Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH:22]=2)[CH:5]=[C:6]([CH3:16])[C:7]=1OS(C(F)(F)F)(=O)=O.[CH3:30][N:31](C)C=O>CCOCC.[C-]#N.[Zn+2].[C-]#N.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>[C:30]([C:7]1[C:2]([CH3:1])=[CH:3][C:4]([C:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH:22]=2)=[CH:5][C:6]=1[CH3:16])#[N:31]
Reactant: Cc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc(C)c1OS(=O)(=O)C(F)(F)F
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOCC
Product: Cc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc(C)c1C#N
Temperature: 100 °C

Procedure:
A mixture of tert-butyl 4-(3,5-dimethyl-4-[(trifluoromethyl)sulfonyl]oxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (2.80 g, 0.00643 mol) and zinc cyanide (1.51 g, 0.0128 mol) in N,N-dimethylformamide (15.0 mL, 0.194 mol)was degassed with nitrogen for 15 min. To the mixture was added tetrakis(triphenylphosphine)palladium(0) (0.74 g, 0.00064 mol). The reaction mixture was heated at 100 Celsius for 4 h. The mixture was diluted with ether, washed with aq. sodium bicarbonate, brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified on silica gel, eluting with 0 to 10% EtOAc in hexane, to generate the titled compound (1.08 g, 53.66%). LCMS (M+H) 313.1
Reaction SMILES: C([O:4][C@@H:5]([C:30]([NH:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=1)=[O:31])[C@@H:6](CC([O-])=O)[C:7]([N:9]([C:17]1[CH:25]=[C:24]2[C:20]([CH:21]=[CH:22][NH:23]2)=[CH:19][CH:18]=1)[CH2:10][CH2:11][O:12]S(C)(=O)=O)=[O:8])(=O)C.C([O-])([O-])=O.[K+].[K+].Cl.O>CO.CCOCC>[C:39]([C:36]1[CH:37]=[CH:38][C:33]([NH:32][C:30](=[O:31])[C@H:5]([OH:4])[C@H:6]2[O:12][CH2:11][CH2:10][N:9]([C:17]3[CH:25]=[C:24]4[C:20]([CH:21]=[CH:22][NH:23]4)=[CH:19][CH:18]=3)[C:7]2=[O:8])=[CH:34][CH:35]=1)#[N:40]
Reactant: CC(=O)O[C@@H](C(=O)Nc1ccc(C#N)cc1)[C@@H](CC(=O)[O-])C(=O)N(CCOS(C)(=O)=O)c1ccc2cc[nH]c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: N#Cc1ccc(NC(=O)[C@H](O)[C@H]2OCCN(c3ccc4cc[nH]c4c3)C2=O)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 17.2 %

Procedure:
To a solution of compound 18-2 (0.34 g) in MeOH (10.2 mL), was added K2CO3 (272 mg) at 0° C. The reaction mixture was stirred at 0° C. overnight. Then 1N HCl (2 mL), H2O (5 mL) and Et2O (15 mL) were added into the reaction mixture. The precipitate was collected by filtration and was rinsed with H2O and Et2O to obtain compound 18-3 (40 mg) as a colorless amorphous solid.
Reaction SMILES: [CH:1]1[CH:6]=[N:5][C:4]2[N:7]([OH:10])[N:8]=[N:9][C:3]=2[CH:2]=1.[C:11]1([S:17](Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([S:17]([O:10][N:7]2[C:4]3[N:5]=[CH:6][CH:1]=[CH:2][C:3]=3[N:9]=[N:8]2)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: On1nnc2cccnc21
Product: O=S(=O)(On1nnc2cccnc21)c1ccccc1

Procedure:
HOAt is reacted with phenylsulfonyl chloride in accordance with the procedure described in Example 2 to afford the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([C:8]([N:10]2[CH2:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[S:13][C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)=[O:9])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO>[NH2:1][C:4]1[CH:26]=[CH:25][C:7]([C:8]([N:10]2[CH2:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[S:13][C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2ccccc2Sc2ccccc21
Reactant: [H][H]
Solvent: CO
Product: Nc1ccc(C(=O)N2Cc3ccccc3Sc3ccccc32)cc1
Yield: 89.2 %

Procedure:
A mixture of 2.2 g of 10,11-dihydro-10-(4-nitrobenzoyl)dibenz[b,f][1,4]thiazepine in 150 ml of methanol is shaken in a Parr hydrogenator under 50 pounds per square inch of hydrogen for 72 hours. The mixture is filtered through diatomaceous earth and the filtrate evaporated in vacuo. The residue is recrystallized from chloroform-hexane to give 1.8 g of crystals, m.p. 52°-55° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[O:11]1[CH2:16]COC[CH2:12]1.O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl>[CH3:12][O:11][CH2:16][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: C1COCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Product: COCc1ccc(C(C)=O)cc1
Temperature: 100 °C
Reaction time: 7 h
Yield: 31 %

Procedure:
To a mixture of 4′-bromoacetophenone (300 mg, 1.51 mmol) and 1,4-dioxane (4 ml) were added water (0.4 ml), cesium carbonate (1.48 g, 4.54 mmol), potassium methoxymethyl trifluoroborate (459 mg, 3.02 mmol) and 1′,1′-bis(diphenylphosphino)ferrocenedichloropalladium (II) (110 mg, 0.151 mmol). Then, the reaction mixture was stirred at 100° C. (external temperature) for 7 hours. After the reaction mixture was cooled at room temperature, water and methylene chloride were added to the mixture, followed by filtration using Celite. The separated organic layer was washed with an aqueous saturated sodium chloride solution. The organic layer was separated, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate) to obtain the title compound (76 mg, 31%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=C2N.IC.COC(C)(C)C.C([O-])([O-])=O.[Na+].[Na+].[CH3:26][N:27]([CH:29]=O)[CH3:28]>O>[Br:1][C:2]1[CH:10]=[C:9]2[C:8](=[CH:4][CH:3]=1)[NH:7][N:6]=[C:29]2[N:27]([CH3:28])[CH3:26]
Reactant: CN(C)C=O
Reactant: Nc1n[nH]c2ccc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: CI
Product: CN(C)c1n[nH]c2ccc(Br)cc12
Temperature: 80 °C
Yield: 2 %

Procedure:
To a 25 mL round-bottom flask, was added 5-bromo-1H-indazol-3-amine (2.0 g, 9432 μmol), 2.0 M iodomethane in tert-butyl methyl ether (587 μL, 9432 μmol), 1.5 g of Na2CO3, and 5 mL of DMF. The reaction mixture was heated to 80° C. for 6 hours. The reaction mixture was then diluted with 30 mL of water and extracted twice with 50 mL of EtOAc. The organic layers were combined, concentrated, and purified by a silica gel column chromatography separation on an ISOC instrument, eluting with 0-60% EtOAc in hexane to give 5-bromo-N,N-dimethyl-1H-indazol-3-amine (45 mg, 2.0% yield), MS m/z: 241 (M+1); and 5-bromo-N-methyl-1H-indazol-3-amine (550 mg, 26% yield), MS m/z: 227 (M+1).
Reaction SMILES: C[C:2]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:3]=1[OH:4].[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)([CH3:19])[CH3:18])=[CH:13][CH:12]=1.[C:27](=O)(OC1C=CC=CC=1)OC1C=CC=CC=1>>[CH3:19][C:17]([C:14]1[CH:13]=[CH:12][C:11]([OH:10])=[CH:16][CH:15]=1)([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[CH3:18].[CH3:27][O:9][C:7]1[CH:8]=[CH:2][C:3]([OH:4])=[CH:5][CH:6]=1
Reactant: Cc1cc(O)ccc1O
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Product: COc1ccc(O)cc1
Temperature: 180 °C
Reaction time: 3 h

Procedure:
To a 1 L glass reaction vessel, methylhydroquinone (1.045 moles, 129.73 g), bisphenol-A (0.055 moles, 12.56 g) and diphenyl carbonate (1.19 moles, 254.50 g) were added. The system was purged and backfilled with nitrogen three times. The system was heated to about 180° C. to melt the material and stirring began. The molten liquid was light yellow. The catalysts were added (TMAH followed by NaOH) via a syringe. The system underwent all 11 segments shown in Table 1. After about 3 hours, the polymer was stranded to give between 96-100 g of stranded polymer. Four batches were prepared.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:19]=[N:20][N:21]([CH2:23][CH3:24])[CH:22]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl.CO.[OH-].[NH4+]>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:19]=[N:20][N:21]([CH2:23][CH3:24])[CH:22]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCn1cc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)cn1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1cc(Nc2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.4 %

Procedure:
To a solution of N-tert-butyl-2-(1-ethyl-1H-pyrazol-4-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (82 mg, 179 μmol) in dichloromethane (2.7 mL) was added trifluoroacetic acid (409 mg, 276 μL, 3.58 mmol) and the mixture stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the residue obtained diluted with dichloromethane (3 mL), methanol (1.5 mL) and ammonium hydroxide (0.4 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrated then purified by chromatography (silica, 15-65% dichloromethane/[10% dichloromethane/methanol/0.5% ammonium hydroxide]) to give N-tert-butyl-2-(1-ethyl-1H-pyrazol-4-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (33 mg, 101 μmol, 56%) as a yellow solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.16 (s, 1H), 9.06 (s, 1H), 7.90 (d, J=3.3, 1 H), 7.85 (s, 1H), 7.84 (s, 1H), 7.73 (s, 1H), 7.59 (s, 1H), 4.08 (q, J=7.3, 2 H), 1.42 (s, 9H), 1.36 (t, J=7.3, 3 H); MS (EI/CI) m/z: 328.1 [M+H].
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][S:7][C@H:6]2[CH2:9][C@@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:11](=[O:12])[N:5]12)(=O)[NH2:2].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1>[C:1]([C@@H:4]1[CH2:8][S:7][C@H:6]2[CH2:9][C@@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[C:11](=[O:12])[N:5]12)#[N:2]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@@H]2SC[C@@H](C(N)=O)N2C1=O
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@@H]2SC[C@@H](C#N)N2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 538 mg of tert-butyl (3R,6R,7aS)-(3-carbamoyl-5-oxohexahydropyrrolo[2,1-b]thiazol-6-yl)-carbamate in 35 ml of tetrahydrofuran was cooled in an ice bath and, after addition of 0.75 ml of triethylamine and 0.37 ml of trifluoroacetic anhydride, stirred at room temperature overnight. The volatile constituents were stripped off in vacuo at 30° C., and the oily residue was purified by column chromatography (silica gel, mobile phase: ethyl acetate:n-heptane=1:1).
Reaction SMILES: COC(=O)[CH:4]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15](=[O:18])[CH2:14]2)[C:5](OC)=O.[OH-:20].[Na+].[CH3:22][OH:23]>>[O:18]=[C:15]1[CH2:14][C:13]2[C:17](=[C:9]([CH2:4][CH2:5][C:22]([OH:23])=[O:20])[CH:10]=[CH:11][CH:12]=2)[NH:16]1
Reactant: COC(=O)C(C(=O)OC)c1cccc2c1NC(=O)C2
Reactant: [OH-]
Reactant: CO
Agent: [Na+]
Product: O=C(O)CCc1cccc2c1NC(=O)C2
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
A solution of 2,3-dihydro-2-oxo-1H-indole-7-propandioic acid dimethyl ester (4.6 g, 0.0166 moles) is dissolved in methanol (50 ml) and 1N sodium hydroxide (33.2 ml, 0.0332 mole) is added. The mixture is stirred at 50° C. for 90 minutes then concentrated at reduced pressure. The residue is dissolved in water (75 ml) and methanol (50 ml). The solution is made acidic with excess Dowex 50X-8 acidic ion exchange resin and heated with stirring at 70° C. for 24 hours. The solution is cooled, filtered, and concentrated to dryness to yield 2,3-dihydro-2-oxo-1H-indole-7-propanoic acid. The 2,3-dihydro-2-oxo-1H-indole-7-propanoic acid is purified by flash chromatography on silica (elution with 9:1 dichloromethane:methanol) NMR spectra: ('H-CDCl3) δ 7.30-7.10 (m, 3H), δ 6.50-6.25 (b, 1H) δ 3.80-3.70 (m, 2H), δ 3.70 (5, 2H), δ 3.28-3.22 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH2:17][C:18](=O)[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-].ClC1C=CC=C[N+]=1C.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]#[C:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)(=[O:15])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)CC(=O)c2ccc(Cl)cc2)CC1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)C#Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.2 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-(4-chlorobenzoylmethanesulfonyl)piperazine (640 mg) and 2-chloro-1-methylpyridinium iodide (650 mg) in dichloromethane (8 ml) was added dropwise triethylamine (4 ml) at 0° C., and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated and purified with silica gel column chromatography (hexane/ethyl acetate=2/1) to give a colorless solid of 1-(tert-butoxycarbonyl)-4-[2-(4-chlorophenyl)ethynesulfonyl]piperazine (521 mg).
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:5]2[CH:12]=[C:11]([C:13]3[N:17]([CH3:18])[N:16]=[N:15][N:14]=3)[CH:10]=[CH:9][C:6]=2[S:7][CH:8]=1)#[N:2]>C1COCC1>[NH2:2][CH2:1][CH2:3][C:4]1[C:5]2[CH:12]=[C:11]([C:13]3[N:17]([CH3:18])[N:16]=[N:15][N:14]=3)[CH:10]=[CH:9][C:6]=2[S:7][CH:8]=1
Reactant: Cn1nnnc1-c1ccc2scc(CC#N)c2c1
Solvent: C1CCOC1
Product: Cn1nnnc1-c1ccc2scc(CCN)c2c1
Yield: 66.9 %

Procedure:
Following the procedure of Example 11, Step 7, 26.1 mg (0.102 mmol) of 3-cyanomethyl-5-(1-methyltetrazol-5-yl)benzo[b]thiophene in 2 ml of THF was reacted with 0.36 ml (0.36 mmol) of 1.0M borane-tetrahydrofuran complex in THF. Chromatography on flash silica, eluting with CH2Cl2 /MeOH/NH3 (aq) (60:8:1) gave 17.7 mg (67%) of the title product as a colourless oil. The oxalate salt was prepared using oxalic add in methanol/ether to give the title product oxalate as a white solid, m.p. 206°-212° C. Analysis found: C, 47.55; H, 4.05; N, 19.65%. Calcd for C12H13N5S. 1.1 C2H2O4 : C, 47.59; H, 4.28; N, 19.54%. δ (D2O) 3.32-3.35 (2H, m), 3.40-3.44 (2H, m), 4.22 (3H, s), 7.64 (1H, s), 7.73 (1H, d, J=8.4 Hz), 8.19 (1H, s), 8.22 (1H, d, 8.5 Hz).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.[Cl:18][C:19]1[CH:30]=[CH:29][C:22]([C:23](N(OC)C)=[O:24])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:30]=[CH:29][C:22]([C:23]([C:2]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[O:24])=[CH:21][CH:20]=1
Reactant: CON(C)C(=O)c1ccc(Cl)cc1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: [Li]CCCC
Product: COc1ccc(C(=O)c2ccc(Cl)cc2)c(C(=O)O)c1

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with 4-chloro-N-methoxy-N-methylbenzamide. It is used in crude form in the following reaction.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:8][C:7](=[O:9])[NH:6][C:5](=[O:10])[CH:4]=1.[CH3:11][NH:12][CH3:13]>>[CH3:11][N:12]([CH2:2][C:3]1[NH:8][C:7](=[O:9])[NH:6][C:5](=[O:10])[CH:4]=1)[CH3:13]
Reactant: O=c1cc(CCl)[nH]c(=O)[nH]1
Reactant: CNC
Product: CN(C)Cc1cc(=O)[nH]c(=O)[nH]1

Procedure:
reacting 6-(chloromethyl)uracil with dimethylamine to form crystalline derivative of 6-(dimethylaminomethyl)uracil,
Reaction SMILES: [OH-].[K+].C(O)COCCOCCO.O=[C:14]([C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=1)[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18].O.NN>>[CH3:18][CH:17]([CH3:19])[CH2:16][CH2:15][CH2:14][C:20]1[CH:21]=[CH:22][C:23]([Br:26])=[CH:24][CH:25]=1
Reactant: CC(C)CCC(=O)c1ccc(Br)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCOCCO
Product: CC(C)CCCc1ccc(Br)cc1
Temperature: 100 °C
Reaction time: 8.5 h

Procedure:
A mixture of 6.45 g (115 mmol) of potassium hydroxide and 42 ml of triethylene glycol was heated at around 100 degrees C. until the potassium hydroxide was dissolved. The mixture was allowed to cool and then treated with 10 g (39 mmol) of 4-(1-oxo-4-methylpentyl) bromobenzene (Compound 31) followed by 3 g (94 mmol) of hydrazine hydrate. The mixture was slowly brought to reflux and heated at reflux for 1 hour. The apparatus was modified for distillation and the mixture heated until approximately 7 ml of liquid had distilled over and the flask temperature had reached 220 degrees C. The apparatus was again modified for reflux and the mixture was heated at reflux for 5 hours and then stirred at room temperature for 8.5 hours. The mixture was then heated to 100 degrees C. and poured into 40 ml of water and the flask rinsed with an additional 25 ml of water. This diluted mixture was acidified to pH=2 with conc. HCl and extracted with ether. The ether extract was washed successively with water and saturated NaCl and then dried (MgSO4). The solvent was removed in vacuo and the residue subjected to kugelrohr distillation (70 degrees C., 0.05 mm) to give the title compound as a colorless oil. PMR (CDCl3): δ0.88 (6H, d, J~6 Hz), 1.12-1.26 (2H, m), 1.48-1.66 (3H, m), 2.54 (2H, t, J~7.7 Hz) 7.06 (2H, d, J~8.3 Hz), 7.39 (2H, d, J~8.3 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[C@@H:10]([N:16]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.[CH2:45](O)[CH2:46][OH:47]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CO.C(Cl)Cl>[CH:27]1[C:28]2[N:16]([C@@H:10]([CH2:11][CH2:12][C:13]([O:15][CH2:45][CH2:46][OH:47])=[O:14])[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:29])[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]=2[CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)CC[C@@H](C(=O)OCc1ccccc1)n1c2ccccc2c2ccccc21
Reactant: OCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: O=C(CC[C@@H](C(=O)OCc1ccccc1)n1c2ccccc2c2ccccc21)OCCO
Temperature: 0 °C
Reaction time: 12 h
Yield: 71 %

Procedure:
To a solution of 22 (1.2 g, 3.10 mmol) in CH2Cl2 (20 mL) were added DCC (0.703 g, 3.40 mmol) and catalytic amount of DMAP (0.057 g, 0.46 mmol) under nitrogen atmosphere. The reaction mixture was cooled to 0° C. and ethylene glycol (0.770 g, 0.680 mL, 12.4 mmol) in CH2Cl2 (5 mL) was added dropwise. The reaction mixture was allowed to warm up to room temperature and stirred for 12 h. The solid DCU was removed by filtration and the filtrate was evaporated under reduced pressure. The crude residue obtained was dissolved in CH2Cl2 (100 mL), washed with water (40 mL×2), brine (40 mL×2), dried over Na2SO4, filtrated and then concentrated to get a yellow residue. A flash chromatography using CH3OH:CH2Cl2 (1:99) as eluent afforded (S)-1-benzyl 5-(2-hydroxyethyl) 2-(9H-carbazol-9-yl)pentanedioate 23 (0.950 g, 71%) as a yellow gummy liquid.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[Li:10]CCCC>C1(C)C=CC=CC=1>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N-:3][CH:2]=1.[Li+:10]
Reactant: [Li]CCCC
Reactant: c1ccc2[nH]cnc2c1
Solvent: Cc1ccccc1
Product: [Li+]
Product: c1ccc2[n-]cnc2c1

Procedure:
A slurry of benzimidazole (8.50 g, 36.3 mmol) in toluene (40 mL) at 0° C. was treated with 25.8 mL of a 2.8 M n-BuLi (72.2 mmol) solution in hexanes. This solution mixture was then refluxed for one day during which time the slurry became off-white. The slurry was then filtered over a medium glass frit and dried to give a white solid.
Reaction SMILES: [OH:1][C:2]1([CH:14]=[CH:13][CH:12]=[CH:11][CH:10]1[C:15]([F:18])([F:17])[F:16])[CH2:3][C:4]1[N:8]([CH3:9])[CH:7]=[N:6][N:5]=1.[CH3:19][C:20]([CH3:25])([CH3:24])[C:21](Cl)=[O:22].[H-].[Na+]>C1COCC1>[CH3:19][C:20]([CH3:25])([CH3:24])[C:21]([O:1][C:2]1([CH:14]=[CH:13][CH:12]=[CH:11][CH:10]1[C:15]([F:18])([F:17])[F:16])[CH2:3][C:4]1[N:8]([CH3:9])[CH:7]=[N:6][N:5]=1)=[O:22]
Reactant: Cn1cnnc1CC1(O)C=CC=CC1C(F)(F)F
Reactant: CC(C)(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cnnc1CC1(OC(=O)C(C)(C)C)C=CC=CC1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 50.3 %

Procedure:
0.6 g of 3-(1-hydroxy-2'-trifluoromethylbenzyl)-4-methyl-1,2,4-triazole were dissolved in 20 ml THF, with the aid of sonification. An additional 10 ml THF were added to help dissolve the solid material. The solution was cooled to 0° C. 0.56 g of trimethylacetyl chloride were added slowly and the mixture turned cloudy. After 5 minutes, 0.1 g NaH (60%) added in small portions. The ice/water cooling bath was removed and the reaction mixture was stirred overnight. An additional 0.06 g of NaH was added at room temperature and after another 6 hours, there was no major change. 3 drops of water were added to the cloudy reaction mixture (no hydride was present), followed by diethyl ether. The solid was removed by filtration and washed with diethyl ether. The filtrate was dried (MgSO4), filtered and concentrated to an oil. The oil was purified on a silica gel column by elution with 100% ethylacetate to yield 0.4 g of 3-(1-trimethylacetoxy-2'-trifluoromethylbenzyl)-4-methyl-1,2,4-triazole in the form of an oil.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:7]([C:11]([OH:13])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[C:39](Cl)([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:28]=[N:29][N:30]([C:39]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)([C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=4)[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[N:31]=3)=[CH:17][CH:16]=2)[C:7]([C:11]([OH:13])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of E3174 (234.58 g, 0.54 mol) in DCM (4500 mL) was added triethylamine (85 mL, 0.59 mol) followed by a solution of trityl chloride (159 g, 0.56 mol) in DCM (800 mL) and the reaction mixture was stirred at rt overnight. The reaction mixture was washed with water, dried (MgSO4), filtered, and concentrated in vacuo. Chromatography over silica eluting with 20-80% acetone/heptane afforded the title compound as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].F[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Reactant: Fc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1OC2(CCN(C(=O)c3cn(-c4ccccn4)c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a solution of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) in dry DMF was added NaH (1 eq) and the reaction mixture stirred at room temperature for 30 min and then treated with 2-fluoropyridine (1.5 eq) and heated at 140° C. under microwave irradiation for 15 min. Purification by preparative HPLC gave the desired product in 36% yield.