Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C:7]=1[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:5])[CH3:2].[F:29][C:30]([F:41])([F:40])[C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([C:30]([F:41])([F:40])[F:29])[CH:36]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C:7]=1[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:5])[CH3:2]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1cccc(Cl)c1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3cccc(C(F)(F)F)c3)ccc2n1-c1cccc(Cl)c1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 1-(3-chlorophenyl)-2-ethoxycarbonylmethyl-5-hydroxyindole-3-carboxylic acid ethyl ester (135 mg, 0.34 mmol, see step (b) Example 8) and 3-trifluoromethylphenylboronic acid (96 mg, 0.50 mmol). Yield 110 mg (60%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.P([S-])(OCC)(OCC)=[S:12].O>Cl.C(OCC)(=O)C>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]([NH2:8])=[S:12])=[CH:5][CH:4]=1
Reactant: CSc1ccc(C#N)cc1
Reactant: CCOP(=S)([S-])OCC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CSc1ccc(C(N)=S)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 67 %

Procedure:
4-Methylthiobenzonitrile (12 g) was dissolved in a 4N solution of hydrogen chloride in ethyl acetate (130 mL). To this solution was added O,O-diethyl dithiophosphate (15 mL) and the mixture was stirred at room temperature for 22 hours. Water (100 mL) was added to the reaction mixture and extracted with ethyl acetate. After the insoluble materials were filtered off, the filtrate was washed with a saturated aqueous solution of sodium chloride and dried and, thereafter, the solvent was distilled off. The residue was recrystallized from ethyl acetate to obtain 10 g of the title compound (yield 67%).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=1)[CH2:3][OH:4].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl.C(OCC)C>[CH3:1][C:2]([CH3:21])([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:9]=1)[CH:3]=[O:4]
Reactant: CC(C)(CO)COCc1cccc(Oc2ccccc2)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C=O)COCc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Yield: 48.3 %

Procedure:
A solution of 2,2-dimethyl-3-(3-phenoxybenzyloxy)propan-1-ol (15 g) in dry dichloromethane (50 cm3) was added dropwise to a stirred suspension of pyridinium chlorochromate (18.75 g) in dichloromethane (100 cm3) whilst the reaction temperature was maintained within the range 0°-5° C. When the addition was complete, the mixture was allowed to warm to the ambient temperature (ca. 25° C.) over a period of 2 hours. After the reaction mixture had been diluted with diethyl ether, the ethereal layer was decanted and filtered through celite. The solvent was removed by evaporation and the residual oil purified by column chromatography using a silica gel column and eluting with dichloromethane as eluent, to yield 2,2-dimethyl-3-(3-phenoxybenzyloxy)propane-1-al (7.2 g) as an orange oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH:10]=O)=[CH:3][CH:2]=1.[C:15]([O:19][C:20](=[O:29])[NH:21][CH:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1)([CH3:18])([CH3:17])[CH3:16].[BH4-].[Na+].C([O-])([O-])=O.[Na+].[Na+]>CO>[C:15]([O:19][C:20](=[O:29])[NH:21][CH:22]1[CH2:23][CH2:24][CH:25]([NH:28][CH2:10][C:9]2[CH:12]=[CH:13][CH:14]=[C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH:8]=2)[CH2:26][CH2:27]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: O=Cc1cccc(-c2ccncc2)c1
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCC(NCc2cccc(-c3ccncc3)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
To a solution of 3-pyridinyl benzaldehyde (10) (205 mg, 1.1 mmol) in methanol (20 ml) was added NT-Boc-1,4-diaminocyclohexane (6) (300 mg, 1.4 mmol), and the mixture was stirred at room temperature for 30 min. To this solution was added NaBH4 (0.5 g, 13.2 mmol) in portions at 0° C., and the reaction mixture was stirred at room temperature overnight. The reaction was worked up by addition of saturated aqueous Na2CO3 (2 ml), and the mixture was then extracted with chloroform (3×6 ml). The combined organic layers were dried over anhydrous MgSO4. The solvent was removed under vacuum and the residue was purified by a flash chromatography on silica gel (CH2Cl2/MeOH=10/1) to give 18 (398 mg) in 95% yield; 1H NMR (300 MHz, CDCl3): 8.66 (d, J=8.1 Hz, 2H), 7.39-7.61 (m, 6H), 4.30-4.50 (br, 1H), 3.88 (s, 2H), 3.30-3.50 (br, 1H), 2.40-2.60 (m, 1H), 1.90-2.10 (m, 4H), 1.70-1.90 (br, 1H), 1.44 (s, 9H), 1.06-1.40 (m, 4H) 13C NMR (75 MHz, CDCl3): 155.2, 150.0, 148.3, 141.5, 138.1, 129.1, 128.7, 126.6, 125.5, 121.6, 79.0, 55.6, 51.0, 49.4, 31.9, 28.3; HRMS (ESI) calcd for C23H31N3O2 (M+H+) 382.24890; found 382.24896.
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:48])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:47])[CH2:12][CH2:13][C@@:14]3([CH:31]4[O:35][C:34](=[O:36])[N:33]([C:37]5([C:40]6[N:45]=[CH:44][C:43]([Cl:46])=[CH:42][N:41]=6)[CH2:39][CH2:38]5)[CH2:32]4)[CH2:26][C:25](=[O:27])[C:24]([CH:28]([CH3:30])[CH3:29])=[C:15]32)[C:6]1([CH3:50])[CH3:49])(=O)C.Cl>O1CCOCC1.CO>[Cl:46][C:43]1[CH:42]=[N:41][C:40]([C:37]2([N:33]3[CH2:32][CH:31]([C@:14]45[CH2:26][C:25](=[O:27])[C:24]([CH:28]([CH3:29])[CH3:30])=[C:15]4[C@@H:16]4[C@@:11]([CH3:47])([CH2:12][CH2:13]5)[C@@:10]5([CH3:48])[C@@H:19]([C@:20]6([CH3:23])[C@@H:7]([CH2:8][CH2:9]5)[C:6]([CH3:49])([CH3:50])[C@@H:5]([OH:4])[CH2:22][CH2:21]6)[CH2:18][CH2:17]4)[O:35][C:34]3=[O:36])[CH2:39][CH2:38]2)=[N:45][CH:44]=1
Reactant: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@@H]4C5=C(C(C)C)C(=O)C[C@]5(C5CN(C6(c7ncc(Cl)cn7)CC6)C(=O)O5)CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(C2CN(C3(c4ncc(Cl)cn4)CC3)C(=O)O2)CC1=O
Temperature: 40 °C
Reaction time: 8 h
Yield: 17.5 %

Procedure:
To a solution of (3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(3-(1-(5-chloropyrimidin-2-yl)cyclopropyl)-2-oxooxazolidin-5-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (107) (350 mg, 0.496 mmol) in 1,4-dioxane (10 mL) and methanol (5 mL) was added hydrochloric acid (5 mL, 165 mmol). The reaction mixture was stirred at 40° C. overnight. The solvents were removed under reduced pressure and taken up in DCM (100 ml), washed with sat. NaHCO3 (20 ml), water (20 ml) and brine (20 ml), dried over sodium sulfate, filtered and concentrated to give residue, which was subjected to a silica gel column eluting with petroleum ether/EtOAc (6:1 to 3:1) to give 3-(1-(5-chloropyrimidin-2-yl)cyclopropyl)-5-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-hydroxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)oxazolidin-2-one (130 mg, 0.087 mmol, 17%) as a white solid. LC/MS: m/z calculated 663.4. found 664.3 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][CH:38]=[CH:37][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:19][CH:18]2[O:33][CH2:34][C:35]#[CH:36])=[CH:13][CH:12]=1.I[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[NH:48][S:49]([CH3:52])(=[O:51])=[O:50].O>CN(C)C=O.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:52][S:49]([N:48]1[C:43]2[C:42](=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:36]=[C:35]1[CH2:34][O:33][CH:18]1[CH:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]3[CH:37]=[CH:38][CH:39]=[CH:40][C:3]=3[O:2][CH3:1])=[CH:16][CH:15]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:19]1)(=[O:51])=[O:50]
Reactant: CS(=O)(=O)Nc1ccccc1I
Reactant: C#CCOC1CN(C(=O)OCc2ccccc2)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2cc3ccccc3n2S(C)(=O)=O)cc1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
The solution of 0.108 g of benzyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-prop-2-ynyloxypiperidine-1-carboxylate, 0.098 g of N-(2-iodophenyl)methanesulphonamide in 0.5 ml of N,N-dimethylformamide and 1.0 ml of triethylamine are admixed with stirring with 0.011 g of bis(triphenylphosphine)palladium(II) chloride and 0.005 g of copper(I) iodide. The reaction mixture is stirred at 80° C. over 20 hours, then cooled, admixed with water (5 ml) and extracted with ethyl acetate (3×5 ml). The organic phases are washed with brine (1×5 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as an orange oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.13 (1:2 EtOAc-heptane); Rt=6.07.
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:4]=2[N:3]=1.CO.O.[NH2:23]N>C(O)(=O)C>[NH:1]([C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:5]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:4]=2[N:3]=1)[NH2:23]
Reactant: NN
Reactant: Cc1ccc2c(c1)C(c1ccccc1)=NCC(N)=N2
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: Cc1ccc2c(c1)C(c1ccccc1)=NCC(NN)=N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2.5 parts of 2-amino-7-methyl-5-phenyl-3H-1,4-benzodiazepine, 100 parts by volume of methanol and 1.2 parts of glacial acetic acid is added 2.5 parts of 100% hydrazine hydrate. The mixture is stirred for 1 hour at room temperature and treated in a similar manner to Example 1, whereby 2-hydrazino-7-methyl-5-phenyl-3H-1,4-benzodiazepine is yielded as crystals. Recrystallization from a mixture of chloroform and diethyl ether affords colorless crystals melting at 240° C to 241° (decomposition).
Reaction SMILES: COC(C1C=C(OC2C=CC(S(C)(=O)=O)=CC=2)C=C2OC(C)CC=12)=O.[C:26]([O:30][C:31]([C:33]1[CH:43]=[C:42]([OH:44])[C:36]2[CH2:37][CH:38]([CH2:40][OH:41])[O:39][C:35]=2[CH:34]=1)=[O:32])([CH3:29])([CH3:28])[CH3:27].[N:45]1([C:49]([C:51]2[CH:56]=[CH:55][C:54](F)=[CH:53][C:52]=2[F:58])=[O:50])[CH2:48][CH2:47][CH2:46]1>>[C:26]([O:30][C:31]([C:33]1[CH:43]=[C:42]([O:44][C:54]2[CH:55]=[CH:56][C:51]([C:49]([N:45]3[CH2:48][CH2:47][CH2:46]3)=[O:50])=[C:52]([F:58])[CH:53]=2)[C:36]2[CH2:37][CH:38]([CH2:40][OH:41])[O:39][C:35]=2[CH:34]=1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)c1cc(O)c2c(c1)OC(CO)C2
Reactant: O=C(c1ccc(F)cc1F)N1CCC1
Agent: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2c1CC(C)O2
Product: CC(C)(C)OC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)c(F)c2)c2c(c1)OC(CO)C2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-hydroxy-2-hydroxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (200f) and azetidin-1-yl-(2,4-difluoro-phenyl)-methanone. 1H NMR (400 MHz, CDCl3) δ 1.57 (s, 9 H) 2.26-2.38 (m, 2 H) 3.06-3.17 (m, 1 H) 3.67-3.78 (m, 1 H) 3.81-3.90 (m, 1 H) 4.09-4.18 (m, 3 H) 4.18-4.25 (m, 2 H) 4.92-5.02 (m, 1 H) 6.63-6.68 (m, 1 H) 6.78 (dd, J=8.59, 2.27 Hz, 1 H) 7.21 (d, J=1.26 Hz, 1 H) 7.49-7.56 (m, 1 H) 8.02 (s, 1 H); LCMS for C24H24FNO6 m/z 444.00 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[OH-].[Na+].[C:15](=[S:17])=[S:16].[CH3:18]I>CN(C)C=O.O>[NH:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:15](=[S:17])[S:16][CH3:18])=[CH:11][CH:10]=2)[CH2:5][CH2:6][C:7]1=[O:12]
Reactant: S=C=S
Reactant: CI
Reactant: Nc1ccc2c(c1)CCC(=O)N2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CSC(=S)Nc1ccc2c(c1)CCC(=O)N2
Temperature: 25 °C

Procedure:
To a solution of 6-amino-3,4-dihydrocarbostyril (3.24 g) in dimethylformamide (10 ml) is added 20N aqueous sodium hydroxide (1.2 ml) with stirring at room temperature. To the mixture is further added carbon disulfide (1.57 ml), and the mixture is stirred at the same temperature for 1 hour. To the reaction mixture is added methyl iodide (1.56 ml) under ice-cooling, and the mixture is stirred at the same temperature for 2.5 hours. After the reaction, the reaction mixture is poured into water, and the resulting precipitate is separated by filtration, washed with water, purified by silica gel column chromatography (solvent; chloroform:methanol=100:1), and recrystallized from methanol twice to give methyl (3,4-dihydrocarbostyril-6-yl)-dithiocarbamate (2.0 g) as yellow needles, m.p. 203.5°-205.0° C.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4][C@H:3]1[NH2:13].[C:14](=S)=[S:15].O>C(O)C>[F:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C@H:2]1[NH:1][C:14](=[S:15])[NH:13][C@@H:3]1[CH2:4][CH2:5]2
Reactant: N[C@@H]1CCc2cc(F)ccc2[C@H]1N
Reactant: S=C=S
Solvent: CCO
Solvent: O
Product: Fc1ccc2c(c1)CC[C@H]1NC(=S)N[C@H]21
Yield: 82 %

Procedure:
Trans-1,2-diamino-6-fluoro-1,2,3,4-tetrahydronaphthalene (3.84 g, 21.3 m mol) was dissolved in ethanol (40 ml) and carbon disulfide (1.4 ml, 23.4 m mol) was added to the solution. After the resulting white suspension was stirred for a while, water (20 ml) was added to the suspension and they were heated under reflux for 30 minutes. The reaction mixture was cooled with ice and the precipitate was filtered. The solid was washed in turn with water (three portions of 20 ml, totaling 60 ml), ethyl ether (20 ml) and n-hexane (50 ml) and dried under vacuum to give trans-7-fluoro-3a,4,5,9b-tetrahydronaphth[1,2-d]imidazoline-2-thione as a yellowish grey solid (3.88 g, 17.4 m mol) in 82% yield. The product was recrystallized from acetone-acetonitrile to give light-yellow needles melting at 256.5° to 257.5° C. (decomposition). The data on spectroscopy were as follows:
Reaction SMILES: C1[C:14]2[C:5](=C[C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)C=CC=1.CI.[Mg].C1[C:31]2[C:22](=C[C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)C=CC=1.[Mg].C1C2C(=CC=CC=2)C=C1.CC(CC(C)=O)=O.CC(CC(C)=O)=O.CC(CC(C)=O)=O.[Co:63]>C1COCC1>[CH:22]1([Co:63][CH:5]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:13]=[CH:14]2)[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[CH:31]1
Reactant: c1ccc2cc3ccccc3cc2c1
Reactant: [Co]
Agent: C1=Cc2ccccc2C1
Agent: [Mg]
Solvent: CI
Solvent: C1CCOC1
Solvent: CC(=O)CC(C)=O
Product: C1=CC([Co]C2C=Cc3ccccc32)c2ccccc21
Temperature: 23 °C

Procedure:
1.1 g (6.2 mMoles) of anthracene, 350 ml of THF and 0.1 ml of methyliodide are added to 14.4 g (600 mMoles) of magnesium powder (particle size <0.15 mm) in an inert gas atmosphere. A yellow-brown solution is formed while stirring at 23° C., orange-colored magnesium anthracene precipitating therefrom after 100 minutes. The reaction mixture is treated for about 3 hours in an ultrasonic bath (continuous peak HF output 240 watts, 35 kHz) and subsequently heated with stirring to 60° C. After the addition of 34.8 g (300 mMoles) of indene, the heat source is removed and 35.6 g (100 mMoles) of solid cobalt-(III) acetylacetonate are added over a period of 40 minutes. The reaction mixture changes color to dark brown with an increase in temperature to 68° C. After cooling to 23° C., the reaction mixture is filtered off from excess magnesium through a G-3-glass frit and the clear brown red filtrate is concentrated by evaporation to dryness (max. bath temperature 30° C.) in a high vacuum (10-3Torr). The residue is taken up in 500 ml of pentane and any insoluble fractions are isolated by filtration through a G-3-glass frit. The filter cake is washed several times with a total of 500 ml of pentane until the filtrate is substantially colorless. The clear red-brown filtrate is concentrated to approximately 200 ml and the complex left to crystallize out at -80° C. The supernatant mother liquor is removed under pressure and washed 2 to 3 times with approximately 50 ml of pentane cooled to -80° C. Drying in vacuo (0.1 Torr) gives 10.3 g (35 mMoles=35.5% of the theoretical) of bis-(indenyl)-cobalt in the form of glittering black crystals.
Reaction SMILES: Br[C:2]1[C:3]([CH3:17])=[C:4]([O:14][CH2:15][CH3:16])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[C:12]=1[CH3:13].[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1>>[CH2:15]([O:14][C:4]1[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[C:12]([CH3:13])=[C:2]([N:28]2[CH2:27][CH2:26][N:25]([C:22]3[CH:21]=[CH:20][C:19]([F:18])=[CH:24][CH:23]=3)[CH2:30][CH2:29]2)[C:3]=1[CH3:17])[CH3:16]
Reactant: CCOc1c(C)c(Br)c(C)c2c1OC(C)(C)C2
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: CCOc1c(C)c(N2CCN(c3ccc(F)cc3)CC2)c(C)c2c1OC(C)(C)C2
Yield: 40.8 %

Procedure:
By using 5-bromo-7-ethoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran (600 mg, 2.01 mmol) synthesized in Reference example 98 and 1-(4-fluorophenyl)piperazine (723 mg, 4.01 mmol), the reaction was carried out in the same manner as Example 1 to synthesize the title compound 327 mg (yield 41%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:7][C:6]=2[CH:14]=1.C([Li])CCC.CN(C)[CH:22]=[O:23].[Cl-].[NH4+]>C(OCC)(=O)C.O1CCCC1>[F:11][C:10]([F:13])([F:12])[C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([CH:22]=[O:23])=[CH:14][C:6]=2[CH:7]=1
Reactant: FC(F)(F)c1cc2cc(Br)ccc2o1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=Cc1ccc2oc(C(F)(F)F)cc2c1
Temperature: 25 °C
Yield: 38 %

Procedure:
To a tetrahydrofuran solution (12 mL) of 5-bromo-2(trifluoromethyl)benzofuran (587 mg, 2.21 mmol), n-butyl lithium (hexane solution, 1.59 mol/L) (1.70 mL, 2.66 mmol) was added at −78° C. and the resultant solution was stirred for 40 minutes. To the reaction solution, N,N-dimethylformamide (257 μL, 3.32 mmol) was added and the resultant mixture was stirred for 3 hours while the temperature of the mixture was raised to room temperature. After completion of the reaction, saturated ammonium chloride aqueous solution was added to the reaction solution and extraction with ethyl acetate from the resultant mixture was performed. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (180 mg, yield 39%).
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].[Cl:8][C:9]1[N:10]=[C:11]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:12]2[CH2:17][NH:16][CH2:15][C:13]=2[N:14]=1.CCN(CC)CC.C(Cl)(=O)C.[OH-].[Na+]>CN(C=O)C>[Cl:8][C:9]1[N:10]=[C:11]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:12]2[CH2:17][N:16]([C:3](=[O:4])[CH3:2])[CH2:15][C:13]=2[N:14]=1
Reactant: Clc1nc2c(c(N3CCOCC3)n1)CNC2
Reactant: O=C(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CC(=O)Cl
Product: CC(=O)N1Cc2nc(Cl)nc(N3CCOCC3)c2C1
Temperature: 20 °C
Reaction time: 0.03 h

Procedure:
To a stirring solution of 4-(2-chloro-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)morpholine trifluoroacetate (intermediate 20) (2.16 g, 2.0 mmol) in DMF (10 ml), was added Et3N (560 uL, 4.0 mmol). Reaction mixture was stirred at room temperature (20° C.) for 2 minutes followed by the addition of acetyl chloride (157 uL, 2.2 mmol) followed by stirring at room temperature overnight. The reaction mixture was basified (with 2M NaOH) before partitioning between water (25 ml) and DCM (50 ml). The organic layer was recovered, passed through a hydrophobic frit and the solvent removed in vacuo, affording the title compound as a pink solid, which was used without further purification.
Reaction SMILES: [O-]CC.[Na+].[C:5]([CH2:7][C:8]([NH2:10])=[O:9])#[N:6].[N:11]1([CH2:17][C:18]#[C:19][C:20](=O)[CH3:21])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.Cl>CCO>[CH3:21][C:20]1[NH:10][C:8](=[O:9])[C:7]([C:5]#[N:6])=[C:18]([CH2:17][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:19]=1
Reactant: N#CCC(N)=O
Reactant: CC(=O)C#CCN1CCOCC1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(CN2CCOCC2)c(C#N)c(=O)[nH]1
Reaction time: 0.25 h
Yield: 32.3 %

Procedure:
To a stirred solution of 21 wt % sodium ethoxide in EtOH (4.2 g, 12.96 mmol) in EtOH (30 mL) was added 2-cyanoacetamide (1.1 g, 13.08 mmol). The reaction was stirred for 15 min then a solution of 5-(4-morpholinyl)-3-pentyn-2-one (2.0 g, 11.96 mmol) in EtOH was added to the reaction in one portion. (The reaction quickly turned dark red.) The reaction was stirred overnight at RT, neutralized with 6 N HCl (2.17 mL, 13.02 mmol) and evaporated to dryness under vacuum. Dried under vacuum overnight. The remaining dark solid was triturated with a solution of (9:1) CH2Cl2, MeOH (50 mL), filtered from insoluble material, washed with (9:1) CH2Cl2, MeOH, and the filtrate evaporated to dryness under vacuum. The dark solid was triturated with a solution of (1:1) EtOAc in hexanes, filtered, washed with (1:1) EtOAc in hexanes, and dried under vacuum to give a brown solid (removed a lot of fast running non-polar impurities). The crude product was purified by silica gel chromatography (Analogix, SF25-60 g, 0 to 15% CH2Cl2/20% (5% NH4OH in MeOH) in CH2Cl2). The pure fractions were combined, evaporated to dryness, triturated with hexanes and dried under vacuum to give the product 6-methyl-4-(4-morpholinylmethyl)-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (0.90 g, 3.86 mmol, 32.3% yield) as a light tan solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)[CH:2]=1.[CH3:16][O:17][C:18]([CH:20]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:19]>C(Cl)(Cl)Cl>[CH3:16][O:17][C:18](=[O:19])/[CH:20]=[CH:12]/[C:11]1[CH:14]=[CH:15][C:8]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:9][CH:10]=1
Reactant: O=Cc1ccc(Cc2cccnc2)cc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)/C=C/c1ccc(Cc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 45.3 %

Procedure:
A mixture of 200 mg of 4-(3-pyridylmethyl)benzaldehyde (prepared as described in Reference Example 1), 0.14 g of methoxycarbonylmethylenetriphenylphosphorane and 5 ml of chloroform was stirred at room temperature for 3 days, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using methylene chloride as eluent to give 48 mg of the title compound having the following physical characteristics:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:20]=[CH:19][C:7]([CH2:8][NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.Cl[C:24]1[N:29]=[CH:28][C:27]([CH2:30][CH3:31])=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>>[CH2:30]([C:27]1[CH:26]=[N:25][C:24]([N:9]([CH2:8][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:21])([F:22])[F:1])=[CH:20][CH:19]=2)[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:29][CH:28]=1)[CH3:31]
Reactant: CCc1cnc(Cl)nc1
Reactant: Oc1ccc(CCNCc2ccc(OC(F)(F)F)cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cnc(N(CCc2ccc(O)cc2)Cc2ccc(OC(F)(F)F)cc2)nc1
Yield: 76.2 %

Procedure:
Condensation of 4-(2-{[4-(trifluoromethoxy)benzyl]amino}ethyl)phenol (500 mg; 1.61 mmol) with 2-chloro-5-ethyl-pyrimidine (0.19 ml; 1.54 mmol) as per general procedure E (conditions: 5 ml of DIEA, 200C, 16 hr) provided the title compound (490 mg; 76% yield).