](=[O:15])[CH3:14])[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: CC(=O)Nc1cc(C)nc2ccccc12
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1cc(C)nc2c1CCCC2
Yield: 78.6 %

Procedure:
Reaction of N-(2-methyl-quinolin-4-yl)acetamide (136 mg, 0.679 mmol) using the general procedure for small scale hydrogenations (workup with NaOH in place of saturated NaHCO3) provided N-(2-methyl-5,6,7,8-tetrahydroquinolin-4-yl)acetamide (109 mg, 78%): 1H NMR δ 1.83–1.90 (m, 4H), 2.21 (s, 3H), 2.47 (s, 3H), 2.46–2.2.53 (m, 2H), 2.84–2.87 (m, 2H), 7.18 (br s, 1H), 7.82 (br s, 1H); 13C NMR δ 22.7, 22.8, 23.5, 24.6, 25.3, 33.1, 112.3, 117.3, 143.7, 156.4, 157.3, 169.0; MS m/z: 205 (M+H+).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=1.[CH:21](OC)=[O:22]>C1COCC1.Cl>[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[C:19]=1[CH:21]=[O:22]
Reactant: Clc1cncc(Cl)c1
Reactant: COC=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=Cc1c(Cl)cncc1Cl
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (1.6M in hexanes, 9.3 ml, 14.9 mmol) was added dropwise at 0° C. to a solution of diisopropylamine (1.95 ml, 14.9 mmol) in THF (30 ml). After 15 min. at 0° C., the solution was cooled to −78° C. and 3,5-dichloropyridine (2.0 g, 13.5 mmol) was added. After 1 h, methyl formate (0.92 ml) was added and the mixture warmed to room temperature over 2 h, diluted with 1N hydrochloric acid and extracted twice with ethyl acetate. The extracts were washed with brine, dried over sodium sulphate and evaporated to give a yellow oil which solidified, m.p. 110-111° C.
Reaction SMILES: C([O:5][C:6](=[O:31])[CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH:28]=[CH:29][CH:30]=1)[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][C:15]=1[F:27])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:11]2[CH:10]=[C:9]([CH:30]=[CH:29][CH:28]=2)[O:8][CH2:7][C:6]([OH:31])=[O:5])=[C:15]([F:27])[CH:16]=1)[CH3:26]
Reactant: CCOC(=O)CCc1ccc(OCc2cccc(OCC(=O)OC(C)(C)C)c2)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc(OCc2cccc(OCC(=O)O)c2)c(F)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
To a solution of ethyl 3-(4-{[3-(2-tert-butoxy-2-oxoethoxy)benzyl]oxy}-3-fluorophenyl)propanoate (0.43 g, 0.98 mmoL) in dichloromethane (15 mL) was added trifluoroacetic acid (1.1 g, 9.80 mmoL), and the mixture was stirred at 50° C. for, 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=9:1) to give the title compound (0.26 g, yield 72%) as white powders.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([NH:9][C:10]2[CH:31]=[CH:30][C:13]([CH2:14][N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([CH2:24][C:25]([O:27]CC)=[O:26])=[N:16]3)=[CH:12][CH:11]=2)=[O:8])[CH:4]=[N:3]1.O.[OH-].[Li+].O.Cl>O1CCCC1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:14][N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([CH2:24][C:25]([OH:27])=[O:26])=[N:16]3)=[CH:30][CH:31]=2)=[O:8])[CH:4]=[N:3]1
Reactant: CCOC(=O)Cc1nn(Cc2ccc(NC(=O)c3cnn(C)c3)cc2)c2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(C(=O)Nc2ccc(Cn3nc(CC(=O)O)c4ccccc43)cc2)cn1
Yield: 94.3 %

Procedure:
Ethyl 2-[1-[4-(1-methyl-1H-pyrazol-4-carboxamido)benzyl]-1H-indazol-3-yl]acetate (279 mg, 0.67 mmol) was dissolved in tetrahydrofuran (20 mL), and in an ice bath, 10 mL aqueous solution dissolving lithium hydroxide monohydrate (84 mg, 2.0 mmol) was added. It was reacted at room temperature for 3 h, and the reaction was monitored to be complete by TLC. Water was added into the system, and adjusted to pH≈3-4 with diluted hydrochloric acid. A solid precipitated, which was filtered and dried to obtain a white solid 246 mg, at a yield of 94.5%.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.Cl[C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19]>C(OCC)(=O)C>[CH:21]([O:20][C:18]([NH:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8])=[O:19])([CH3:23])[CH3:22]
Reactant: CC(C)OC(=O)Cl
Reactant: COC(=O)c1sccc1N
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)c1sccc1NC(=O)OC(C)C
Temperature: 60 °C
Yield: 89.2 %

Procedure:
22.1 g (0.141 mol) of methyl 3-aminothiophene-2-carboxylate was dissolved in 100 ml of ethyl acetate, and to this was added 11.7 g (0.148 mol) of pyridine. 18.1 g (0.148 mol) of isopropyl chloroformate was added dropwise while cooling with ice over 30 minutes. After completion of the addition, the solution was heated to 60° C. and stirred with heating for 3 hours. After completion of the reaction, the reaction solution was washed sequentially with a 5% aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=7/3) to obtain 30.6 g of the intended compound as a crystal (yield: 85%). The crystal herein obtained was not analyzed and used for the next reaction.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](Cl)=[O:21])=[CH:15][CH:14]=1>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([C:20](=[O:21])[CH2:19][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]ccc1C
Reactant: O=C(Cl)Cc1ccc(F)cc1
Product: CCOC(=O)c1[nH]cc(C(=O)Cc2ccc(F)cc2)c1C

Procedure:
4-[2-(4-Fluorophenyl)-acetyl]-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (94) was synthesized from 3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (84) and (4-fluorophenyl)-acetyl chloride following the procedure described in Example 32. Crude yield: 94%. 1H-NMR (400 MHz, CDCl3): δ 1.36 (t, 3H), 2.61 (s, 3H), 4.01 (s, 2H), 4.35 (q, 2H), 7.01 (m, 2H), 7.22 (m, 2H), 7.50 (d, 1H), 9.70 (s broad, 1H) ppm. 13C-NMR (100 MHz, CDCl3): □ 11.79, 14.38, 46.36, 60.89, 115.51, 127.27, 129.93, 130.77, 162.04, 193.62 ppm. DEPT (100 MHz, CDCl3): CH3 carbons: 11.79, 14.38; CH2 carbons: 46.36, 60.89; CH carbons: 115.51, 127.27, 129.93, 130.77 ppm. LC/MS: 77.48%, m/z=289.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[N+:10]([C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=O)([O-:12])=[O:11]>C(O)C>[N+:10]([C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=[N:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)([O-:12])=[O:11]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: N#Cc1ccc(N)cc1
Solvent: CCO
Product: N#Cc1ccc(N=Cc2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 78.9 %

Procedure:
The mixture of 4-aminobenzonitrile (20 g, 0.17 mol) and 2-nitrobenzaldehyde (28.2 g, 0.17 mol) in anhydrous ethanol was heated to reflux for 3 h. The reaction mixture was cooled to room temperature. The solvent was removed under reduced pressure. The residue was washed with diethyl ether to give 4-(2-nitrobenzylideneamino)benzonitrile as yellow solid (33.7 g, yield 79.3%) LC/MS m/e obsd. (ESI+) [(M+H)+] 252.10.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[CH2:18][CH2:19][CH3:20].C([Li])CCC.CCCCCC.CN(C)[CH:34]=[O:35]>O1CCCC1>[F:10][C:9]([F:12])([F:11])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH:34]=[O:35])=[C:3]([CH2:18][CH2:19][CH3:20])[CH:4]=1)([OH:17])[C:13]([F:16])([F:15])[F:14]
Reactant: CN(C)C=O
Reactant: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1C=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 48.4 %

Procedure:
To a nitrogen purged 3-necked flask was added 2-(4-bromo-3-propylphenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (2.74 mmol, 1 g) in anhydrous tetrahydrofuran (15 mL). The solution was cooled to −78° C. before the addition of n-butyl lithium in hexane (2.5M, 8.22 mmol, 3.29 mL). The mixture was stirred at −78° C. for 15 minutes before the drop wise addition of N,N-dimethylformamide (3.01 mmol, 0.220 g). The mixture was stirred at −78° C. for 10 minutes and was then allowed to warm to room temperature and stir for 30 minutes. The mixture was quenched with water (10 mL) and diluted with ethyl acetate (100 mL). The organic phase was separated, washed with water (2×50 mL), dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting with 10% ethyl acetate/90% heptane) to afford the title compound (417 mg). MS (ESI) m/z 313.3 [M−H]−
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[N:2]=1.[CH3:12][N:13]=[C:14]=[O:15]>>[CH3:12][NH:13][C:14]([NH:11][CH2:10][CH2:9][NH:8][CH2:7][C:3]1[N:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:15]
Reactant: NCCNCc1cccnn1
Reactant: CN=C=O
Product: CNC(=O)NCCNCc1cccnn1

Procedure:
Reacting N-(3-pyridazinylmethyl)ethylenediamine with methyl isocyanate by the procedure of Example 24, then concentrating and separating the residue by column chromatography gives the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4](SC2C=CC=CC=2)[N:3]=1.CC(C)([O-])C.[K+].[N:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][OH:42])[CH:36]=1>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:14][CH:15]=2)[C:5]([C:20]#[N:21])=[C:4]([O:42][CH2:41][C:37]2[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=2)[N:3]=1
Reactant: CC(=O)Nc1ccc(-c2c(C#N)c(N)nc(Sc3ccccc3)c2C#N)cc1
Reactant: OCc1cccnc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CC(=O)Nc1ccc(-c2c(C#N)c(N)nc(OCc3cccnc3)c2C#N)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
115 mg (0.3 mmol) of N-{4-[2-amino-3,5-dicyano-6-(phenylsulfanyl)-4-pyridinyl]phenyl}acetamide [prepared analogously to Kambe et al., Synthesis, 531-533 (1981)] are, together with 50 mg (0.45 mmol) of potassium tert-butoxide, dissolved/suspended in 1.12 g (=1 ml, 10.3 mmol) of 3-pyridylmethyl alcohol, and the mixture is stirred at 60° C. for 2 h. The precipitate is filtered off with suction and suspended in a mixture of water and ethanol, and 0.3 ml of 5N acetic acid is added. After filtration, the product is purified by preparative HPLC on reversed-phase silica gel (gradient: water/acetonitrile 95:510:90 in 38 minutes).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[N:12]([CH2:13][C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]([CH3:23])[N:15]=3)[C@H:11]([C:24]([F:27])([F:26])[F:25])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.Cl.[C@H:29]12[CH2:35][C@H:32]([NH:33][CH2:34]1)[CH2:31][O:30]2>>[CH3:23][N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([CH2:13][N:12]2[C:4]3=[N:3][C:2]([N:33]4[CH2:34][C@@H:29]5[CH2:35][C@H:32]4[CH2:31][O:30]5)=[CH:7][C:6](=[O:8])[N:5]3[CH2:9][CH2:10][C@H:11]2[C:24]([F:25])([F:27])[F:26])=[N:15]1
Reactant: Cn1nc(CN2c3nc(Cl)cc(=O)n3CC[C@H]2C(F)(F)F)c2ccccc21
Reactant: C1O[C@@H]2CN[C@H]1C2
Agent: Cl
Product: Cn1nc(CN2c3nc(N4C[C@@H]5C[C@H]4CO5)cc(=O)n3CC[C@H]2C(F)(F)F)c2ccccc21

Procedure:
250 mg (0.63 mmol) of (8S)-2-chloro-9-(1-methyl-1H-indazol-3-ylmethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 102.26 mg (0.75 mmol) of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride were used in the reaction. After purification by chromatography on silica gel (eluent: 60/40 DCM/MeOH), 230 mg of (8S)-9-(1-methyl-1H-indazol-3-ylmethyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics of which are as follows:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7]2)[CH2:3][CH2:2]1.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl.C(N(CC)CC)C>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:1]2[CH2:6][CH2:5][C:4]3([C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH:8]=[CH:7]3)[CH2:3][CH2:2]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: C1=CC2(CCNCC2)c2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(Br)cc1)N1CCC2(C=Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Spiro(1H-indene-1,4'-piperidine) (15 mg, 81.1 μmol) and p-bromobenzenesulfonyl chloride (21 mg, 81.1 μmol) were combined in CH2Cl2 and treated with triethylamine (2 drops). The mixture was stirred at ambient temperature for 15 min, then poured onto a silica gel column and eluted with 1:1 CH2Cl2 : hexane. The product fractions were combined and evaporated to dryness in vacuo to provide the title compound as a solid which was dried in vacuo overnight at ambient temperature: (m.p. 177°-178°).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[CH:5]=1)([OH:3])=[O:2].[Si](C=[N+]=[N-])(C)(C)[CH3:15]>CO.C1C=CC=CC=1>[CH3:15][O:2][C:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[CH:5]=1)=[O:3]
Reactant: CC(=O)Nc1cc(C(=O)O)ccn1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)c1ccnc(NC(C)=O)c1

Procedure:
4-Carboxy-2-acetylaminopyridine (3.4 g, 19 mmol) was dissolved in methanol/benzene (100 mL, 1:1). TMS-diazomethane was added (1M, Aldrich) with cooling until the yellow color just persisted, then the solvent was removed under reduced pressure. The product was purified by silica gel column chromatography (50/50 hexane/ethyl acetate) and 3.0 g of product was recovered.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].ClC(OCC(C)C)=O.CN1CCOCC1.[CH3:20][N:21]1[C:35]2[C:36]3[C:23]([CH2:24][C@@H:25]4[C@@H:30]([C:31]=3[CH:32]=[CH:33][CH:34]=2)[CH2:29][C@@H:28]([CH2:37][NH:38][NH2:39])[CH2:27][N:26]4[CH3:40])=[CH:22]1>C(#N)C>[CH3:20][N:21]1[C:35]2[C:36]3[C:23]([CH2:24][C@@H:25]4[C@@H:30]([C:31]=3[CH:32]=[CH:33][CH:34]=2)[CH2:29][C@@H:28]([CH2:37][NH:38][NH:39][C:1](=[O:4])[CH3:2])[CH2:27][N:26]4[CH3:40])=[CH:22]1
Reactant: CN1C[C@H](CNN)C[C@@H]2c3cccc4c3c(cn4C)C[C@H]21
Reactant: CC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CC(=O)NNC[C@@H]1C[C@@H]2c3cccc4c3c(cn4C)C[C@H]2N(C)C1
Temperature: -15 °C
Yield: 59.1 %

Procedure:
0.6 g of acetic acid are dissolved in 25 ml of acetonitrile with stirring. The solution is cooled to -15° C., and 1.39 ml of isobutyl chloroformate and 1.1 ml of N-methyl-morpholine are added. After 5 minutes of stirring a solution of 2.8 g of 1,6-dimethyl-8β-hydrazinomethyl-ergoline in 10 ml of acetonitrile is added to the mixture. The mixture is slowly (within 30 minutes) warmed to room temperature, stirred at room temperature for 2 hours, then evaporated in vacuo. The residue is dissolved in 200 ml of chloroform, and 100 ml of water are added. The pH of the aqueous phase is adjusted to 8 with 10% aqueous ammonia, and the mixture is shaken. The organic phase is separated, and the aqueous phase is extracted thrice with 100 ml of chloroform. The chloroform fractions are combined and evaporated to dryness in vacuo. The residue is subjected to column chromatography in order to remove the occasional impurities. 60 g of silica gel are used as adsorbent, and the column is eluted with a 30:0.3:9 mixture of chloroform, water and methanol. The effluent is analyzed by thin layer chromatography. The fractions containing a substance with an Rf value of 0.75 are combined, evaporated in vacuo, and the residue is crystallized from alcohol. 1.9 g (60.4%) of 1,6-dimethyl-8β-[(N'-acetyl-hydrazino)-methyl]-ergoline are obtained; m.p.: 190°-192° C., [α]D20 =-29.7° (c=1, in 96% ethanol).
Reaction SMILES: [CH:1]1[CH:6]=[C:5](C(O)=O)[C:4]([C:10]([O:12]O)=O)=CC=1.[S:14]([O-:17])([O-])=[O:15].[Na+].[Na+]>CCOCC>[CH2:10]([S:14]([CH:4]1[CH2:5][CH2:6][CH2:1][C:10]1=[O:12])(=[O:17])=[O:15])[CH2:4][CH2:5][CH3:6]
Reactant: O=C(O)c1ccccc1C(=O)OO
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CCCCS(=O)(=O)C1CCCC1=O

Procedure:
2-Buthylthiocyclopentanone (88 g) was reacted with a 30% excess solution of mono-perphthalic acid in ether at 0° C. After the reaction was completed, the excess mono-perphthalic acid was treated with sodium sulfite, and the resultant solution was washed, evaporated to remove the solvent, and then distilled, thereby giving 2-butylsulfonylcyclopentanone (78 g).