Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH2:28][CH2:29][C:30](=[O:33])[NH:31][N:32]=2)=[CH:23][CH:22]=1>C(OCC)(=O)C>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH2:28][CH2:29][C:30](=[O:33])[NH:31][N:32]=2)=[CH:23][CH:22]=1)[CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(CCCc1ccccc1)c1ccc(O)cc1O
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Solvent: CCOC(C)=O
Product: O=C1CCC(c2ccc(N=C(CCCc3ccccc3)c3ccc(O)cc3O)cc2)=NN1
Temperature: 150 °C

Procedure:
A mixture containing 0.2 g of 1-(2,4-dihydroxyphenyl)4-phenylbutan-1-one and 6-(4-aminophenyl)-4,5-dihydropyridazin-3(2H)one was heated for 24 h at 150° C. The product was treated with ethyl acetate. Yield 0.2 g (88%), m.p. 274°-280° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].C1O[C:10]2([CH2:19][CH2:18][C:13]3([NH:17][CH2:16][CH2:15][CH2:14]3)[CH2:12][CH2:11]2)[O:9]C1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[N:17]1([C:2]([O:4][CH2:5][CH3:6])=[O:3])[C:13]2([CH2:18][CH2:19][C:10](=[O:9])[CH2:11][CH2:12]2)[CH2:14][CH2:15][CH2:16]1
Reactant: C1CNC2(C1)CCC1(CC2)OCCO1
Reactant: CCOC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCCC12CCC(=O)CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.6 %

Procedure:
Ethyl chloroformate (1.90 mL, 2.16 g, 19.9 mmol) was added drop-wise to a cold (0° C.), stirred solution of 1-azaspiro[4.5]decan-8-one ethylene ketal (3.00 g, 15.2 mmol), triethylamine (3.20 mL, 2.32 g, 23.0 mmol) and catalytic 4-(dimethylamino)pyridine (10 mg) in dry dichloromethane (25 mL) under a nitrogen atmosphere. The ice bath was removed and the reaction was stirred 4 h at ambient temperature and poured into saturated aqueous sodium bicarbonate (10 mL). The mixture was shaken and the organic layer drawn off. The aqueous layer was extracted with dichloromethane (25 mL), and the combined dichloromethane extracts were dried (Na2SO4) and concentrated by rotary evaporation. The residue (3.5 g) was combined with 2% aqueous sulfuric acid (50 mL) and stirred 3 h at ambient temperature. The mixture was extracted with ethyl acetate (4×20 mL), and the combined extracts were washed successively with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride (10 mL each) and dried (Na2SO4). The residue from concentration of the dried extracts was dissolved dichloromethane (100 mL) and stirred for 1 h with silica gel (5 g). The silica gel was then removed by filtration, and the filtrate was concentrated, leaving 2.35 g (68.7%) of viscous colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:15][CH:14]=2)[N:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC.[C:54]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[CH2:62][C:63]([O:65][CH3:66])=[O:64])#[CH:55]>CN(C=O)C.C1(C)C=CC=CC=1.[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>[C:21]([O:20][C:19]([NH:18][CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([C:55]#[C:54][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=3[CH2:62][C:63]([O:65][CH3:66])=[O:64])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)=[O:25])([CH3:24])([CH3:23])[CH3:22]
Reactant: C#Cc1ccccc1CC(=O)OC
Reactant: CC(C)(C)OC(=O)NCc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(CNC(=O)OC(C)(C)C)cc2)ncc1C(F)(F)F
Temperature: 120 °C

Procedure:
A suspension of tert-butyl 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzylcarbamate (A12) (500 mg, 1.24 mmol), CuI (12 mg, 0.06 mmol), PPh3 (16 mg, 0.06 mmol), and Et3N (346 μL, 2.28 mmol) in DMF (3 mL) was sonicated for 5 minutes before the addition of PdCl2(PPh3)2 (44 mg, 0.06 mmol) and methyl 2-(2-ethynylphenyl)acetate (K1) (324 mg, 1.86 mmol). The resulting mixture was heated under microwave irradiation at 120° C. for 20 minutes then adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to yield a yellow solid. The solid was suspended in toluene and the resulting suspension sonicated for 10 minutes. The resulting suspension was filtered and the filter cake dried to give the title compound A13 as a yellow solid (412 mg, 61%); 1H NMR (400 MHz, d6-DMSO) δ 10.44 (s, 1H), 8.82 (s, 1H), 7.68 (d, J=8.4 Hz, 2H), 7.63 (d, J=7.6 Hz, 1H), 7.58-7.52 (m, 1H), 7.50-7.40 (m, 2H), 7.36 (t, J=6.0 Hz, 1H), 7.22 (d, J=8.5 Hz, 2H), 4.10 (d, J=6.0 Hz, 2H), 3.96 (s, 2H), 3.62 (s, 3H), 1.40 (s, 9H). LCMS-A: rt 6.497 min; m/z 539 [M−1]−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][N:19](C)[CH2:18][CH2:17]3)[C:6]=2[CH:23]=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][N:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:18][CH2:17]3)[C:6]=2[CH:23]=1
Reactant: CCOC(=O)Cl
Reactant: CN1CCN(C2=Nc3ccccc3Sc3ccc(Cl)cc32)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCN(C2=Nc3ccccc3Sc3ccc(Cl)cc32)CC1
Temperature: 0 °C
Yield: 69.6 %

Procedure:
A mixture of 0.86 g of 2-chloro-11-(4-methyl-1-piperazinyl)dibenzo[b,f][1,4]thiazepine and 0.81 g of ethyl chloroformate in 5 ml of toluene was refluxed for 5 hrs. Ice water was added to the reaction mixture and made alkaline with sodium bicarbonate. The mixture was extracted with methylene chloride and the methylene chloride layer was washed with water, dried and concentrated. The residue was chromatographed on silica gel using methylene chloride as an eluent to give 0.70 g of colorless crystals, which were recrystallized from a mixture of isopropyl ether and n-pentane to give colorless prisms, mp 96.5°-97.5° C.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][C@H:17]([CH2:21]OS(C)(=O)=O)[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[OH:27][C@@H:28]1[CH2:32][CH2:31][NH:30][CH2:29]1>CN1C(=O)CCC1>[C:4]1([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][CH:17]([CH2:21][N:30]4[CH2:31][CH2:32][C@@H:28]([OH:27])[CH2:29]4)[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=1
Reactant: O[C@@H]1CCNC1
Reactant: CS(=O)(=O)OC[C@H]1CCc2ccc(S(=O)(=O)c3cccc(F)c3)cc2O1
Solvent: CN1CCCC1=O
Product: O=S(=O)(c1ccccc1)c1ccc2c(c1)OC(CN1CC[C@@H](O)C1)CC2
Temperature: 110 °C
Yield: 83.6 %

Procedure:
Methanesulfonic acid (R)-7-(3-fluoro-benzenesulfonyl)-chroman-2-ylmethyl ester (0.052 g, 0.13 mmol), (R)-3-hydroxypyrrolidine (0.035 g) and NMP (0.5 mL were sealed in a tube and heated to 110° C. for 18 hours. The reaction mixture was cooled and partitioned between water and diethyl ether. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography to give 40.6 mg of (R)-1-(7-benzenesulfonyl-chroman-2-ylmethyl)-pyrrolidin-3-ol, MS (M+H)=374.
Reaction SMILES: [C:1]([O:5][CH2:6]C)(=[O:4])[CH:2]=[CH2:3].[CH2:8]([N:15]([CH2:21]OC)[CH2:16][Si](C)(C)C)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:8]([N:15]1[CH2:21][CH2:3][CH:2]([C:1]([O:5][CH3:6])=[O:4])[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C=CC(=O)OCC
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Ethyl acrylate (86 g, 1.0 mole) in dichloromethane (2 L) was cooled to 0° C. and treated with N-benzyl-N-(methoxymethyl)-N-[(trimethylsilyl)methyl]amine (D8) (300 g, 80% pure by 1H NMR, 1 mole) with stirring over a period of 10 min whilst maintaining the temperature between -5° C. and 0° C. A solution of trifluoroacetic acid in dichloromethane (100 ml, 1 molar) was added at such a rate that the temperature did not rise above 5° C. and the reaction allowed to warm to room temperature overnight. The solution was then washed with saturated aqueous potassium carbonate solution, dried over sodium sulphate and concentrated in vacuo to a gum. The gum was distilled in vacuo to afford the title compound (D16) as a single main fraction. Bpt 150°-160° at 8 mm (232 g, 100%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.[CH:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.FC(F)(F)C1C=C(Cl)C=CC=1C(O)C1C=CC=CC=1>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:13]([OH:22])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1
Reactant: COc1ccc(C=O)cc1
Reactant: FC(F)(F)c1ccccc1[Mg]Br
Agent: OC(c1ccccc1)c1ccc(Cl)cc1C(F)(F)F
Product: COc1ccc(C(O)c2ccccc2C(F)(F)F)cc1

Procedure:
This material was prepared from 2-(trifluoromethyl)phenylmagnesium bromide (16 mmol) and p-anisaldehyde (1.86 mL, 15 mmol) using the procedure described for compound (96) (4.34 g, 100%).
Reaction SMILES: CN(C(O[N:9]1N=N[C:11]2C=CC=N[C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Br:34][C:35]1[CH:36]=[C:37]([C:43]([OH:45])=O)[C:38]([O:41][CH3:42])=[N:39][CH:40]=1.Cl.C(N)C>CN(C=O)C.C(OCC)(=O)C.O>[Br:34][C:35]1[CH:40]=[N:39][C:38]([O:41][CH3:42])=[C:37]([CH:36]=1)[C:43]([NH:9][CH2:10][CH3:11])=[O:45]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1ncc(Br)cc1C(=O)O
Agent: CCN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCNC(=O)c1cc(Br)cnc1OC
Reaction time: 0.17 h

Procedure:
As shown in step 4(b)-i of Scheme 4(b), HATU (8.194 g, 2.55 mmol) and DIPEA (5.570 g, 7.507 mL, 43.10 mmol) was added to a solution of 5-bromo-2-methoxypyridine-3-carboxylic acid (5 g, 21.55 mmol) in DMF (50 mL). The resulting solution was stirred for 10 minutes followed by the addition of ethanamine hydrochloric acid (1.757 g, 2.196 mL, 21.55 mmol). The resulting solution was stirred at room temperature for 5 hours. To the reaction mixture was added water (100 mL) and ethyl acetate (100 mL). The organic layer was separated and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0-2% methanol in dichloromethane gradient) to produce 5-bromo-N-ethyl-2-methoxynicotinamide as off white solid (Compound 2015, 3.4 g): 1H NMR (DMSO-d6) δ 8.41 (d, J=2.5 Hz, 1H), 8.31 (s, 1H), 8.20-8.13 (m, 1H), 3.95 (s, 3H), 3.35-3.23 (m, 2H), 1.11 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].FC(F)(F)S(O[CH2:22][C:23]([F:26])([F:25])[F:24])(=O)=O.CCOC(C)=O>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:6][N:7]=1
Reactant: OCc1ccc(Cl)nc1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: FC(F)(F)COCc1ccc(Cl)nc1
Temperature: 25 °C
Yield: 34.2 %

Procedure:
(6-Chloropyridin-3-yl)methanol (1.0 g, 6.97 mmol) was dissolved in THF (20 mL), potassium tert-butoxide (0.860 g, 7.66 mmol) was added and the mixture stirred at room temperature. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (1.78 g, 7.66 mmol) was added dropwise with ice cooling and then the mixture stirred at room temperature for 2 h. EtOAc (50 mL) and water (50 mL) were added, the organic layer was separated and the aqueous layer neutralised to pH 6. The aqueous layer was then further extracted with EtOAc (3×20 mL), combined organic layers were dried over sodium sulfate and concentrated to yield a yellow solid. This was purified by FCC, eluting with a gradient of 0-50% EtOAc in heptane to afford the title compound as a colourless oil (0.537 g, 34%). 1H NMR (500 MHZ, CDCl3) δ ppm 8.30 (1H, d), 7.61 (1H, dd), 7.30 (1H, d), 4.61 (2H, s) and 3.82 (2H, q).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O=S(Cl)Cl.[CH3:21]O>>[Cl:1][C:2]1[CH:10]=[C:9]([S:11]([F:16])([F:12])([F:13])([F:14])[F:15])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:21])=[O:5]
Reactant: CO
Reactant: O=C(O)c1ccc(S(F)(F)(F)(F)F)cc1Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(S(F)(F)(F)(F)F)cc1Cl

Procedure:
4.3 g of 2-chloro-4-pentafluorosulfanylbenzoic acid were dissolved in 50 ml of methanol and, at RT, 5.6 ml of SOCl2 were slowly added dropwise. After boiling under reflux for 6 hours and removal of the volatile constituents in vacuo, the residue was taken up in 100 ml of toluene, and the volatile constituents were again removed in vacuo. 4.1 g of a colorless oil were obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C>[N:27]1([C:2]2[N:3]=[C:4]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28]1
Reactant: c1ccc2c(c1)CCN2
Reactant: CN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: CN(C)C1CCN(Cc2cc3nc(N4CCc5ccccc54)nc(N4CCOCC4)c3s2)CC1
Temperature: 150 °C
Yield: 37.2 %

Procedure:
A microwave vessel was charged with [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-dimethyl-amine (0.2 g), indoline (0.12 g), p-toluenesulfonic acid (0.01 g), and DMF (3 mL). The vessel was sealed and heated at 150° C. under microwave irradiation for 4 h. The reaction mixture was cooled to room temperature and the solid precipitate was filtered and purified by chromatography (silica, 0 to 20% of a 49:1 MeOH:NH4OH mixture in dichloromethane) to furnish the title compound (0.09 g, 38%) as an off-white solid. MS m/e 479 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.36-1.65 (m, 2H) 1.85 (d, J=11.30 Hz, 2H) 2.06 (t, J=10.74 Hz, 2H) 2.44 (br. s., 6H) 2.97 (d, J=11.30 Hz, 2H) 3.12 (t, J=8.48 Hz, 3H) 3.67-3.93 (m, 10H) 4.17 (t, J=8.67 Hz, 2H) 6.84 (t, J=7.35 Hz, 1H) 7.03-7.29 (m, 3H) 8.31 (d, J=7.91 Hz, 1H).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([F:26])[CH:25]=1>>[F:19][C:20]1[CH:21]=[C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)[CH:23]=[C:24]([F:26])[CH:25]=1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Reactant: OB(O)c1cc(F)cc(F)c1
Product: N#Cc1cc(-c2cc(F)cc(F)c2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, light grey solid (65 mg, 77%), MS (ISP) m/z=338.6 [(M+H)+], mp 211° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 3,5-difluoro-phenylboronic acid (51.3 mg, 0.325 mmol).
Reaction SMILES: C(OC([CH:8]([NH2:19])[C@H:9]1[CH2:13][CH2:12][C@@H:11]([O:14]S(C)(=O)=O)[CH2:10]1)=O)(C)(C)C.O[C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[C:27](=[O:31])[NH:26][CH:25]=[CH:24]2.C(=O)([O-])[O-].[K+].[K+].C([O-])(O)=O.[Na+].FC(F)(F)C(O)=O>CN(C)C=O.CO.ClCCl>[NH2:19][CH2:8][C@H:9]1[CH2:13][CH2:12][C@@H:11]([O:14][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[C:27](=[O:31])[NH:26][CH:25]=[CH:24]3)[CH2:10]1
Reactant: CC(C)(C)OC(=O)C(N)[C@H]1CC[C@@H](OS(C)(=O)=O)C1
Reactant: O=c1[nH]ccc2cc(O)ccc12
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC[C@H]1CC[C@@H](Oc2ccc3c(=O)[nH]ccc3c2)C1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
A solution of the methanesulfonic acid (1R,3S)-3-(tert-butoxycarbonyl-aminomethyl)cyclopentyl ester in N,N-dimethylformamide (2 ml) was added over 15 minutes to a stirred solution of 6-hydroxy-2H-isoquinolin-1-one (161 mg, 1 mmol) and potassium carbonate (276 mg) in N, N-dimethylformamide (2 ml) at 100° C. The mixture was stirred at 90° C. for 4 h then allowed to cool to ambient temperature and stirred overnight. Saturated aqueous NaHCO3 was added, the mixture was extracted with chloroform: isopropanol (3:1) and the organic phase concentrated in vacuo to give a residue. A dichloromethane: trifluoroacetic acid solution (3:1, 3 ml) was added to the residue and the resultant mixture stirred for 3.5 h, then concentrated in vacuo to give a residue. The residue was loaded onto a pre-acidified SCX column using methanol and eluted with 2M ammonia in methanol to afford crude (1R,3S)-6-(3-aminomethylcyclopentyloxy)-2H-isoquinolin-1-one, which was purified by prep-HPLC (2 mg); EI-MS: m/z=259.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23]C(OC(C)(C)C)=O)[CH2:19][C@H:18]2[C:31]([O:33][CH3:34])=[O:32])[C:13]1=[O:35])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:23][C@H:20]1[CH2:19][C@@H:18]([C:31]([O:33][CH3:34])=[O:32])[C@@H:17]([N:14]2[CH2:15][CH2:16][C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[C:13]2=[O:35])[CH2:22][CH2:21]1
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](N)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
A solution of (1R,2S,5R)-methyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butoxycarbonylamino)-cyclohexanecarboxylate in CH2Cl2 (10 mL) was treated with TFA (15 mL) and stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo and the residue dissolved in CH2Cl2 and washed with NaHCO3(aq), brine, and dried over MgSO4. The solution was filtered and concentrated in vacuo to give 0.75 g (59%) of (1R,2S,5R)-methyl 5-amino-2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)cyclohexanecarboxylate as a white solid. MS found: (M+H)+=390.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][O:13][C:14]2[C:22]([F:23])=[CH:21][C:17]([C:18](O)=[O:19])=[C:16]([F:24])[CH:15]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C(N(C(C)C)C(C)C)C.[CH3:34][N:35]([CH3:40])[S:36]([NH2:39])(=[O:38])=[O:37]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][O:13][C:14]2[C:22]([F:23])=[CH:21][C:17]([C:18]([NH:39][S:36]([N:35]([CH3:40])[CH3:34])(=[O:38])=[O:37])=[O:19])=[C:16]([F:24])[CH:15]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ncc(COc2cc(F)c(C(=O)O)cc2F)cc1Cl
Reactant: CN(C)S(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)Oc1ncc(COc2cc(F)c(C(=O)NS(=O)(=O)N(C)C)cc2F)cc1Cl
Reaction time: 18 h

Procedure:
To 4-((5-chloro-6-isopropoxypyridin-3-yl)methoxy)-2,5-difluorobenzoic acid (Preparation 9, 0.05 g, 0.14 mmol) in solution in DCM (5 mL) is added WSCDI (0.04 g, 0.21 mmol), DMAP (0.026 g, 0.21 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.09 mL, 0.42 mmol). After 10 minutes was added N,N-dimethylsulfamide (0.026 g, 0.21 mmol) and the reaction was left at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and purified using reverse phase preparative HPLC to afford the title compound.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O)=[O:4].[NH2:23][CH2:24][CH2:25][CH2:26][NH2:27].O>C(O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:6]2[NH:5][C:3](=[O:4])[N:23]3[CH2:24][CH2:25][CH2:26][NH:27][C:8]3([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7]=2[CH:16]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1NC(=O)C(Cl)(Cl)Cl
Reactant: NCCCN
Solvent: CCO
Solvent: O
Product: O=C1Nc2ccc(Cl)cc2C2(c3ccccc3)NCCCN12
Reaction time: 8 h
Yield: 79.5 %

Procedure:
To a solution of 1.89 g of 2-trichloroacetamido-5-chlorobenzophenone in 50 ml of ethanol was added 2.22 g of 1,3-diaminopropane, and the resultant mixture was allowed to stand at room temperature overnight. Then, the reaction mixture was poured into 300 ml of water, and the precipitate thus formed was separated by filtration, washed with ether and dried to give 1.25 g of 10-chloro-1,2,3,4,7,11b-hexahydro-11b-phenyl-6H-pyrimido[1,2-C]quinazolin-6-one, having a melting point of 275° - 276°C.
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH2:9].C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C.C(O[C:26](=[N:28][C:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:27])C>O>[CH3:27][C:26]1[N:28]=[C:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:10])[N:9]=1
Reactant: Cc1ccccc1NN
Reactant: CCOC(C)=NC(=O)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: Cc1nc(-c2ccccc2)n(-c2ccccc2C)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 84 %

Procedure:
Next, into a 300-mL recovery flask were put 8.68 g of o-tolylhydrazine hydrochloride, 100 mL of carbon tetrachloride, and 35 mL of triethylamine (Et3N), and the mixture was stirred at room temperature for 1 hour. After a predetermined time elapsed, 8.72 g of N-(1-ethoxyethylidene)benzamide obtained in Step 1 above was added to this mixture, and the mixture was stirred at room temperature for 24 hours. After a predetermined time elapsed, water was added to the reaction mixture, and the aqueous layer was subjected to extraction with chloroform. The organic layer was washed with saturated brine, and dried with anhydrous magnesium sulfate added thereto. The obtained mixture was gravity-filtered, and the filtrate was concentrated to give an oily substance. The obtained oily substance was purified by silica gel column chromatography. Dichloromethane was used as a developing solvent. The obtained fraction was concentrated to give 3-methyl-1-(2-methylphenyl)-5-phenyl-1H-1,2,4-triazole (abbreviation: HMptzl-mp) (an orange oily substance, 84% yield). A synthesis scheme of Step 2 is shown in (a-2) below
Reaction SMILES: [Si:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]([CH:18]([F:20])[F:19])[N:14]([C:21]3[N:26]=[C:25](Cl)[N:24]=[C:23]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[N:22]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N:34]1([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>C1COCC1>[Si:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]([CH:18]([F:20])[F:19])[N:14]([C:21]3[N:22]=[C:23]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[N:24]=[C:25]([N:37]4[CH2:36][CH2:35][N:34]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39][CH2:38]4)[N:26]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(O[Si](C)(C)C(C)(C)C)cccc43)n2)CC1

Procedure:
Reaction of 4-(tert-butyldimethylsilyloxy)-1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole with 2.2 equivalents of tert-butyl 1-piperazinecarboxylate in THF at room temperature gave a quantitative yield of tert-butyl 4-[4-[4-(tert-butyldimethylsilyloxy)-2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperazine-1-carboxylate as an oil: 1H NMR (CDCl3) δ 7.91 (d, J=8.2 Hz, 1H), 7.45 (t, JHF=53.6 Hz, 1H), 7.26 (t, J=8.1 Hz, 1H), 6.83 (d, J=7.9 Hz, 1H), 3.85 (m, 8H), 3.77 (m, 4H), 3.53 (m, 4H), 1.50 (s, 9H), 1.05 (s, 9H), 0.30 (s, 6H); MS (APCI+) 648.7 [MH+].