Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:10]=[C:6]2[N:5]([CH2:22][CH3:23])[C:4](=[O:24])[CH:3]=1.[N:25](OCCC(C)C)=[O:26].O>CN(C)C=O>[NH2:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:10]=[C:6]2[N:5]([CH2:22][CH3:23])[C:4](=[O:24])[C:3]=1[N:25]=[O:26]
Reactant: CCn1c(=O)cc(N)n2nc(COCc3ccc(OC)cc3)nc12
Reactant: CC(C)CCON=O
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)c(N=O)c(N)n2nc(COCc3ccc(OC)cc3)nc12
Temperature: 25 °C

Procedure:
3.7 g of the precursor (7-amino-4-ethyl-2-[(4-methoxybenzyloxy)methyl]-s-triazolo[1,5-a]pyrimidin-5-one) are dissolved in 17 ml of dimethylformamide, and 2.69 ml of isoamyl nitrite are added whilst cooling with ice. Afterwards it is stirred at ambient temperature. After the reaction is complete (about 3 hours) 34 ml of water are added at 5-10° C. The solid obtained is separated off, washed with water and diethyl ether and recrystallised from 80 ml of ethanol. 2.0 g of 7-amino-4-ethyl-2-[(4-methoxybenzyloxy)methyl]-6-nitroso-s-triazolo[1,5-a]pyrimidin-5-one are left.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[N+:10]([C:13]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:14]=1[C:15](O)=[O:16])([O-:12])=[O:11].Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:15](=[O:16])[C:14]2[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:13]=2[N+:10]([O-:12])=[O:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cc1
Reactant: Cc1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2cc(C)ccc2[N+](=O)[O-])cc1
Reaction time: 12 h
Yield: 49.9 %

Procedure:
To a stirred solution of 4-methoxyaniline (1.4 g, 11 mmol) and 2-nitro-5-methylbenzoic acid (2.0 g, 11 mmol) in dimethylformamide (20 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.17 g, 16.5 mmol). After 12 h, the solvent was removed in vacuo. The residue was dissolved in ethyl acetate and washed twice with 1 M aqueous citric acid, once with water, twice with saturated aqueous sodium bicarbonate solution, once with water, and once with saturated aqueous sodium chloride solution. The organic phase was dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was triturated with diethyl ether, filtered, and dried in vacuo to give 1.57 g (50%) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH:4]=[C:5]1[C:9]2=[N:10][C:11]3[CH:12]=[CH:13][C:14]([C:19]([NH2:21])=O)=[CH:15][C:16]=3[C:17](=[O:18])[N:8]2[CH2:7][CH2:6]1.N1C=CC=CC=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>CN(C)C=O>[C:19]([C:14]1[CH:13]=[CH:12][C:11]2[N:10]=[C:9]3[C:5](=[CH:4][C:3]4[CH:22]=[CH:23][CH:24]=[CH:25][C:2]=4[CH3:1])[CH2:6][CH2:7][N:8]3[C:17](=[O:18])[C:16]=2[CH:15]=1)#[N:21]
Reactant: Cc1ccccc1C=C1CCn2c1nc1ccc(C(N)=O)cc1c2=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1ccccc1C=C1CCn2c1nc1ccc(C#N)cc1c2=O
Temperature: 70 °C
Reaction time: 4 h
Yield: 70.5 %

Procedure:
3-(2-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-pyrrolo[2,1-b]quinazoline-7-carboxamide (2.7 g) in dimethylformamide (100 ml) containing pyridine (2.6 ml) was reacted with p-toluenesulfonyl chloride (3.1 g) under stirring at 70° C. for 4 hours. After cooling and dilution with water, the precipitate was filtered and washed with water until neutral: crystallization from chloroform-ethanol gave 1.8 g of 7-cyano-3-(2-methyl-benzylidene)-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline-9-one, m.p. 234°-236° C., NMR (CDCl3 -DMSO-CF3COOD) δ ppm: 2.50 (s) (3H, --CH3), 3.29 (m) (2H, C-2 protons), 4.28 (t) (2H, C-1 protons), 7.30-7.60 (m) (4H, phenyl protons), 7.89 (m) (2H, C-5 and C-6 protons), 8.16 (d) (1H, C-8 proton), 8.59 (t) (1H, =CH--).
Reaction SMILES: CS[CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=2)[NH:5][C:4]1=[O:18]>[Ni].O.O1CCCC1>[C:12]1([C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[NH:5][C:4](=[O:18])[CH2:3]3)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CSC1C(=O)Nc2ccc(-c3ccccc3)cc21
Agent: [Ni]
Solvent: C1CCOC1
Solvent: O
Product: O=C1Cc2cc(-c3ccccc3)ccc2N1

Procedure:
To a slurry of 11.2 g. (0.044 mole) of 3-methylthio-5-phenylindolin-2-one in 500 ml. of tetrahydrofuran was added 100 g. of a commercial Raney nickel/water preparation portionwise over a 2 hr. period. The mixture was filtered through celite and the filtrate was concentrated. A small amount of methylene chloride was added to the residue and the resulting solid was collected by filtration. This solid was recrystallized from toluene to give 6.2 g. (67%) of product as a tan solid, m.p. 214°-15° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH:18]3[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[CH2:25]([O:27][NH2:28])[CH3:26].C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[CH2:25]([O:27][N:28]=[C:21]1[CH2:22][CH2:23][CH:18]([N:15]2[CH2:14][CH2:13][CH:12]([N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:9](=[O:11])[CH3:10])[CH2:17][CH2:16]2)[CH2:19][CH2:20]1)[CH3:26]
Reactant: CC(=O)N(c1ccc(F)cc1)C1CCN(C2CCC(=O)CC2)CC1
Reactant: CCON
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CCON=C1CCC(N2CCC(N(C(C)=O)c3ccc(F)cc3)CC2)CC1
Temperature: 80 °C

Procedure:
N-(4-fluorophenyl)-N-(1-(4-oxocyclohexyl)piperidin-4-yl)acetamide (100 mg; 0.3 mmol; 1 eq.) was dissolved in pyridine (2 mL). O-ethylhydroxylamine (22 mg, 0.36 mmol; 1.2 eq.) was added. The solution was heated to 80° C. for 30 min. Saturated NaHCO3 (10 mL) was added and the solution was extracted with EtOAc (2×20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by reversed-phase HPLC (2-99% CH3CN/H2O gradient with 0.05% TFA) to provide the desired product. LC/MS m/z 333.2, Retention time=1.79; 10-99% CH3CN/H2O gradient with 0.05% TFA).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=1.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(COc2cccc(Cl)c2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(COc2cccc(Cl)c2)cc1
Reaction time: 4 h

Procedure:
A mixture of compound 35c (340 mg, 1.18 mmol) and LiOH (114 mg, 4.74 mmol) in THF/MeOH/H2O (3/3/3 mL) was stirred for 4 h. A 15% citric acid solution (10 mL) was added. The mixture was then extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The resultant residue, compound 35d (230 mg) was dried under reduced pressure for 18 h and used without further purification.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>C(O)(=O)C>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:21][C:22](=[O:24])[CH3:23])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reaction time: 16 h
Yield: 100.8 %

Procedure:
(R)—N2-indan-1-yl-quinoline-2,6-diamine (551 mg, 2 mmol) was dissolved in acetic acid (5 mL) then acetic anhydride (378 ul, 4 mmol) was added and the mixture was stirred at for 16 h. The reaction mixture was extracted with ethyl acetate and sat. NaHCO3-sol., the organic layers were combined, dried over MgSO4, filtered and the solvents evaporated to give the title compound as a light brown foam (640 mg, 100%); MS: m/e=318.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][C:8](=O)[NH:9]2)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]>O=S(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:13][C:3]3[CH:2]=[CH:11][CH:10]=[C:5]([CH3:6])[CH:4]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: O=c1ncc2cc([N+](=O)[O-])c(F)cc2[nH]1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cccc(Nc2ncnc3cc(F)c([N+](=O)[O-])cc23)c1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 175.8 %

Procedure:
A suspension of 7-fluoro-6-nitroquinazolone (2.40 g, 11.48 mmol) in neat SOCl2 (25 mL) containing 2 drops of DMF was refluxed for 3 hours until it became clear. The excess SOCl2 was then removed in vacuo and dry benzene was added to the residue and then distilled under reduced pressure to remove all traces of SOCl2 giving crude 4-chloro-7-fluoro-6-nitroquinazoline, which was dissolved in dry CH2Cl2 (50 mL) and added to a stirred solution of m-toluidine in isopropanol (i-PrOH) (30 mL). The reaction mixture was stirred at 20° C. for 30 minutes and then hexane (200 mL) was added to precipitate the product as the HCl salt. The precipitate was filtered, washed with hexane, and then dissolved in MeOH/H2O (4:1, 150 mL) with gentle warming. Excess Et3N was then added to the solution followed by water (400 mL) to precipitate the product as the free base which was then filtered, washed with water and dried under reduced pressure to give 7-fluoro-4-[(3-methylphenyl)-amino]-6-nitroquinazoline (3.01 g, 88%) as a yellow powder, mp (CH2Cl2/hexane) 191-192° C.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([O:17][C:18]([NH:20][C:21]1([C:24]([OH:26])=O)[CH2:23][CH2:22]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(CC)C(C)C)(C)C.[Br:36][C:37]1[C:38]([NH2:44])=[N:39][CH:40]=[C:41]([Br:43])[N:42]=1>CN(C)C=O.ClCCl.C(OCC)(=O)C>[Br:36][C:37]1[C:38]([NH:44][C:24]([C:21]2([NH:20][C:18](=[O:19])[O:17][C:13]([CH3:14])([CH3:15])[CH3:16])[CH2:22][CH2:23]2)=[O:26])=[N:39][CH:40]=[C:41]([Br:43])[N:42]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Reactant: Nc1ncc(Br)nc1Br
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(C(=O)Nc2ncc(Br)nc2Br)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.1 %

Procedure:
1,1′-Carbonyldiimidazole (4.37 g, 27.0 mmol) was added to a stirred solution of 1-(tert-butoxycarbonylamino)cyclopropanecarboxylic acid (4.93 g, 24.50 mmol) in N,N-dimethylformamide (6 mL) and dichloromethane (12 mL) at room temperature. The resulting clear yellow mixture was stirred at room temperature under nitrogen for 4 h. N,N-Diisopropylethylamine (8.54 mL, 49.0 mmol) was added followed by 3,5-dibromopyrazin-2-amine (9.29 g, 36.8 mmol). The resulting mixture was heated at 50° C. under a reflux condenser under nitrogen for 60 h. The resulting mixture was diluted with ethyl acetate and washed with water. The layers were separated and the organic layer washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was taken up in dichloromethane and purified using flash chromatography (Biotage) (5-60% ethyl acetate in hexane). Fractions containing the desired product were combined and concentrated under reduced pressure. The residue was triturated with 15% ethyl acetate in hexane and dried under high vacuum to give the desired product (5.349 g, 12.27 mmol, 50% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 9.92 (br. s., 1H), 8.76 (s, 1H), 7.70 (br. s., 1H), 1.41 (s, 9H), 1.34-1.40 (m, 2H), 1.02-1.09 (m, 2H); MS (ESI) m/z 437.3 [M+1]+, 459.1 [M+Na]+.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]4[CH2:55][CH2:54][CH2:53][C@@H:52]4[C:56]([O:58][CH3:59])=[O:57])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[Cl:60][C:61]1[CH:69]=[CH:68][C:64]([C:65](Cl)=[O:66])=[CH:63][CH:62]=1>>[Cl:60][C:61]1[CH:69]=[CH:68][C:64]([C:65]([NH:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]3[CH:49]=[C:48]4[C:44]([CH2:45][N:46]([C@@H:51]5[CH2:55][CH2:54][CH2:53][C@@H:52]5[C:56]([O:58][CH3:59])=[O:57])[C:47]4=[O:50])=[CH:43][CH:42]=3)=[CH:39][CH:40]=2)=[O:66])=[CH:63][CH:62]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)[C@H]1CCC[C@H]1N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)[C@H]1CCC[C@H]1N1Cc2ccc(-c3ccc(NC(=O)c4ccc(Cl)cc4)cc3)cc2C1=O
Yield: 95 %

Procedure:
The compound of example 595 was prepared analogous to compound of example 97 by reaction of compound of example 592 with 4-chloro benzoyl chloride.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].Cl>CN(C=O)C>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: CCCCCCCCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOc1cc(OCCCCCCCCCCCC)cc(C(=O)OC)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
Methyl 3,5-dihydroxybenzoate (4.2 g, 25 mmol) was dissolved in 25 mL of dry DMF and then 13.86 g (100 mmol) of K2CO3 was added in the reaction mixture, where the above mixture was stirred at 80° C. for 1 h under a N2 atmosphere and then 1-bromododecane (12.4 g, 50 mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred at 90° C. for 24 h under N2. At the end of the reaction, the mixture was poured onto ice, 2N—HCl and extracted with MC, H20, NaHCO3 and brine. The solvent was removed in vacuo. The crude solid was purified by column chromatograph with 10% EA and hexane to yield 75% of the product. 1H-NMR (300 MHz, CDCl3) δ 7.1 (d, 2H), 6.6 (t, 1H), 4.0 (t, 4H), 3.9 (s, OCH3), 1.7-1.8 (m, 4H), 1.4-1.6 (m, 4H), 1.1-1.3 (m, 32H), 0.9 (t, 6H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Si:7]([O:14][CH2:15][C@H:16]1[NH:19][C:18](=[O:20])[C@H:17]1[NH:21][C:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].Br[CH2:42][C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=1)=[O:44]>C(#N)C.CN(C)C=O>[Si:7]([O:14][CH2:15][C@H:16]1[N:19]([CH2:42][C:43]([O:45][CH2:46][C:47]2[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[CH:51][CH:52]=2)=[O:44])[C:18](=[O:20])[C@H:17]1[NH:21][C:22]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: COc1ccc(COC(=O)CBr)cc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1ccc(COC(=O)CN2C(=O)[C@@H](NC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2CO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 114.7 %

Procedure:
Cesium carbonate (1.58 g) was added to a stirred solution of (3S,4S)-4-t-butyldimethylsilyloxymethyl-3-tritylaminoazetidin-2-one (1.45 g) (IV) (H. Mastalerz et al., J. Med. Chem., 1988, 31, 1190-1196) in a mixture of acetonitrile (44 ml) and dimethylformamide (35 ml). 4-Methoxybenzyl bromoacetate (1.44 g) was then added and the mixture stirred at room temperature for 48 h. The mixture was then partitioned between ethyl acetate and water, the organic phase was washed four times with water, and then with brine. The solution was dried over magnesium sulphate and evaporated. The title compound (2.29 g) was isolated by column chromatography of the residue (Silica gel, 3:1 hexane:ethyl acetate as eluent). [α]D21 -9.0°; νmax (CHCl3) 3352, and 1755 cm-1 ; δ(CDCl3) -0.04 (3H, s), 0.00 (3H, s), 0.88 (9H, s), 1.69 (1H, br s), 2.54 (1H, dd, J 3.33 and 11.68 Hz), 3.19 (1H, dd, J 2.05 and 11.68 Hz), 3.38 (1H, m), 3.51 (1H, d, J 17.98 Hz), 3.90 (3H, s), 4.46 (1H, d, J 17.98 Hz), 4.54 (1H, m), 5.06 (1H, d, J 11.79 Hz), 5.15 (1H, d, J 11.81 Hz), 6.94 (2H, d, J 8.68 Hz), 7.2-7.65 (17H, m).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][C@H:5]2[O:7][C@H:8]([C@@H:10]([OH:13])[CH2:11][CH3:12])[CH2:9][C@H:4]2[O:3]1.[C:15](Cl)(=[O:19])[CH:16]([CH3:18])[CH3:17]>N1C=CC=CC=1.CCOC(C)=O>[CH3:17][CH:16]([CH3:18])[C:15]([O:13][C@H:10]([C@H:8]1[O:7][C@@H:5]2[O:6][C:2]([CH3:1])([CH3:14])[O:3][C@@H:4]2[CH2:9]1)[CH2:11][CH3:12])=[O:19]
Reactant: CC(C)C(=O)Cl
Reactant: CC[C@H](O)[C@@H]1C[C@H]2OC(C)(C)O[C@H]2O1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC[C@H](OC(=O)C(C)C)[C@@H]1C[C@H]2OC(C)(C)O[C@H]2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a cooled solution of (1S)-1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]propan-1-ol (compound 6e, 505.6 mg, 2.5 mmol) in pyridine was added isobutyryl chloride (0.39 mL, 3.72 mmol) dropwise while cooled with an ice-water bath. After the addition, the mixture was warmed to room temperature and stirred at room temperature overnight. The resulting mixture was diluted with EtOAc and washed with a saturated NH4Cl solution. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 0-30% EtOAc in petroleum ether) to afford 470 mg of [(1S)-1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]propyl] 2-methylpropanoate (compound 42a).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][C:19](=[O:21])[N:18]([N:22]([CH3:35])[CH:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)[CH2:25][CH2:24]3)[CH:17]([C:36](O)=[O:37])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl.[CH2:40]([S:42][CH2:43][CH2:44][NH2:45])[CH3:41]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][C:19](=[O:21])[N:18]([N:22]([CH3:35])[CH:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=4)[CH2:25][CH2:24]3)[CH:17]([C:36]([NH:45][CH2:44][CH2:43][S:42][CH2:40][CH3:41])=[O:37])[CH2:16]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: CN(C1CCN(c2ccncc2)CC1)N1C(=O)CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1C(=O)O
Reactant: CCSCCN
Agent: Cl
Product: CCSCCNC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC(=O)N1N(C)C1CCN(c2ccncc2)CC1
Yield: 145.5 %

Procedure:
Similarly to Example 120 and using 4-[(6-chloro-2-naphthyl)sulfonyl)-1-[methyl[1-(4-pyridinyl)-4-piperidinyl]amino]-6-oxo-2-piperazinecarboxylic acid (0.18 g) obtained in Example 110 and 2-(ethylthio)ethylamine hydrochloride (0.065 g), the title compound (0.16 g) was obtained as a pale yellow powder.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.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:20]1([C:2]2[CH:19]=[CH:18][C:5]3[CH2:6][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:9][O:10][C:4]=3[CH:3]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCOc2cc(Br)ccc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOc2cc(-c3ccccc3)ccc2C1
Yield: 90.8 %

Procedure:
A mixture of tert-butyl 8-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.609 mmol), a solution of phenylboronic acid (111 mg, 0.912 mmol) in ethanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml) and tetrakis(triphenylphosphine)palladium(0) (84.2 mg, 0.0729 mmol) in toluene (5 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (180 mg, 90.9%) as an oil.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:14]2[NH:13][C:12](=[O:15])[N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>CN(C)C=O.O>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][N:13]1[C:14]2[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:7][CH:8]=[CH:9][C:10]=2[N:11]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[C:12]1=[O:15])[CH3:35]
Reactant: CCC(CC)c1cccc2c1[nH]c(=O)n2C(=O)OC(C)(C)C
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1c(=O)n(C(=O)OC(C)(C)C)c2cccc(C(CC)CC)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.5 %

Procedure:
To a solution of tert-butyl 4-(1-ethylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate (Reference Example 7; 4.94 g, 16.2 mmol) in N,N-dimethylformamide (40 mL) were added potassium carbonate (2.47 g, 17.9 mmol) and ethyl bromoacetate (1.98 mL, 17.9 mmol), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 5-20% ethyl acetate/n-hexane gradient mixture to give the title compound (6.17 g, 15.8 mmol, 98%) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[C:12]3[CH2:20][NH:19][CH2:18][CH2:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:5][CH:4]=1.F[C:24]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:25]=1[C:26]#[N:27].C(#N)C.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[F:32][C:29]1[CH:30]=[CH:31][C:24]([N:19]2[CH2:18][CH2:17][C:13]3[N:14]=[CH:15][N:16]=[C:11]([NH:10][CH2:9][C:6]4[CH:7]=[N:8][C:3]([C:2]([F:21])([F:1])[F:22])=[CH:4][CH:5]=4)[C:12]=3[CH2:20]2)=[C:25]([CH:28]=1)[C:26]#[N:27]
Reactant: N#Cc1cc(F)ccc1F
Reactant: FC(F)(F)c1ccc(CNc2ncnc3c2CNCC3)cn1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N#Cc1cc(F)ccc1N1CCc2ncnc(NCc3ccc(C(F)(F)F)nc3)c2C1
Yield: 11.7 %

Procedure:
A 2 mL microwave vial was charged with N-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (50 mg, 0.16 mmol), 2,5-difluorobenzonitrile (130 mg, 0.97 mmol), acetonitrile (0.4 mL) and N,N-diisopropylethylamine (84 μL, 0.48 mmol). The mixture was subjected to microwave irradiation at 200° C. for 4 h. After cooling the mixture was diluted with chloroform (7 mL), and washed with 0.1 M NaH2PO4 (10 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by semi-preparative HPLC (100×20.2 mm, C18 column; 20-90% MeCN/H2O [10 mM diethylamine]) to yield an off-white solid (8 mg).