Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:4]=[N:3]1.[NH2:24][CH2:25][CH:26]([OH:31])[C:27]([F:30])([F:29])[F:28]>>[CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH:24][CH2:25][CH:26]([OH:31])[C:27]([F:30])([F:29])[F:28])=[O:15])=[CH:11][N:10]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:4]=[N:3]1
Reactant: NCC(O)C(F)(F)F
Reactant: Cn1nnc(-c2ccccn2)c1COc1ccc(C(=O)O)cn1
Product: Cn1nnc(-c2ccccn2)c1COc1ccc(C(=O)NCC(O)C(F)(F)F)cn1
Yield: 62 %

Procedure:
As described for example 26b, 6-(3-methyl-5-pyridin-2-yl-3H-[1,2,3]triazol-4-ylmethoxy)-nicotinic acid (75 mg, 0.24 mmol) was converted, using 3-amino-1,1,1-trifluoro-2-propanol instead of 4-aminotetrahydropyran, to the title compound (63 mg, 62%) which was obtained as a white solid. MS: m/e=423.1 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]C)=[CH:9][CH:8]=1.[BrH:15]>>[BrH:15].[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1
Reactant: COc1ccc(Cc2ncc[nH]2)cc1
Agent: Br
Product: Oc1ccc(Cc2ncc[nH]2)cc1

Procedure:
To a suspension of 5.21 g of 50% sodium hydride in 100 ml of dry dimethylformamide was added slowly 7.39 g of imidazole at room temperature, and the mixture was stirred for 20 minutes. A solution of 20 g of p-methoxybenzyl chloride in 30 ml of dry dimethylformamide was added to the mixture at room temperature over a period of 1 hour, and then the reaction mixture was stirred for 18 hours at 50° C. After removal of the solvent under reduced pressure, 100 ml of dichloromethane was added to the residual oil and the mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residual solid was recrystallized from diethyl ether-ligroin to give 14.7 g of p-(1-imidazolylmethyl)anisole as colorless platelets. Then a solution of 14.7 g of p-(1-imidazolylmethyl)anisole in 50 ml of 47% hydrobromic acid was refluxed for 3 hours. After concentration under reduced pressure, the residual solid was recrystallized from ethanol-diethyl ether to give 18.4 g of p-(1-imidazolylmethyl)phenol hydrobromide as colorless platelets. M.P.: 189°-190° C.
Reaction SMILES: Cl.[C@@H:2]12[CH2:8][C@@H:5]([CH2:6][CH2:7]1)[CH2:4][C@H:3]2[N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[CH2:11][CH2:10]1.[C:23](O)([CH3:26])([CH3:25])[CH3:24].[Cl-].[Cl-].[Cl-].[Al+3]>[N+](C1C=CC=CC=1)([O-])=O>[C@@H:2]12[CH2:8][C@@H:5]([CH2:6][CH2:7]1)[CH2:4][C@H:3]2[N:9]1[CH2:10][CH2:11][CH:12]([C:15]2[CH:20]=[C:19]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[CH2:13][CH2:14]1
Reactant: COc1ccccc1C1CCN([C@@H]2C[C@@H]3CC[C@H]2C3)CC1
Reactant: CC(C)(C)O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(C(C)(C)C)cc1C1CCN([C@@H]2C[C@@H]3CC[C@H]2C3)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl)-4-(2-methoxyphenyl)piperidine hydrochloride (397, 64 mg, 0.20 mmol) was suspended in nitrobenzene (1.0 mL) and treated with 1.0 eq tert-butanol (15 mg), followed by 3.0 eq of aluminum trichloride in nitrobenzene (600 μL 1.0 M solution, 0.60 mmol). The reaction was stirred at room temperature for 2 hours, then quenched with 1.0 N HCl (5.0 mL). The aqueous layer was separated, basified with 1.0 N NaOH (pH 12) and extracted with dichloromethane (10 mL). The extract was dried (Na2SO4), filtered, concentrated in vacuo and dissolved in methanol:acetonitrile (1.0 mL, 1:1 v/v). The solution was filtered (Whatman 0.2 μm PTFE) and subjected to reverse-phase HPLC purification (5-50% CH3CN/0.08% TFA) to yield [1-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl)-4-(5-tert-butyl-2-methoxy-phenyl)piperidine] (compound no. 325) as the TFA salt. LC/MS (RP-C18, 10-99% CH3CN/0.05% TFA gradient over 5 min) m/z 342.2 [M+H]+, retention time 2.70 min.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:12]=3[C:13]=2[CH3:14])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>O1CCCC1.CO>[CH:1]1([CH:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:12]=3[C:13]=2[CH3:14])[OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1c(C(=O)C2CCCCC2)oc2cccc(F)c12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(O)C2CCCCC2)oc2cccc(F)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyclohexyl(4-fluoro-3-methyl-1-benzofuran-2-yl)methanone (2.6 g) synthesized in the above-mentioned (1) was dissolved to in tetrahydrofuran (40 mL) and methanol (4 mL), and sodium borohydride (90%, 0.83 g) was added to the solution under ice-cooling. The ice bath was removed, the reaction mixture was stirred at room temperature for 1 hr then ice-cooled again, and water (5 mL) and 1N hydrochloric acid (10 mL) were carefully added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (2.5 g, quantitative) as a pale-yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6](B(O)O)[CH:7]=1.Cl[C:14]1[N:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])[CH2:24]2)=[O:22])[CH:15]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:32]([O:31][C:29]([N:25]1[CH2:26][CH2:27][CH2:28][CH:23]([C:21](=[O:22])[NH:20][C:16]2[CH:15]=[C:14]([C:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[O:11][CH3:12])[N:19]=[CH:18][N:17]=2)[CH2:24]1)=[O:30])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C(Nc1cc(Cl)ncn1)C1CCCN(C(=O)OCc2ccccc2)C1
Reactant: COc1ccc(F)cc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(F)cc1-c1cc(NC(=O)C2CCCN(C(=O)OCc3ccccc3)C2)ncn1
Temperature: 25 °C
Reaction time: 30 h
Yield: 66.7 %

Procedure:
To a solution of 5-fluoro-2-methoxyphenyl boronic acid (0.20 g, 1.1 mmol) in a mixture of THF and water (6 ml, 1:1), benzyl 3-(6-chloropyrimidin-4-ylcarbamoyl)piperidine-1-carboxylate (0.35 g, 1.0 mmol) was added at 0° C. followed by palladium acetate (12 mg, 0.054 mmol), PPh3 (31 mg, 0.12 mmol) and saturated solution of sodium carbonate (2 ml). The reaction mixture was stirred at room temperature for 30 h and then filtered through a celite bed which was washed with ethyl acetate. The aqueous layer was extracted with ethyl acetate, the organic layers were combined, washed with brine, dried and evaporated under reduced pressure. The crude product was purified by column chromatography, using hexane/ethyl acetate (4:1) as eluent, to provide 0.31 g (yield: 53.8%) of 3-[6-(5-fluoro-2-methoxy-phenyl)-pyrimidin-4-ylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=[O:12])([O-:3])=[O:2].S(Cl)(Cl)=O.[CH3:18]O>>[CH3:18][O:12][C:11](=[O:13])[CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A round bottom flask with magnetic stirrer was charged with (2-nitro-phenyl)-acetic acid (10.0 g, 55.0 mmol) and methanol (70 mL) under an argon atmosphere. To the resulting yellow solution at room temperature was added thionyl chloride (12.1 mL, 166 mmol) dropwise via addition funnel (Note: Reaction is very exothermic). The resulting reaction mixture was stirred at room temperature for 12-18 hours and concentrated in vacuo to afford 13.3 g of crude (2-nitro-phenyl)-acetic acid methyl ester as an orange oil. This material was used directly in subsequent reactions.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:16][CH3:17])[CH2:3][O:4][C:5]([C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=1)=[O:6].S(Cl)([Cl:20])=O>>[CH3:1][C@@H:2]([CH2:16][CH3:17])[CH2:3][O:4][C:5]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([Cl:20])=[O:12])=[CH:9][CH:8]=1)=[O:6]
Reactant: O=S(Cl)Cl
Reactant: CC[C@H](C)COC(=O)c1ccc(C(=O)O)cc1
Product: CC[C@H](C)COC(=O)c1ccc(C(=O)Cl)cc1

Procedure:
The resulting carboxylic acid was treated with thionyl chloride to obtain 4-[(S)-2-methylbutoxycarbonyl]benzoyl chloride.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[F:20][C:21]([F:30])([F:29])[C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:19]=[CH:18][C:15]([CH2:16][NH:26][C:25]3[CH:27]=[CH:28][C:22]([C:21]([F:20])([F:29])[F:30])=[CH:23][CH:24]=3)=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CC(C)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Product: CC(C)N1CCN(C(=O)c2ccc(CNc3ccc(C(F)(F)F)cc3)cc2)CC1

Procedure:
Prepared from the product of Example 15 and 4-trifluoromethylaniline.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:16])[NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:7]=1[C:8]([OH:10])=O)[CH3:2].C(N(CC)CC)C.C(Cl)CCl>C(Cl)Cl.CCOC(C)=O>[CH2:1]([NH:3][C:4]1[O:16][C:8](=[O:10])[C:7]2[C:11]([CH3:15])=[CH:12][CH:13]=[CH:14][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCNC(=O)Nc1cccc(C)c1C(=O)O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNc1nc2cccc(C)c2c(=O)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.3 %

Procedure:
To a stirred solution of 2-(3-ethylureido)-6-methylbenzoic acid (250 mg, 1.125 mmol) and triethylamine (170 mg, 1.69 mmol) in 10 mL CH2Cl2 at room temperature was added EDC (501 mg, 1.69 mmol). After stirring at room temperature for 3 hours, the reaction mixture was diluted with EtOAc and washed sequentially with 1N HCl and sat'd. NaHCO3. The organic fraction was dried (MgSO4), filtered and evaporated under reduced pressure. Silica gel chromatography of the residue (1:1 EtOAc/hexane) afforded 127 mg of product: Anal. Calc'd. for C11H12N2O2.0.25H2O: C, 63.30; H, 6.04; N, 13.42. Found: C, 63.32; H, 5.92; N, 13.10. 1H-NMR (300 MHz, d6-DMSO) δ 1.14 (t, J=7 Hz, 3H), 2.60 (s, 3H), 3.27 (pent, J=7 Hz, 2H), 6.95 (d, J=8 Hz, 1H), 7.02 (d, J=8 Hz, 1H), 7.50 (t, J=8 Hz, 1H), 7.90 (br. t, J=7 Hz, 1H, exchangeable).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[C:18]([NH2:19])=[CH:17][CH:16]=[C:15]([CH3:20])[N:14]=2)=[O:12])=[N:6]1.Br[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#[N:26]>>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[C:18]([NH:19][C:22]3[CH:29]=[CH:28][CH:27]=[C:24]([C:25]#[N:26])[CH:23]=3)=[CH:17][CH:16]=[C:15]([CH3:20])[N:14]=2)=[O:12])=[N:6]1
Reactant: N#Cc1cccc(Br)c1
Reactant: COCCn1ccc(NC(=O)c2nc(C)ccc2N)n1
Product: COCCn1ccc(NC(=O)c2nc(C)ccc2Nc2cccc(C#N)c2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid [1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-amide in accordance with the general method of example, step using 3-Bromobenzonitrile instead of 3-bromopyridineto yield the final compound as a light yellow solid, MS (ISP): m/e=377.5 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH3:32])[C:15]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH2:31])[N:26]=3)=[C:16]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=3)[C:10]=2[C:9]1=[O:33])=O)(C)(C)C.[ClH:34]>O1CCOCC1>[ClH:34].[NH2:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][C:16]1[C:10]2[C:9](=[O:33])[NH:8][CH2:13][CH2:12][C:11]=2[N:14]([CH3:32])[C:15]=1[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([NH2:31])[N:26]=1
Reactant: Cn1c2c(c(Cc3cccc(N)c3)c1-c1ccnc(N)n1)C(=O)N(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c2c(c(Cc3cccc(N)c3)c1-c1ccnc(N)n1)C(=O)NCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A suspension of 3-(3-Amino-benzyl)-2-(2-amino-pyrimidin-4-yl)-1-methyl-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (0.030 g, 0.066 mmol) in 4 N HCl in dioxane (2 ml) was stirred at room temperature for 1 h. The solvent was removed under vacuum, affording 3-(3-Amino-benzyl)-2-(2-amino-pyrimidin-4-yl)-1-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one hydrochloride (0.028 g, 0.062 mmol, 100%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].O.C(=O)([O-])[O-].[Na+].[Na+].[CH2:23]([O:30][C:31](Cl)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(OCC)(=O)C>[CH2:23]([O:30][C:31]([NH:1][C@@H:2]([CH2:7][C:8]1[CH:9]=[C:10]([F:15])[CH:11]=[C:12]([F:14])[CH:13]=1)[C:3]([O:5][CH3:6])=[O:4])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OCc1ccccc1

Procedure:
Methyl (2S)-2-amino-3-(3,5-difluorophenyl)propanoate (XV, EXAMPLE 11, 0.300 g, 1.40 mmol, 1 equivalent) and water (10 mL) are mixed. Sodium carbonate (0.15 g, 1.40 mmol, 1 equivalent) of is added followed by benzylchloroformate (0.2 mL, 0.24 g, 1.4 mmol, 1 equivalent) and the mixture stirred at 20-25° until complete as measured by HPLC. Once the reaction is complete, ethyl acetate (20 mL) is added and the phases separated. The aqueous phase is extracted with ethyl acetate (2×20 mL), and the combined organic phases are dried over sodium sulfate, filtered, and concentrated. The concentrate is crystallized from hexanes/ethyl acetate to give the title compound, mp=540; NMR (DMSO-d6) δ 7.84, 7.28, 7.06, 4.98, 4.35, 3.68, 3.12 and 2.88.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:44]2([CH3:45])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:43]2[CH2:42][CH2:41][C@@:40]2([CH3:46])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:24]/[CH:25]=[CH:26]/[C:27]([CH2:38][CH3:39])([O:30][Si](CC)(CC)CC)[CH2:28][CH3:29])[CH3:22])[CH2:12][C@@H:11]([O:47][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@@H:9]1[C@@:44]2([CH3:45])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:43]2[CH2:42][CH2:41][C@@:40]2([CH3:46])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:24]/[CH:25]=[CH:26]/[C:27]([CH2:38][CH3:39])([OH:30])[CH2:28][CH3:29])[CH3:22])[CH2:12][C@@H:11]([OH:47])[CH2:10]1
Reactant: CCC(/C=C/CO[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)(CC)O[Si](CC)(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(O)(/C=C/CO[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C)CC
Yield: 77.8 %

Procedure:
By the same procedure as in Example 9, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-{(E)-(4-ethyl-4-triethylsilyloxy-2-hexenyloxy)}pregna-5,7,16-triene (84.0 mg, 0.105 mmol), tetrahydrofuran (3 ml) and 1M tetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) were reacted (heating under reflux for 5.5 hours) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×1, dichloromethane:ethyl acetate:ethanol=20:80:1, developed once) to give the title compound as a colorless oil (37.3 mg, 78%).
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([CH2:9][NH2:10])=[O:8].C(=O)(O)[O-].[Na+].[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>>[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:10][CH2:9][C:7]([C:3]2[O:2][CH:6]=[CH:5][CH:4]=2)=[O:8])=[O:23])=[CH:20][CH:19]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: NCC(=O)c1ccco1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(C(=O)NCC(=O)c2ccco2)cc1
Yield: 85.7 %

Procedure:
8.0 g of (2-furylcarbonyl)methylamine hydrochloride, 10.5 g of sodium bicarbonate and 10.1 g of 4-methoxybenzoyl chloride are treated in the same manner as described in Preparation 1-(1). 11.0 g of N-(4-methoxybenzoyl)-(2-furylcarbonyl)methylamine are thereby obtained. Yield: 85.3%
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[C:15](Cl)(=[O:17])[CH3:16]>C(Cl)Cl.CCN(CC)CC>[CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([C:15](=[O:17])[CH3:16])[CH2:3]1
Reactant: CC1(C)CNc2cc([N+](=O)[O-])ccc21
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CC(C)(C)c2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3,3-dimethyl-6-nitroindoline (450 mg) in CH2Cl2 (15 mL) and Et3N (0.6 mL) at −10° C. was added acetyl chloride (180 μL, 2.5 mmol). The mixture was stirred at rt overnight and quenched by addition of sat. aq. NaHCO3, and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried (MgSO4) and concentrated. The residue was purified by column to give a light yellow solid (390 mg, 71% for two steps).
Reaction SMILES: [Br:1][CH2:2][CH2:3][N:4]1[C:8]([C:9](=[O:11])[CH3:10])=[CH:7][C:6]([N:12]2[C:16]([CH3:17])=[CH:15][CH:14]=[C:13]2[CH3:18])=[N:5]1.[BH4-].[Na+]>CO>[Br:1][CH2:2][CH2:3][N:4]1[C:8]([CH:9]([OH:11])[CH3:10])=[CH:7][C:6]([N:12]2[C:16]([CH3:17])=[CH:15][CH:14]=[C:13]2[CH3:18])=[N:5]1
Reactant: CC(=O)c1cc(-n2c(C)ccc2C)nn1CCBr
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(C)n1-c1cc(C(C)O)n(CCBr)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 100-mL round-bottomed flask equipped with a magnetic stirrer was charged with 150e (2.1 g, 1.0 eq., 6.8 mmol), NaBH4 (1.29 g, 5.0 eq., 34.0 mmol), and methanol (50 mL). The mixture was stirred at room temperature for 2 h and quenched with water (30 mL). It was then concentrated under reduced pressure and the residue was extracted with dichloromethane (3×50 mL). The combined organic layer was concentrated under reduced pressure to afford crude 150f, which was used in the next step without further purification. MS-ESI: [M+H]+ 311.9
Reaction SMILES: [CH:1]12[CH2:9][CH:5]3[CH2:6][CH:7]([CH2:8]1)[C:3]([NH:10][C:11]([NH2:13])=[S:12])([CH2:4]3)[CH2:2]2.Br[C:15]1([C:19](OCC)=[O:20])[CH2:18][CH2:17][CH2:16]1>>[CH:1]12[CH2:9][CH:5]3[CH2:6][CH:7]([CH2:8]1)[C:3]([NH:10][C:11]1[S:12][C:15]4([C:19](=[O:20])[N:13]=1)[CH2:18][CH2:17][CH2:16]4)([CH2:4]3)[CH2:2]2
Reactant: NC(=S)NC12CC3CC(CC1C3)C2
Reactant: CCOC(=O)C1(Br)CCC1
Product: O=C1N=C(NC23CC4CC(CC2C4)C3)SC12CCC2

Procedure:
Synthesis was performed from N-tricyclo[3.3.1.0˜3,7˜]non-3-ylthiourea and ethyl 1-bromocyclobutanecarboxylate according to Method D.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[O:12])[NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:17]([Li])[CH2:18][CH2:19]C.BrCC#C>O1CCCC1.CCCCCC>[CH2:19]([N:7]1[C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](=[O:12])[NH:11][C:5]2[CH:4]=[CH:3][CH:2]=[N:1][C:6]1=2)[C:18]#[CH:17]
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Reactant: [Li]CCCC
Agent: C#CCBr
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C#CCN1c2ccccc2C(=O)Nc2cccnc21

Procedure:
To a suspension of 7.4 g (0.035 mol) of 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one in 150 ml of anhydrous tetrahydrofuran, 44.8 ml (approx. 0.07 mol) of a 15% solution of n-butyl-lithium in n-hexane was added dropwise with stirring at a reaction temperature of from 0° to +10° C. After it had all been added, the mixture was stirred for 30 minutes at ambient temperature before a solution of 4.16 g (0.035 mol) of 3-bromo-prop-1-yne in 25 ml of anhydrous tetrahydrofuran was added dropwise. The resulting mixture was stirred for a further 2 hours at ambient temperature, added to 1 liter of saturated aqueous saline solution and the resulting mixture was extracted exhaustively with ethylacetate. The combined ethylacetate extracts were washed twice more with 100 ml of saturated saline solution, dried over sodium sulphate with the addition of 1 g of activated charcoal and evaporated down in vacuo. The residue was purified on silica gel by chromatography using dichloromethane/ethyl acetate 95/5 (v/v) as eluant. 8.5 g (97% of theory) of colourless crystals were obtained, m.p. 199° C. (decomposition).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[NH:13][CH:12]([NH:16][CH2:17][CH2:18][CH2:19][CH3:20])[NH:11][C:10]2=[O:21])=[CH:5][CH:4]=1.Br.[OH-].[Na+]>O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:10](=[O:21])[NH:11][CH:12]([NH:16][CH2:17][CH2:18][CH2:19][CH3:20])[NH:13][C:14]2=[O:15])=[CH:7][CH:8]=1
Reactant: CCCCNC1NC(=O)N(c2ccc(OC)cc2)C(=O)N1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCNC1NC(=O)N(c2ccc(O)cc2)C(=O)N1
Temperature: 25 °C
Yield: 52.5 %

Procedure:
A mixture of 3-(4-methoxyphenyl)-6-n-butylamino-tetrahydro-1,3,5-triazine-2,4-dione (1.0 g.) and hydrobromic acid (48% w/v; 20 ml.) was heated under reflux for 16 hours. The mixture was cooled to room temperature, diluted with water (100 ml.), and the aqueous solution adjusted to pH 6-7 by addition of aqueous sodium hydroxide solution. The white solid produced was separated by filtration, washed with water (3×70 ml.) and dried (over phosphorus pentoxide) to give 3-(4-hydroxyphenyl)-6-n-butylamino-tetrahydro-1,3,5-triazine-2,4-dione (0.5 g., 63%), m.p. 263°-265° C.
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[S:24][N:23]=[C:22]([NH:25]CC5C=CC(OC)=CC=5)[N:21]=4)[CH:18]=3)[N:13]([S:35]([C:38]3[CH:44]=[CH:43][C:41]([CH3:42])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[CH:12]=2)[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2]>C(O)(C(F)(F)F)=O>[CH:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[S:24][N:23]=[C:22]([NH2:25])[N:21]=4)[CH:18]=3)[N:13]([S:35]([C:38]3[CH:39]=[CH:40][C:41]([CH3:42])=[CH:43][CH:44]=3)(=[O:36])=[O:37])[CH:12]=2)[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(CNc2nsc(-c3ccc4c(c3)c(-c3cncc(NC(C)C)n3)cn4S(=O)(=O)c3ccc(C)cc3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(NC(C)C)n3)c3cc(-c4nc(N)ns4)ccc32)cc1
Yield: 123.6 %

Procedure:
A solution of 5-(3-(6-(isopropylamino)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,2,4-thiadiazol-3-amine (0.5 g, 0.80 mmol) in TFA (5 mL) was heated in Biotage microwave at 100° C. for 30 min. TFA was removed in vacuo and the residue was washed with Et2O (10 mL) to give the crude 5-(3-(6-(isopropylamino)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-1,2,4-thiadiazol-3-amine (0.5 g) as an off yellow solid, which was used for next step without any purification. MS (ESI, pos. ion) m/z: 506.0 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=1.[CH:17]([C:19]1[CH:20]=[CH:21][C:22]([OH:28])=[C:23]([CH:27]=1)[C:24]([OH:26])=[O:25])=[O:18]>CN(C)C=O>[F:16][C:11]1[CH:10]=[C:9]([CH2:8][O:28][C:22]2[CH:21]=[CH:20][C:19]([CH:17]=[O:18])=[CH:27][C:23]=2[C:24]([O:26][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=2)=[O:25])[CH:14]=[CH:13][C:12]=1[F:15]
Reactant: Fc1ccc(CBr)cc1F
Reactant: O=Cc1ccc(O)c(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccc(F)c(F)c2)c(C(=O)OCc2ccc(F)c(F)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cesium carbonate (17.65 g, 54.2 mmol) and 4-(bromomethyl)-1,2-difluorobenzene (5.78 ml, 45.1 mmol) were added to a solution of 5-formyl-2-hydroxybenzoic acid (3 g, 18.06 mmol) in dimethylformamide (100 ml) was added) at room temperature. The mixture was stirred at room temperature overnight. The mixture was then filtered, the dimethylformamide was evaporated and the residue was diluted with ethyl acetate (100 ml) and washed with water (3×50 ml). The organic layer was dried (MgSO4) and evaporated under reduced pressure to give an oil which solidified on standing solidified. The solid was triturated with an 8:1 mixture of hexane/ethyl acetate. The solid was filtered and dried in air under vacuum to yield the title compound as a white solid. 7 g.