Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[CH:2].C(O)(=O)C1C=CC=CC=1.[CH2:28]([O:30][C:31](=[O:39])[C:32]1[CH:37]=[CH:36][C:35](I)=[CH:34][CH:33]=1)[CH3:29]>C(N(CC)CC)C.[Cu]I.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>[CH2:13]([N:12]([CH2:16][CH2:17][CH3:18])[C:9]1([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:35]3[CH:36]=[CH:37][C:32]([C:31]([O:30][CH2:28][CH3:29])=[O:39])=[CH:33][CH:34]=3)=[CH:4][CH:5]=2)[CH2:10][CH2:11]1)[CH2:14][CH3:15]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc(C2(N(CCC)CCC)CC2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C(O)c1ccccc1
Solvent: CCN(CC)CC
Product: CCCN(CCC)C1(c2ccc(C#Cc3ccc(C(=O)OCC)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure F; [1-(4-ethynylphenyl)-cyclopropyl]-dipropylamine (Intermediate 123, 34.0 mg, 0.16 mmol) and ethyl-4-iodo benzoate (Reagent A, 59.0 mg, 0.21 mmol) in triethyl amine (6 mL) was treated with copper(I)iodide (13.0 mg, 0.07 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (49 mg, 0.07 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-4% EtOAc-hexanes) afforded the title compound as a yellow oil.
Reaction SMILES: OC[N:3]1[C:7]2[N:8]=[CH:9][C:10]3[N:11]([C:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:21])[CH3:20])=[N:13][CH:14]=3)[C:6]=2[CH:5]=[C:4]1[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]([CH3:33])[CH:23]=1.[NH4+].[OH-]>CO>[CH3:32][O:31][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[N:24]([CH3:33])[CH:23]=[C:22]2[C:4]1[NH:3][C:7]2[N:8]=[CH:9][C:10]3[N:11]([C:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:21])[CH3:20])=[N:13][CH:14]=3)[C:6]=2[CH:5]=1
Reactant: COc1ccc2c(c1)c(-c1cc3c(ncc4cnc(CCCNC(C)=O)n43)n1CO)cn2C
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2c(c1)c(-c1cc3c(ncc4cnc(CCCNC(C)=O)n43)[nH]1)cn2C
Temperature: 60 °C
Yield: 20.9 %

Procedure:
To a solution of N-(3-(6-(hydroxymethyl)-7-(5-methoxy-1-methyl-1H-indol-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)propyl)acetamide (0.128 g, 0.287 mmol) in MeOH (3 mL) at rt was added 30 wt % aqueous NH4OH (0.37 mL, 2.87 mmol) and the mixture was heated to about 60° C. for about 30 min. The mixture was cooled to about 0° C. and was sonicated to provide a solid which was collected by filtration. The solid material was taken up in EtOAc (15 mL) and washed with water (10 mL). The organics were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by a 12 g silica column eluting with 0 to 10% MeOH in DCM to provide N-(3-(7-(5-methoxy-1-methyl-1H-indol-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)propyl)acetamide (0.025 g, 21%): LC/MS (Table 2, Method c) Rt=1.25 min; MS m/z 417 (M+H)+. Syk IC50=A
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[Cl:11][O-].[Ca+2].Cl[O-]>CC(C)=O.O.C(O)(=O)C>[Cl:11][C:8]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[C:4]([CH:7]=1)[CH:5]=[O:6]
Reactant: COc1ccccc1C=O
Reactant: [O-]Cl
Agent: [Ca+2]
Solvent: CC(=O)O
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(Cl)cc1C=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methoxybenzaldehyde (2g) in acetone (20 ml), water (40 ml) and acetic acid (4 ml) were added. Under ice cooling, calcium hypochlorite (5.25 g) was added, and then the mixture was stirred at that temperature for 1 hour and at room temperature for 2 hours. The reaction solution was extracted with methyl tert-butyl ether (20 ml×2), and the organic layer was washed with an aqueous sodium thiosulfate solution, then dried over magnesium sulfate. The solvent was distilled off in vacuo and the obtained residue was purified by slurry in heptane. The precipitated crystals were collected by filtration and dried in vacuo to obtain the title compound in an amount of 2.2 g as a colorless crystal.
Reaction SMILES: [N:1]1([C:10]2[C:11]([C:16]#[N:17])=[N:12][CH:13]=[CH:14][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1>N.[Ni]>[N:1]1([C:10]2[C:11]([CH2:16][NH2:17])=[N:12][CH:13]=[CH:14][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: N#Cc1ncccc1-n1ccc2ccccc21
Agent: [Ni]
Agent: N
Product: NCc1ncccc1-n1ccc2ccccc21
Reaction time: 4 h
Yield: 57.3 %

Procedure:
A mixture of 3-indol-1-yl-pyridine-2-carbonitrile (164 mg, 0.75 mmol) in NH3 saturated MeOH (6 mL) was treated with Raney nickel (0.25 g), and placed under 40 psi H2 on a Parr shaker, for 4 h. The mixture was filtered through celite and the cake was washed with methanol. The eluant was concentrated under reduced pressure. Purification of the crude material by column chromatography on silica gel (CH2Cl2-MeOH, 96:4 then 9:1) provided 96 mg (57%) of C-(3-Indol-1-yl-pyridin-2-yl)-methylamine as a clear oil. 1H NMR (CDCl3) δ 1.65 (br s, 2H), 3.72 (s, 2H), 6.73 (d, 1H, J=3.3 Hz), 6.95-7.03 (m, 1H), 7.16-7.21 (m, 3H), 7.38 (dd, 1H, J=9, 6 Hz), 7.66-7.71 (m, 2H), 8.71 (d, 1H, J=4.5 Hz).
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:29]2[O:30][CH:31]=[CH:32][C:33]=2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][N:12]([CH:13]([CH3:15])[CH3:14])[C:11]1[C:2]([C:29]2[O:30][CH:31]=[CH:32][C:33]=2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:5]=2
Reactant: CC1(C)OB(c2occc2-c2ccccc2)OC1(C)C
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3occc3-c3ccccc3)c(N(C)C(C)C)nc2c1
Temperature: 95 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
To a solution of methyl 2-chloro-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (140 mg, 0.48 mmol) in dioxane (5.0 mL) and water (3 drops) was added 4,4,5,5-tetramethyl-2-(3-phenylfuran-2-yl)-1,3,2-dioxaborolane (270 mg, 1.00 mmol), K3PO4 (211 mg, 0.99 mmol) and Pd(PPh3)4 (28 mg, 0.02 mmol) with stirring for 1 h at 95° C. in an oil bath maintained under an inert atmosphere of nitrogen. The reaction mixture was concentrated under vacuum to give a residue, which was purified by silica gel chromatography (2% ethyl acetate in petroleum ether) to afford methyl 3-[methyl(propan-2-yl)amino]-2-(3-phenylfuran-2-yl)quinoxaline-6-carboxylate as a light yellow solid (140.0 mg, 73%).
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]([CH2:8]Br)=[CH:6][CH:7]=1)#[N:2].[N-:10]=[N+:11]=[N-:12].[Na+].C(OCC)(=O)C>CN(C=O)C.CCCCCC>[C:1]([C:3]1[S:4][C:5]([CH2:8][N:10]=[N+:11]=[N-:12])=[CH:6][CH:7]=1)#[N:2]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(CBr)s1
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(CN=[N+]=[N-])s1
Yield: 82.7 %

Procedure:
A solution of 2-cyano-5-(bromomethyl)thiophene (compound 24, 3.5 g, 17.3 mmol) and sodium azide (Aldrich, 1.7 g, 26 mmol) in DMF (Aldrich, 60 ml) was stirred at ambient temperature for 10 hours. Flash column chromatography (20% ethyl acetate in hexane) resulted the title compound (2.35 g, 83%). TLC: Rf 0.48 (20% of ethyl acetate in hexane); 1H NMR (CDCl3): δ 4.56 (s, 2H), 7.01 (d, 1H, J=3.7 Hz), 7.55 (d, 1H, J=3.7 Hz).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Co+3:5].[C:6]([O-:9])(=[O:8])[CH3:7].C([O-])(=O)C>C(O)(=O)C>[C:1]([O-:4])(=[O:3])[CH3:2].[Co+2:5].[C:6]([O-:9])(=[O:8])[CH3:7]
Reactant: [Co+3]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: [Co+2]

Procedure:
Experiments conducted at 120° C. using just Cobalt (III) acetate without any promoters in air and using acetic acid as solvent resulted in much quicker oxidation than Cobalt (II) acetate with the promoters as described above, leading to rapid consumption of xylenes, as indicated by the green solution turning pink-purple after approximately an hour. Under identical reaction conditions using Co(II) there was a long induction period before any early phase oxidation.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:6](=[CH:7][N:8](COCC[Si](C)(C)C)[N:9]=2)[CH:5]=[C:4]([CH2:19][O:20][CH2:21][C:22]2([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]2)[CH:3]=1>FC(F)(F)C(O)=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:19][O:20][CH2:21][C:22]2([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]2)[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2
Reactant: Cc1cc(COCC2(c3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)cc2cn(COCC[Si](C)(C)C)nc12
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COCC2(c3ccccc3)CCNCC2)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 4-(((7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (170 mg, 0.300 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 5 mL) and stirred at room temperature for 2 h. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2M ammonia in methanol and concentrated to give 95 mg (94%) as an amorphous solid. 1H-NMR (CDCl3, 500 MHz) δ 7.98 (s, 1H), 7.31-7.40 (m, 4H), 7.29 (s, 1H), 7.24 (m, 1H), 6.88 (s, 1H), 4.42 (s, 2H), 3.45 (s, 1H), 3.41 (s, 2H), 2.95 (m, 2H), 2.77 (m, 2H), 2.46 (s, 3H), 2.17 (m, 2H), 1.97 (m, 2H); 13C NMR (126 MHz, CDCl3) δ ppm 144.3, 140.3, 134.8, 131.5, 128.4, 127.4, 126.8, 126.1, 122.8, 120.0, 117.0, 79.2, 73.6, 50.4, 42.6, 41.9, 33.3, 17.1. Mass spec.: 336.31 (MH)+. Accurate mass spec.: m/z 336.2090 [MH]+, Δ=4.2 ppm.
Reaction SMILES: OC(C(F)(F)F)=O.[N:8]1([C:15]([C:17]2[CH:18]=[C:19]([CH:32]=[CH:33][C:34]=2[F:35])[CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:31])[NH:23][N:22]=2)=[O:16])[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[O:36]=[C:37]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:38](O)=[O:39].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:35][C:34]1[CH:33]=[CH:32][C:19]([CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:31])[NH:23][N:22]=2)=[CH:18][C:17]=1[C:15]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:38](=[O:39])[C:37]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:36])[CH2:10][CH2:9]1)=[O:16]
Reactant: O=C(O)C(=O)c1ccccc1
Reactant: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(C(=O)N1CCCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 85 h
Yield: 42 %

Procedure:
4-(3-(1,4-diazepane-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one TFA salt (320 mg, 0.65 mmol), 2-oxo-2-phenylacetic acid (1.4 g, 9.32 mmol), DIPEA (3 ml, 17.4 mmol), and HATU (1.8 g, 4.72 mmol) were mixed in DMF (50 ml). After the resulting reaction mixture was stirred at room temperature for 85 h, the reaction mixture was partition between DCM and water (100 ml each). The aqueous phase was extracted with DCM (100 ml), and the combined organic phase was washed with water, sat. aqueous sodium bicarbonate, and brine, dried over sodium sulphate, filtered, and concentrated to yield the crude product. Then the crude product was purified by preparative TLC (Petroleum ether:Ethyl Acetate=1:1 to 1:2) to afford the desired product (140 mg, 41%) as a light yellow solid.
Reaction SMILES: [N:1]1([CH2:6][C:7]([N:9]2[CH2:13][C:12](=[CH:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:11][C@H:10]2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)=[CH:27][CH:26]=2)=[O:23])=[O:8])[CH:5]=[N:4][CH:3]=[N:2]1>[Pd].CO>[N:1]1([CH2:6][C:7]([N:9]2[CH2:13][C@@H:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:11][C@H:10]2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)=[CH:27][CH:26]=2)=[O:23])=[O:8])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1CC(=Cc2ccc(F)cc2)CN1C(=O)Cn1cncn1
Agent: [Pd]
Solvent: CO
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@H](Cc2ccc(F)cc2)CN1C(=O)Cn1cncn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.4 %

Procedure:
Step (c) A flask was charged with (S)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(4-fluorobenzylidene)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (15 mg, 0.027 mmol), palladium on carbon (10%, 50 mg) and methanol (5 mL) and the mixture was placed under a hydrogen atmosphere (balloon). The mixture was stirred for 2 hours at ambient temperature and then concentrated. Product was purified from the residue by chromatography (EtOAc to EtOAc/MeOH (9:1)+1% NEt3) to give Compound 76, (2S,4S)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (10 mg, 0.019 mmol, 69%), as an off-white solid. 1H-NMR (400 MHz, CDCl3): 8.61 (s, 1H), 8.22 (s, 1H), 7.98 (s, 1H), 7.45 (d, J=10.0 Hz, 2H), 7.18-7.14 (m, 2H), 7.03-6.91 (m, 8H), 5.00 (m, 2H), 4.62 (m, 1H), 3.76 (dd, J=11.2, 7.6 Hz, 1H), 3.25 (m, 1H), 2.85 (dd, J=12.8, 7.6 Hz, 1H), 2.73 (dd, J=12.8, 7.6 Hz, 1H), 2.57 (m, 1H), 2.30 (m, 2H). MS (EI) for C28H25F2N5O3. found 518.2 (MH+).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[N:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][CH:8]=1>C(Cl)Cl>[Cl:3][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([O:6][CH3:5])=[N:12][CH:11]=1
Reactant: COc1ccc(CO)cn1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(CCl)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 216.1 %

Procedure:
Thionyl chloride (0.23 ml, 3.23 mmol) was added to a solution of (6-methoxypyridin-3-yl)methanol (1.10 g, 8.41 mmol) in DCM at 0° C. and the reaction mixture was stirred for 2 h at room temperature. After completion of reaction, the volatiles were evaporated and the reaction mixture was basified with saturated sodium bicarbonate solution. The compound was extracted with DCM (2×30 ml) and washed with brine (15 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and dried to afford 1.1 g (88%) of 5-(chloromethyl)-2-methoxypyridine as a colorless liquid. This compound was directly taken to the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21][N:22]2C(=O)C3=CC=CC=C3C2=O)=[N:19][N:18]=[C:17]1[CH2:33][CH2:34][N:35]([CH3:37])[CH3:36].NN>C(O)C>[CH3:36][N:35]([CH3:37])[CH2:34][CH2:33][C:17]1[N:16]2[C:10]3[CH:11]=[CH:12][C:13]([F:15])=[CH:14][C:9]=3[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:22][CH2:21][C:20]2=[N:19][N:18]=1
Reactant: CN(C)CCc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc(F)cc1C(=O)c1ccccc1Cl
Agent: NN
Solvent: CCO
Product: CN(C)CCc1nnc2n1-c1ccc(F)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 1C, 2'-chloro-5-fluoro-2-[3-[2-(dimethylamino)ethyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone in ethanol is refluxed with hydrazine to give 1-[2-(dimethylamino)ethyl]-8-fluoro-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [C-:1]#[N:2].[K+].[F:4][CH:5]([F:15])[O:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Br)=[CH:9][CH:8]=1>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:4][CH:5]([F:15])[O:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][C:1]#[N:2])=[CH:9][CH:8]=1
Reactant: FC(F)Oc1ccc(CBr)cc1
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: N#CCc1ccc(OC(F)F)cc1
Temperature: 100 °C
Yield: 81.6 %

Procedure:
100 g of potassium cyanide were dissolved in 160 ml of water, and 15 g of tetrabutylammonium bromide and 230 g of 4-difluoromethoxy-benzyl bromide were then added. The mixture was then heated to 100° C. for 1 hour and, after cooling, was extracted twice with methylene chloride. After drying over sodium sulphate, the organic phase was first freed from solvent and then distilled. 145 g of 4-difluoromethoxy-benzyl cyanide were obtained. Boiling point=106°-8° C./0.3 mm Hg; nD20 =1.4822.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]([CH2:21][CH3:22])[C:6](=[O:20])[O:7][C:8]1[C:17]([Cl:18])=[C:16]2[C:11]([CH2:12][CH2:13][NH:14][C:15]2=[O:19])=[CH:10][CH:9]=1)[CH3:4].[CH2:23]([O:30][C:31]1[C:36]([CH2:37]Cl)=[C:35]([CH3:39])[CH:34]=[C:33]([CH3:40])[N:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C=O)C>[CH2:21]([N:5]([CH2:3][CH3:4])[C:6](=[O:20])[O:7][C:8]1[C:17]([Cl:18])=[C:16]2[C:11]([CH2:12][CH2:13][N:14]([CH2:37][C:36]3[C:31]([O:30][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:32][C:33]([CH3:40])=[CH:34][C:35]=3[CH3:39])[C:15]2=[O:19])=[CH:10][CH:9]=1)[CH3:22]
Reactant: CCN(CC)C(=O)Oc1ccc2c(c1Cl)C(=O)NCC2
Reactant: Cc1cc(C)c(CCl)c(OCc2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)Oc1ccc2c(c1Cl)C(=O)N(Cc1c(C)cc(C)nc1OCc1ccccc1)CC2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.3 %

Procedure:
To a suspension of NaH (2.2 g, 54 mmol, 60% in oil) in dry DMF (20 mL) was added dropwise a solution of 8-chloro-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl diethylcarbamate (1f, 8.0 g, 27 mmol) in dry DMF (40 mL) at 0° C. under N2. The mixture was stirred at 0° C. for 15 minutes. 2-(Benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine (Cpd Z, 8.5 g, 32.4 mmol) was added. The mixture was stirred at room temperature overnight. To the reaction mixture was added dropwise H2O (200 mL) carefully. The mixture was extracted with EtOAc (2×150 mL). The combined organic layers were washed with brine (4×200 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/EtOAc, 3:1) to give 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-chloro-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl diethylcarbamate (1g, 14 g, 99%) as yellow oil.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6](=[O:28])[CH:7]([CH:13]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)[CH3:14])[C:8]([O:10]CC)=[O:9])[CH3:4].CCOC(C)=O>CCO.C(Cl)Cl>[CH2:3]([O:5][C:6](=[O:28])[CH:7]([CH:13]([CH:15]1[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:19][CH2:20]1)[CH3:14])[C:8]([OH:10])=[O:9])[CH3:4]
Reactant: CCOC(=O)C(C(=O)OCC)C(C)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(=O)O)C(C)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 119.9 %

Procedure:
A solution of KOH (84 mg, 1.16 mmol) in EtOH (2 mL) was added dropwise to a solution of 2-[1-(1-tert-butoxycarbonyl-piperidin-4-yl)-ethyl]-malonic acid diethyl ester (0.39 g, 1.01 mmol) in methylene chloride (4 mL) and EtOH (10 mL) at 0° C. The resulting mixture was stirred at room temperature over night. EtOAc was added and the mixture was washed with 0.5 M HCl and brine, dried and concentrated under reduced pressure to give 416 mg of crude 2-[1-(1-tert-butoxycarbonyl-piperidin-4-yl)-ethyl]-malonic acid monoethyl ester.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH:16]([NH:19][CH3:20])[CH2:15][CH2:14]2)=O)=[CH:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][N:13]2[CH2:14][CH2:15][CH:16]([NH:19][CH3:20])[CH2:17][CH2:18]2)=[CH:2]1
Reactant: CNC1CCN(C(=O)Cc2coc3ccccc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CNC1CCN(CCc2coc3ccccc23)CC1
Reaction time: 48 h

Procedure:
7.2 g of the product obtained in Step C are added to a suspension of 2 g of LiAlH4 in 210 ml of tetrahydrofuran. After 48 hours at room temperature, the reaction mixture is hydrolysed with 1.4 ml of water, 1.1 ml of 20% sodium hydroxide solution and 5 ml of water. After filtration and concentration, chromatography over silica gel enables the expected product to be isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[S:14][C:13]([CH:15](O)[CH3:16])=[CH:12][C:11]=1[N+:18]([O-:20])=[O:19].[Br:21]P(Br)Br>ClCCl>[Br:21][CH:15]([C:13]1[S:14][C:10]([S:9][C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[C:11]([N+:18]([O-:20])=[O:19])[CH:12]=1)[CH3:16]
Reactant: BrP(Br)Br
Reactant: CC(O)c1cc([N+](=O)[O-])c(Sc2ccc(Cl)cc2Cl)s1
Solvent: ClCCl
Product: CC(Br)c1cc([N+](=O)[O-])c(Sc2ccc(Cl)cc2Cl)s1
Temperature: 25 °C
Yield: 113.9 %

Procedure:
To a solution of 1-[5-(2,4-dichlorophenyl)sulfanyl-4-nitro-2-thienyl]ethanol from example 26 (0.6 g, 1.7 mmol) in dichloromethane (10 mL), was added tribromophosphane (0.28 mL, 2.55 mmol). The resulting reaction mixture was kept under reflux for 2 hours. After this time, the reaction mixture was cooled to ambient temperature, quenched with sat'd sodium carbonate aqueous solution and extracted with ethyl acetate. The combined organic phase was dried (Na2SO4) and concentrated to afford the title compound (800 mg). The crude product was used as such for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[N:6][CH:7]=1.Br[C:16]1[CH:17]=[CH:18][C:19]2[C:20]3[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26][C:21]=3[N:22]([CH3:25])[C:23]=2[CH:24]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]([C:16]3[CH:17]=[CH:18][C:19]4[C:20]5[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26][C:21]=5[N:22]([CH3:25])[C:23]=4[CH:24]=3)[C:10](=[O:14])[CH:9]=2)=[N:6][CH:7]=1
Reactant: O=c1cc(-c2ccc(Cl)cn2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(Cl)cn5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 30.3 %

Procedure:
4-(5-Chloropyridin-2-yl)pyridin-2(1H)-one (111 mg, 0.537 mmol) and tert-butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (200 mg, 0.54 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (80 mg, 30%) as a green solid: 1H NMR (500 MHz, CDCl3) δ 8.69 (d, J=2.2 Hz, 1H), 7.79 (dd, J=8.5, 2.4 Hz, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.53 (d, J=7.2 Hz, 2H), 7.36 (d, J=1.5 Hz, 1H), 7.17 (d, J=1.5 Hz, 1H), 7.07 (d, J=7.4 Hz, 1H), 6.98 (dd, J=7.1, 1.8 Hz, 1H), 4.65 (br s, 2H), 3.85 (br s, 2H), 3.65 (s, 3H), 2.83 (br s, 2H), 1.50 (s, 9H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][C:7]2([CH3:15])[CH3:14].Cl[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][N:18]=1>CS(C)=O>[CH3:14][C:7]1([CH3:15])[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([O:3][C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][N:18]=3)[CH:5]=2)[C:9](=[O:13])[CH2:8]1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC1(C)CC(=O)c2ccc(O)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(C)CC(=O)c2ccc(Oc3ccc(C#N)cn3)cc21
Temperature: 25 °C
Yield: 70.7 %

Procedure:
Add NaH (60%/oil, 196 mg, 4.91 mmol) to a mixture of 5-hydroxy-3,3-dimethyl-1-indanone (787 mg, 4.46 mmol) and DMSO (10 ml) stirring at ambient temperature under nitrogen. After ten minutes, add 6-chloronicotinonitrile (619 mg, 4.46 mmol) dissolved in DMSO (10 ml) and stir the resulting mixture at 60° C. overnight. Quench the reaction with saturated aqueous NH4Cl and extract with EtOAc (2×). Wash extract with water and brine, dry (MgSO4) and concentrate on rotary evaporator to a brown, oily solid. Purify on silica gel (10% EtOAc/DCM) to give 877 mg of 6-(3,3-Dimethyl-1-oxo-indan-5-yloxy)-nicotinonitrile as a yellow solid.