Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]([CH3:13])[CH:8]([CH3:14])[N:7]([CH:15]3[CH2:17][CH2:16]3)[C:6]=2[N:18]=1.I[CH3:20].[H-].[Na+]>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:20])[C:10](=[O:12])[CH:9]([CH3:13])[CH:8]([CH3:14])[N:7]([CH:15]3[CH2:16][CH2:17]3)[C:6]=2[N:18]=1
Reactant: CC1C(=O)Nc2cnc(Cl)nc2N(C2CC2)C1C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC1C(=O)N(C)c2cnc(Cl)nc2N(C2CC2)C1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a mixture of 0.266 g (0.001 mole) of (rac)-2-chloro-9-cyclopropyl-7,8-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-46) and 0.093 mL (0.0015 mole) of iodomethane at 0 degrees was added 0.06 g (0.0015 mole) of 60% sodium hydride in oil. The mixture was stirred at ambient temperature for 1 hour, then 20 mL of water was added. The precipitate was collected by filtration to give 0.25 g of (rac)-2-chloro-9-cyclopropyl-5,7,8-trimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-46) as an yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[CH3:19][NH:20][CH3:21].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[CH3:19][N:20]([CH3:21])[CH:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:13][CH2:14]1
Reactant: CNC
Reactant: COc1cc(N2CCC(=O)CC2)ccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(N2CCC(N(C)C)CC2)ccc1[N+](=O)[O-]
Yield: 87.6 %

Procedure:
To a solution of 1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinone (Example 57, step B; 1.41 g, 5.6 mmol) in 50 mL 1,2-dichloroethane was added a solution of dimethylamine (2M in THF, 5.6 mL, 11.2 mmol), HOAc (1.3 mL, 22.4 mmol) and sodium triacetoxyborohydride (1.78 g, 8.4 mmol). When TLC indicated the reaction to be complete, the solution was diluted with H2O and extracted with DCM. The aqueous phase was brought to pH>7 with the addition of saturated NaHCO3. This was extracted twice with DCM and EtOAc. The combined organic phases were dried over MgSO4 and concentrated to give 1.37 g (88%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J=9.6 Hz, 1H), 6.54 (dd, J=9.4 and 2.2 Hz, 1H), 6.46 (d, J=2.0 Hz, 1H), 3.99 (d, J=13.2 Hz, 1H), 3.87 (s, 3H), 2.96-2.89 (m, 2H), 2.35-2.30 (m, 1H), 2.15 (s, 6H), 1.79 (d, J=11.6 Hz, 2H), 1.42-1.32 (m, 2H).
Reaction SMILES: [CH2:1]([OH:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH3:10][C:11]([CH3:13])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:10][C:11]1([CH3:13])[O:9][CH2:1][C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[O:4]1
Reactant: OCc1ccccc1O
Reactant: CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC1(C)OCc2ccccc2O1

Procedure:
First the hydroxyl groups of Salicyl alcohol were protected with acetone in refluxing benzene with the catalysis of para-toluenesulfonic acid to give 2,2-Dimethyl-4H-benzo[1,3]dioxine in quantitive yield. Friedel-craft acylation of this compound with AlCl3 and acetyl chloride in refluxing chloroform afforded 1-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)-ethanone in good yield. This was further brominated in chloroform with the catalysis of benzoyl peroxide to give 2-bromo-1-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)-ethanone, which was reduced to the chiral or nonchiral bromohydrine with borane and borane/oxazaborolidine, respectively. The title epoxide was generated by the addition of the above bromohydrine to a suspension of NaH in THF, as described previously.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](Cl)=[O:9])(=[O:4])=[O:3].[N:14]1([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[Na+].[Na+].[F:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1>ClCCl.CO>[N:14]1([CH:20]2[CH2:25][CH2:24][N:23]([C:8]([C:7]3[CH:6]=[C:5]([S:2]([NH:37][C:36]4[CH:38]=[CH:39][C:33]([F:32])=[CH:34][CH:35]=4)(=[O:4])=[O:3])[CH:13]=[CH:12][CH:11]=3)=[O:9])[CH2:22][CH2:21]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C(Cl)c1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1ccc(F)cc1
Reactant: C1CCN(C2CCNCC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C(c1cccc(S(=O)(=O)Nc2ccc(F)cc2)c1)N1CCC(N2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 3-(chlorosulfonyl)benzoyl chloride (0.359 g, 1.5 mmol) in anhydrous dichloromethane (80 mL) was added 1,4′-bipiperidine (0.252 g, 1.5 mmol) in dichloromethane (4 mL) slowly over 10 minutes at room temperature. Then sodium carbonate (0.32 g, 3 mmol) was added. The mixture was stirred at room temperature for 5 hours. Then 4-fluoroaniline (1.167 g, 10.5 mmol) was added. The mixture was stirred at room temperature for 3 days, then sodium carbonate (0.32 g, 3 mmol) and methanol (5 mL) were added. The mixture was stirred for 20 minutes, then filtered, and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate, then methanol/ethyl acetate=1:10) to give the titled compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.40-1.90 (m, 10H), 2.60-3.40 (m, 8H), 4.45 (m, 1H), 7.08 (m, 4H), 7.62 (m, 3H), 7.78 (m, 1H); MS (ESI) m/z 446 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[C:11](Cl)[C:10]([CH3:14])=[N:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].CN1C(=O)CCC1.[CH2:23]([Mg]Br)[CH:24]([CH3:26])[CH3:25].C[Mg]Br>C1COCC1>[C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[C:11]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:10]([CH3:14])=[N:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[Mg]Br
Reactant: Cc1ncc(C(=O)OC(C)(C)C)cc1Cl
Agent: C[Mg]Br
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: Cc1ncc(C(=O)OC(C)(C)C)cc1CC(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
5-Chloro-6-methyl-nicotinic acid tert.-butyl ester (3.09 g, 13.5 mmol), Fe(acac)3 (719 mg, 2.04 mmol) and NMP (1.95 mL, 20 mmol) are dissolved in THF (3M, 500 mL) and cooled at −78° C. A solution of isobutylmagnesium bromide in THF (2M, 13.6 mmol) is slowly added at −75° C. The brown solution turns turbid and yellow. Stirring is continued for 1 h at −75° C. before it is slowly warmed to rt. The reaction is incomplete, further Fe(acac)3 (719 mg, 2.04 mmol) is added and the mixture is cooled again at −70° C. Further methylmagnesium bromide in THF (2M, 13.6 mmol) is slowly added at −70° C. The dark green mixture is slowly warmed to rt and stirred for 15 h. The mixture is carefully quenched with 0.7N aq. HCl (150 mL). The mixture is extracted with EA (6×60 mL). The combined org. extracts are dried over Na2SO4, filtered and evaporated. The residue is purified by reversed phase MPLC to give 6-methyl-5-isobutyl-nicotinic acid tert.-butyl ester as black oil (0.50 g); LC-MS: tR=0.84 min, [M+1]+=250.14.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([CH:25]=[CH:26][CH:27]=1)[CH2:9][N:10]1[C:14]2=[N:15][CH:16]=[N:17][C:18]([N:19]3CCC[CH2:21][CH2:20]3)=[C:13]2[CH:12]=[N:11]1)[CH3:4].[CH:28]([N:31](CC)C(C)C)(C)[CH3:29].Cl[C:38]([O:40][C:41]1[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=1)=[O:39].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([CH:25]=[CH:26][CH:27]=1)[CH2:9][N:10]1[C:14]2=[N:15][CH:16]=[N:17][C:18]([N:19]3[CH2:29][CH2:28][N:31]([C:38]([O:40][C:41]4[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=4)=[O:39])[CH2:21][CH2:20]3)=[C:13]2[CH:12]=[N:11]1)[CH3:4]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOc1cccc(Cn2ncc3c(N4CCCCC4)ncnc32)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOc1cccc(Cn2ncc3c(N4CCN(C(=O)Oc5ccc([N+](=O)[O-])cc5)CC4)ncnc32)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100 %

Procedure:
To a solution of 1-(3-ethoxybenzyl)-4-(1-piperadinyl)-1H-pyrazolo[3,4-d]pyrimidine dihydrochloride (60 mg) in methylene chloride (1.2 mL) is added N,N-diisopropylethylamine (85 μL) and 4-nitrophenyl chloroformate (49 mg) at 0° C., and the mixture is stirred at room temperature for 2.5 hours. The reaction mixture is diluted with chloroform (1 mL) and thereto is added a saturated sodium hydrogencarbonate solution (1.5 mL). After stirring, the organic layer is separated and the aqueous layer is extracted with chloroform. The organic layers are combined, dried over sodium sulfate, and filtered. The filtrate is concentrated and the residue is purified by column chromatography on silica gel (Solvent; n-hexane:ethyl acetate=9:1→0:10) to give 1-(3-ethoxybenzyl)-4-[4-[(4-nitrophenoxy)carbonyl]piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine (72 mg, yield; 100%) as an amorphous powder. MS (APCI) m/z; 504 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:27])=[C:6]([N:8]([CH2:13][C:14]([N:16]([N:18]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)[CH3:17])=[O:15])[CH2:9][C:10]([OH:12])=O)[CH:7]=1.[NH2:28][CH2:29][CH2:30][NH:31]C(=O)OC(C)(C)C>>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:27])=[C:6]([N:8]([CH2:13][C:14]([N:16]([N:18]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)[CH3:17])=[O:15])[CH2:9][C:10]([NH:28][CH2:29][CH2:30][NH2:31])=[O:12])[CH:7]=1
Reactant: Cc1ccc(Cl)cc1N(CC(=O)O)CC(=O)N(C)N1Cc2ccccc2C1
Reactant: CC(C)(C)OC(=O)NCCN
Product: Cc1ccc(Cl)cc1N(CC(=O)NCCN)CC(=O)N(C)N1Cc2ccccc2C1
Product: Cl
Yield: 215.5 %

Procedure:
Using the compound (400 mg, 1.03 mmol) of Example 45, step A, and tert-butyl (2-aminoethyl)carbamate (215 mg, 1.34 mmol), and according to the methods of Example 1, steps B and C, the title compound (372 mg, yield 72%) was obtained as a colorless solid.
Reaction SMILES: [O:1]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:14]=[C:15]([CH:54]=[CH:55][CH:56]=3)[CH2:16][CH2:17][O:18][CH2:19][CH2:20][C:21]([N:23]([CH2:30][CH2:31][N:32]([CH2:40][CH2:41][C:42]3[C:47]4[O:48][CH2:49][C:50](=[O:52])[NH:51][C:46]=4[C:45]([OH:53])=[CH:44][CH:43]=3)[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:22])[CH2:8][CH2:7]2)[CH2:5][NH:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Si:66](Cl)([C:69]([CH3:72])([CH3:71])[CH3:70])([CH3:68])[CH3:67].C(=O)(O)[O-].[Na+]>CN1C(=O)CCC1>[O:1]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:14]=[C:15]([CH:54]=[CH:55][CH:56]=3)[CH2:16][CH2:17][O:18][CH2:19][CH2:20][C:21]([N:23]([CH2:30][CH2:31][N:32]([CH2:40][CH2:41][C:42]3[C:47]4[O:48][CH2:49][C:50](=[O:52])[NH:51][C:46]=4[C:45]([O:53][Si:66]([C:69]([CH3:72])([CH3:71])[CH3:70])([CH3:68])[CH3:67])=[CH:44][CH:43]=3)[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:36])[CH3:37])[CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:22])[CH2:8][CH2:7]2)[CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(O)c2c1OCC(=O)N2)CCN(C(=O)CCOCCc1cccc(CN2CCC3(CC2)CNCCO3)c1)C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N(CCc1ccc(O[Si](C)(C)C(C)(C)C)c2c1OCC(=O)N2)CCN(C(=O)CCOCCc1cccc(CN2CCC3(CC2)CNCCO3)c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl 2-(3-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)phenethoxy)-N-cyclohexylpropanamido)ethyl(2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)ethyl)carbamate [Examples 81-175, step h] (0.97 g) was dissolved in NMP (10 mL) and treated with Hunig's base (1.0 mL) followed by tert-butyldimethylsilyl chloride (0.45 g). The resulting mixture was stirred at room temperature for 3 hours. The solution was poured into saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined extracts were washed three times with water, once with brine, then dried (MgSO4) and concentrated onto flash silica (20 mL) in-vacuo. The resulting powder was purified by flash chromatography on silica eluted with triethylamine:methanol:dichloromethane (1:5:94) to afford the subtitled compound as a white foam. Yield 0.81 g.
Reaction SMILES: O[C:2]1([C:12]2[C:20]([OH:21])=[CH:19][C:15]3[O:16][CH2:17][O:18][C:14]=3[CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].C([SiH](CC)CC)C.CCCCCCC>COC(C)(C)C>[OH:21][C:20]1[C:12]([CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[NH:4][C:3]2=[O:11])=[CH:13][C:14]2[O:18][CH2:17][O:16][C:15]=2[CH:19]=1
Reactant: O=C1Nc2ccccc2C1(O)c1cc2c(cc1O)OCO2
Agent: CC[SiH](CC)CC
Solvent: COC(C)(C)C
Solvent: CCCCCCC
Product: O=C1Nc2ccccc2C1c1cc2c(cc1O)OCO2
Temperature: 10.5 °C
Reaction time: 1 h
Yield: 77.7 %

Procedure:
A 1600 L reactor was charged with 3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one (113.1 kg, 396 mol), evacuated and filled with nitrogen. Trifluoroacetic acid (679 kg) was added in two portions over 20 minutes and the internal temperature was lowered to 10° C. over 1 h. Triethylsilane (69.2 kg, 595 mol) was added over 2 h 05 min at 10-11° C. and the mixture was stirred for a further 0.5 h at 10-11° C. A 1000 L reactor was charged with heptane (524 kg) and tert-butyl methyl ether (63 kg). The contents of the 1000 L reactor were transferred to the 1600 L reactor over 13 minutes at an internal temperature of 10-11° C. The resultant yellow-orange suspension was allowed to warm to 23° C. over 1 h. The solid was collected by filtration, washed with heptane (464 kg) followed by tert-butyl methyl ether (57 kg) and dried at 50° C. under a reduced pressure of 58 to 7 mbar over a period of 25 h to afford 3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one (82.8 kg, 75%) as an off-white solid: purity (HPLC-UV at 300 nm) 98.0% a/a; 1H NMR (300 MHz, DMSO-d6) δ 10.40 (s, 1H), 9.25 (s, 1H), 7.17-7.10 (m, 1H), 6.95-6.81 (m, 3H), 6.55 (s, 1H), 6.43 (s, 1H), 5.92-5.85 (m, 2H), 4.66 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ 177.9, 150.1, 146.6, 142.7, 139.6, 130.9, 127.4, 123.8, 121.2, 115.9, 109.5, 109.0, 100.7, 97.8, 55.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22]([NH2:30])[C:23]([NH2:29])=[CH:24][CH:25]=4)[O:20][C:19]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[N:38]([O-])=O.[Na+]>C(O)(=O)C.O>[C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21]([O:20][C:19]=3[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[C:22]3[NH:30][N:38]=[N:29][C:23]3=[CH:24][CH:25]=4)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=N[O-]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(N)c(N)ccc4c3=O)cc2)CCC1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5nn[nH]c54)c3=O)cc2)CCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
To a suspension of {1-[4-(7,8-diamino-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (80 mg, 0.16 mmol) in glacial acetic acid (2 mL) and water (1 mL) at 0° C. was added NaNO2 (14 mg, 0.20 mmol). The resulting mixture was stirred at 0° C. for 30 mins, before allowing to warm to RT. After 16 hours, further NaNO2 (14 mg, 0.20 mmol) was added and the reaction mixture stirred at RT for a further 3 hours. The resultant mixture was poured onto water and the aqueous mixture was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with NaHCO3 (2×30 mL), brine, dried (NaSO4), filtered, and the solvent removed in vacuo to give the title compound as a brown solid (51 mg, 63%). LCMS (Method G): RT=3.76 min, [M+H]+=509.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[F:10][C:11]([F:19])([CH2:16][O:17][CH3:18])[C:12](OC)=[O:13]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:12](=[O:13])[C:11]([F:19])([F:10])[CH2:16][O:17][CH3:18])=[N:6][CH:7]=1
Reactant: NNc1ccc(Br)cn1
Reactant: COCC(F)(F)C(=O)OC
Solvent: Cc1ccccc1
Product: COCC(F)(F)C(=O)NNc1ccc(Br)cn1

Procedure:
(5-bromo-2-hydrazinylpyridine (1.83 g, 9.73 mmol) and methyl 2,2-difluoro-3-methoxypropanoate (1.00 g, 6.49 mmol) were refluxed in toluene (35 mL) overnight. The reaction mixture was concentrated and purified by chromatography (EtOAc:hexanes=1:4) to give N′-(5-bromopyridin-2-yl)-2,2-difluoro-3-methoxypropanehydrazide.
Reaction SMILES: C([NH:4][CH2:5][C:6]([C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([NH2:16])[CH:10]=1)([CH3:8])[CH3:7])(=O)C.C(N(CC)CC)C.Cl.[C:25](Cl)(=O)[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.N>O.ClCCl>[NH2:4][CH2:5][C:6]([C:9]1[CH:14]=[CH:13][C:12]2[N:15]=[C:25]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)[NH:16][C:11]=2[CH:10]=1)([CH3:7])[CH3:8]
Reactant: CC(=O)NCC(C)(C)c1ccc(N)c(N)c1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Agent: N
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CN)c1ccc2nc(-c3ccncc3)[nH]c2c1
Temperature: 0 °C

Procedure:
To 22.1 g. 4-(2-acetamidomethylprop-2-yl)-1,2-diaminobenzene and 42 ml. triethylamine in 500 ml. dichloromethane are added, while cooling with ice water, 27 g. isonicotinic acid chloride hydrochloride. Stirring is continued at ambient temperature until the reaction of the diamine is complete (thin layer chromatography, silica gel, dichloromethane:methanolic ammonia=10:1 v/v). It is shaken with water and the organic phase is separated off and evaporated to dryness in a vacuum. The residue (24.3 g.) is taken up in 200 ml. ethanol, mixed with 60 ml. concentrated hydrochloric acid and boiled under reflux for 3 days. It is evaporated to dryness in a vacuum, the residue is digested with aqueous ammonia solution at pH=6, 50 ml. dichloromethane are added thereto, filtered off with suction and then washed with iced water and dichloromethane to give 14.1 g. of colourless crystals which are purified by column chromatography (column: diameter 6 cm., length 40 cm., filled with 1 liter silica gel, elution agent dichloromethane:methanolic ammonia 15:1 v/v). After combining the appropriate fractions, removing the elution agent in a vacuum and triturating with ethyl acetate, there are obtained 9.2 g. of the title compound as colourless crystals; m.p. 199°-202° C. 2.7 g. thereof are recrystallised from dioxan to give 2.3 g. of colourless crystals; m.p. 203°- 204° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9]([C:11]1[C:15]2[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:14]=2[O:13][CH:12]=1)=[O:10].[CH2:21]([O:28][CH2:29][C:30]1[CH:35]=[C:34](Cl)[N:33]=[CH:32][N:31]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN1C(=O)CCC1.O.CCOC(C)=O>[CH3:7][O:8][C:9]([C:11]1[C:15]2[CH:16]=[CH:17][C:18]([O:20][C:34]3[CH:35]=[C:30]([CH2:29][O:28][CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:31]=[CH:32][N:33]=3)=[CH:19][C:14]=2[O:13][CH:12]=1)=[O:10]
Reactant: Clc1cc(COCc2ccccc2)ncn1
Reactant: COC(=O)c1coc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1coc2cc(Oc3cc(COCc4ccccc4)ncn3)ccc12
Temperature: 100 °C
Reaction time: 4 h

Procedure:
415 mg (3.0 mMol) K2CO3 and 249 mg (1.5 mMol) KI are added to a solution of 192 mg (1.00 mMol) 6-hydroxy-benzofuran-3-carboxylic acid methyl ester (Step 9.4) and 258 mg (1.1 mMol) 4-benzyloxymethyl-6-chloro-pyrimidine (commercially available; [CAS: 914802-11-2]) in 1.6 ml NMP. This mixture is stirred for 4 h at 100° C., cooled to rt and diluted with water and EtOAc. The aq. phase is separated off and extracted twice with EtOAc. The organic layers are washed with a diluted solution of Na2S2O3 and brine, dried (Na2SO4) and concentrated. Chromatography (Combi Flash; hexane/EtOAc 19:1→1:1) and crystallization from hexane gives the title compound: m.p.: 85-86° C.; MS: [M+1]+=391; TLC(hexane/EtOAc 2:1): Rf=0.38.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][CH2:14][C:15]([CH3:22])([C:18]([O:20]C)=[O:19])[CH2:16][CH2:17][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[K+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH2:13][CH2:14][C:15]([CH3:22])([C:18]([OH:20])=[O:19])[CH2:16][CH2:17][C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)C1(C)CCc2onc(-c3ccc(Cl)cc3)c2CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C(=O)O)CCc2onc(-c3ccc(Cl)cc3)c2CC1
Temperature: 20 °C
Reaction time: 48 h
Yield: 62.3 %

Procedure:
1 g (3.12 mmol) of methyl 3-(4-chlorophenyl)-5,6,7,8-tetrahydro-6-methyl-4H-cyclohept[d]isoxazole-6-carboxylate was dissolved in 60 ml of methanol and a solution of 0.8 g of potassium hydroxide in 4 ml of water was added. The mixture was stirred at 20° C. for 48 hours and then at 50° C. for 6 hours. The methanol was removed by evaporation. Water was added and the mixture was acidified with 2N hydrochloric acid. The mixture was extracted three times with diethyl ether and the extracts were washed with sodium chloride solution and dried over magnesium sulfate. Evaporation and crystallization of the residue from ethyl acetate/hexane gave 0.594 g of 3-(4-chlorophenyl)-5,6,7,8-tetrahydro-6-methyl-4H-cyclohept[d]isoxazole-6-carboxylic acid of melting point 163° C.
Reaction SMILES: [NH:1]([C:8]1[CH:21]=[CH:20][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](OC)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].CC([O-])C.CC([O-])C.CC([O-])C.[Al+3].[Na]>>[C:22]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:11]1[CH:20]=[CH:21][C:8]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: COC(=O)C(C)(C)C
Reactant: OCCCCCCOc1ccc(Nc2ccccc2)cc1
Agent: CC(C)[O-]
Agent: [Al+3]
Agent: [Na]
Product: CC(C)(C)C(=O)OCCCCCCOc1ccc(Nc2ccccc2)cc1
Temperature: 88 °C
Reaction time: 3 h

Procedure:
A mixture of 6-(p-anilinophenoxy)hexanol (28.5 g.) and methyl pivalate (34.5 g.) to which 0.3 g. of aluminum isopropylate and a small chip of sodium metal had been added was heated at 88° C. while stirring for about 3 hours. Gas chromatography indicated that transesterification was not complete. Methyl pivalate was distilled from the reaction allowing the temperature to rise to 160° C. and was then added slowly back to the mixture at such a rate that the temperature could be maintained at 175°-185° C. After two hours, the reaction mixture was stripped of volatiles by heating at 120° C. under reduced pressure (150 mm of mercury). The solid residue obtained on cooling was recrystallized from 2-propanol to afford the ester, 6-(p-anilinophenoxy)hexyl pivalate as a crystalline solid, m.p. 64°-65° C.
Reaction SMILES: [CH3:1][N:2]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([OH:11])=O)[CH:4]=1.[CH3:18][C:19]1[N:20]=[C:21]([NH2:24])[S:22][CH:23]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH3:1][N:2]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([NH:24][C:21]2[S:22][CH:23]=[C:19]([CH3:18])[N:20]=2)=[O:11])[CH:4]=1
Reactant: CN(c1cccnc1)c1ccnc(C(=O)O)c1
Reactant: Cc1csc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1csc(NC(=O)c2cc(N(C)c3cccnc3)ccn2)n1
Yield: 26.9 %

Procedure:
Compound 12 (0.1 g, 0.4 mmol, 1 eq), 4-methylthiazol-2-amine (60 mg, 0.53 mmol, 1.2 eq), 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (348 mg, 0.915 mmol, 2.10 eq), and DIEA (160 μL, 0.915 mmol, 2.10 eq) were dissolved in CH2Cl2 (5 mL) and DMF (1 mL) and stirred rt for 48 h. The reaction was diluted with CH2Cl2 and washed with water (1×). The organics were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 35 mg (25%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.60 (d, J=2.3 Hz, 1H), 8.56 (dd, J=4.7, 1.1 Hz, 1H), 8.33 (d, J=4.8 Hz, 1H), 7.83 (ddd, J=8.2, 2.4, 1.5 Hz, 1H), 7.55 (dd, J=8.1, 4.7 Hz, 1H), 7.31 (s, 1H), 6.94-6.89 (m, 1H), 8.86 (s, 1H), 3.40 (s, 3H), 2.28 (s, 3H); [M+1]+: 326.2.