Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][CH:12]([C:16](=[O:19])[CH2:17]Br)[CH2:13]2)[CH2:9]1)=O)(C)(C)C.[F-].[K+].C1OCCOCCOCCOCCOCCOC1.[F:40][C:41]([F:46])([F:45])[C:42]([O-:44])=[O:43].[F:47]C(F)(F)C(O)=O>C1C=CC=CC=1.ClCCl>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[CH:10]12[CH2:11][CH:12]([C:16](=[O:19])[CH2:17][F:47])[CH2:13][CH:14]1[CH2:15][NH:8][CH2:9]2
Reactant: O=C([O-])C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC2CC(C(=O)CBr)CC2C1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccccc1
Product: O=C(CF)C1CC2CNCC2C1

Procedure:
A mixture of 1-(3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]oct-7-yl)-2-bromo-1-ethanone (0.126 g, 0.380 mmol), potassium fluoride (0.067 g, 1.15 mmol) and 18-crown-6 (0.050 g, 0.19 mmol) in benzene (10 mL) was heated at reflux overnight. The mixture was filtered, and the filtrate was concentrated and purified by silica gel column chromatography, eluting with 20-30% ethyl acetate in hexanes, to obtain the cis isomer (0.022 g), trans isomer (0.030 g), and a mixture of cis/trans 1-(3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]oct-7-yl)-2-fluoro-1-ethanone (0.040 g), as oils. The separated isomers were de-protected and converted into their trifluoroacetate salts by reaction with trifluoroacetic acid in dichloromethane (5 mL) (ambient temperature, 1 h). The solvent was evaporated, and the products were dried by vacuum to obtain 1-(3-azabicyclo[3.3.0]oct-7-yl)-2-fluoro-1-ethanone trifluoroacetate as cis and trans isomers (0.025 g and 0.032 g, respectively) (1H NMR of trans isomer (CD3OD, 300 MHz): δ 5.08 (s, 1H), 4.93 (s, 1H), 3.37-3.29 (m, 2H), 3.24-3.16 (m, 3H), 3.00-2.95 9m, 2H), 2.34-2.22 (m, 2H), 1.69-1.58 (m, 2H); MS (m/z): 172 (M+1); 1H-NMR of cis isomer (CD3OD, 300 MHz): δ 5.13 (s, 1H), 4.98 (s, 1H), 3.60-3.52 (m, 2H), 3.78-3.67 (m, 2H), 3.12-2.96 (m, 3H), 2.38-2.15 (m, 2H), 1.91-1.64 (m, 2H); MS (m/z): 172 (M+1)). The cis isomer exhibited Ki values at rat and human α4β2 of 6.8 nM and 6.3 nM respectively and did not pass HTS for α7. The trans isomer exhibited a Ki value at rat and human α4β2 of 154 nM and 176 nM respectively and exhibited a Ki value at α7 of >10.000 nM.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:10][CH2:9][CH2:8][C:7]=1[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[O:5])[CH3:2].B.N1C=CC=CC=1>C(O)(=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(NCc2ccccn2)CCC1
Agent: B
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CCOC(=O)C1CCCC1NCc1ccccn1
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
A solution of 2-[(pyridin-2-ylmethyl)-amino]-cyclopent-1-enecarboxylic acid ethyl ester (4.78 g, 19.4 mmol) in acetic acid (70 mL) was treated with a 8.0 M solution of borane in pyridine (2.67 mL, 21.4 mmol) and stirred under a nitrogen atmosphere for 30 min. The reaction was quenched with 1.0 M aqueous hydrochloric acid solution (40 mL) for 16 h. The reaction was then poured into a mixture of saturated aqueous sodium bicarbonate solution (200 mL) and ethyl acetate (200 mL) and extracted. The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 0-10% methanol in dichloromethane) to afford the desired product, 2-[(pyridin-2-ylmethyl)-amino]-cyclopentanecarboxylic acid ethyl ester (3.30 g, 13.3 mmol, 68.6%), as a light yellow oil. 1H NMR (400 MHz, DMSO-d6) δ: 1.16 (3H, t, J=7.4 Hz), 1.38-1.79 (4H, m), 1.82-1.96 (2H, m), 2.56 (1H, dd, J1=15.5 Hz, J2=7.0 Hz), 2.88 (1H, dd, J1=14.9 Hz, J2=7.1 Hz), 3.21 (1H, dd, J1=13.7 Hz, J2=6.7 Hz), 4.04 (2H, q, J=7.0 Hz), 3.78 (2H, s), 7.19-7.22 (2H, m), 7.38 (1H, d, J=7.6 Hz), 7.68-7.73 (1H, m), 8.45 (1H, d, J=4.7 Hz). LC-MS (ESI) calcd for C14H20N2O2 248.15, found 249.2 [M+H+].
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]([NH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=[O:12]>O1CCOCC1.C(OCC)(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:9][C:4]1[C:3]2[NH:10][C:11](=[O:12])[N:13]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[C:2]=2[CH:7]=[C:6]([CH3:8])[CH:5]=1
Reactant: Cc1cc(F)c(NC(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c(Br)c1
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(F)c2[nH]c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under an argon atmosphere, bis(3,5,3′,5′-dimethoxy-dibenzylideneacetone) palladium (0) (6% mol, 1.1 mmol, 0.9 g), 1,1′-bis(diphenylphosphino)ferrocene (6% mol, 0.61 g), NatBuO (2 eq., 36 mmol, 3.5 g), were all dissolved in 1,4-dioxane (40 ml) and the system was purged through with argon. The mixture was stirred at room temperature for 15 minutes and 1,1-dimethylethyl 4-({[(2-bromo-6-fluoro-4-methylphenyl)amino]-carbonyl}amino)-1-piperidinecarboxylate (D32) (7.7 g, 17.9 mmol) was added at room temperature and the mixture was heated to 80° C. for 1.5 hours and then to 100° C. for extra 2 hours; the mixture was then cooled to room temperature, diluted with ethyl acetate and the organic phase obtained was washed with water and brine. Organics were dried over Na2SO4, filtered and the solvent was evaporated to afford the crude product that was purified by chromatography (ethyl acetate-n-hexane) to afford the title compound, 4.3 g, 70%, pale-grey solid, M+-H=348.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][C:3]=1[F:10].[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[C:17](B(O)O)[CH:16]=[CH:15][N:14]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].CC(O)CC>[F:10][C:3]1[C:2]([C:17]2[CH:16]=[CH:15][N:14]=[C:13]([C:12]([F:23])([F:22])[F:11])[CH:18]=2)=[N:7][CH:6]=[C:5]([CH2:8][NH2:9])[CH:4]=1
Reactant: NCc1cnc(Cl)c(F)c1
Reactant: OB(O)c1ccnc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCC(C)O
Product: NCc1cnc(-c2ccnc(C(F)(F)F)c2)c(F)c1
Temperature: 100 °C
Reaction time: 10 h

Procedure:
To a flask containing (6-chloro-5-fluoropyridin-3-yl)methanamine 84-1 (353 mg, 2.20 mmol), 2-(trifluoromethyl)pyridin-4-ylboronic acid 33-1 (418 mg, 2.20 mmol), Pd(OAc)2 (29 mg, 0.11 mmol), S-Phos (91 mg, 0.22 mmol) and potassium phosphate (1.40 g, 6.60 mmol) under Argon was added 2-butanol (4 mL). The mixture was stirred at 100° C. for 10 hours. After cooling to room temperature, the mixture was filtered through celite cake. The filtrate was diluted with ethyl acetate, washed with H2O and brine, dried over Na2SO4, and concentrated to dryness by rotary evaporation. The crude product was purified by silica gel flash chromatography, and eluted with 5% methanol containing ˜7N ammonia in dichloromethane to give (3-fluoro-2′-(trifluoromethyl)-2,4′-bipyridin-5-yl)methanamine 84-2 as a pale yellow solid. MS m/z 268.1 (M+1)
Reaction SMILES: C([O:3][C:4](=O)[NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)C.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O=P(Cl)(Cl)Cl>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[C:13]2[C:8]([CH2:7][CH2:6][NH:5][C:4]2=[O:3])=[CH:9][CH:10]=1
Reactant: CCOC(=O)NCCc1ccc(C(F)(F)F)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: O=C1NCCc2ccc(C(F)(F)F)cc21
Temperature: 105 °C
Reaction time: 2 h
Yield: 20.2 %

Procedure:
Using the same procedure and workup as described in Example 1, step 4, [2-(4-trifluoromethyl-phenyl)-ethyl]-carbamic acid ethyl ester (I-16b: 2.7 g, 10.340 mmol) in POCl3 (15 mL) was reacted with P2O5 (2.92 g, 20.69 mmol). The resulting mixture was stirred at 105° C. for 2 hours to afford the crude product. Purification by column chromatography on silica gel (2% methanol in DCM) afforded 450 mg of the product (20.24% yield).
Reaction SMILES: [F:1][C:2]1([F:21])[C:8]([CH3:10])([CH3:9])[O:7][CH2:6][C:5](=[O:11])[NH:4][C@@:3]1([C:13]1[CH:18]=[C:17](I)[CH:16]=[CH:15][C:14]=1[F:20])[CH3:12].[CH3:22][C:23]1[S:24][CH:25]=[C:26]([C:28]#[C:29][Si](C)(C)C)[N:27]=1.C(N(CC)CC)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O>[F:1][C:2]1([F:21])[C:8]([CH3:10])([CH3:9])[O:7][CH2:6][C:5](=[O:11])[NH:4][C@@:3]1([C:13]1[CH:18]=[C:17]([C:29]#[C:28][C:26]2[N:27]=[C:23]([CH3:22])[S:24][CH:25]=2)[CH:16]=[CH:15][C:14]=1[F:20])[CH3:12]
Reactant: Cc1nc(C#C[Si](C)(C)C)cs1
Reactant: CC1(C)OCC(=O)N[C@](C)(c2cc(I)ccc2F)C1(F)F
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(C#Cc2ccc(F)c([C@@]3(C)NC(=O)COC(C)(C)C3(F)F)c2)cs1
Temperature: 40 °C
Reaction time: 16 h
Yield: 90.8 %

Procedure:
A dried pressure tube was charged with (R)-6,6-difluoro-5-(2-fluoro-5-iodo-phenyl)-5,7,7-trimethyl-[1,4]oxazepan-3-one (intermediate B6″.1) (203 mg, 491 μmol), 2-methyl-4-((trimethylsilyl)ethynyl)thiazole (115 mg, 590 μmol), and N,N-dimethylformamide (3 ml) flushed with nitrogen (solution 1). Another dried pressure tube was flushed with argon, thereafter, successively N,N-dimethylformamide (3 ml), bis(triphenylphosphine) palladium(II)chloride (24.6 mg, 34.4 μmol), triphenylphoshine (5.2 mg, 19.7 μmol), copper(I)iodide (1.9 mg, 9.8 μmol), triethylamine (249 mg, 2.46 mmol), and tetrabutylammoniumiodide (185 mg, 491 μmol) were added. The mixture was heated to 40° C., and solution 1 was added dropwise. The temperature was raised to 60° C. and stirring was continued for 16 hours. For the workup, the reaction mixture was evaporated at reduced pressure and the residue directly purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 50:50 as the eluent. The (R)-6,6-difluoro-5-[2-fluoro-5-(2-methyl-thiazol-4-ylethynyl)-phenyl]-5,7,7-trimethyl-[1,4]oxazepan-3-one (182 mg, 91% yield) was obtained as a white foam. MS (ISP): m/z=409.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:7])[S:5][CH:6]=1.[C:8](Cl)(=[O:11])[CH:9]=[CH2:10]>>[C:8]([NH:1][C:2]1[N:3]=[C:4]([CH3:7])[S:5][CH:6]=1)([CH:9]=[CH2:10])=[O:11]
Reactant: C=CC(=O)Cl
Reactant: Cc1nc(N)cs1
Product: C=CC(=O)Nc1csc(C)n1

Procedure:
4-Amino-2-methylthiazole (prepared by hydrolysing 4-acetamido-2-methylthiazole) is treated with acryloylchloride to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[C:5](Cl)=[N:6][CH:7]=1.[CH3:19][O-:20].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[C:5]([O:20][CH3:19])=[N:6][CH:7]=1
Reactant: C[O-]
Reactant: O=C(Nc1cc(Br)cnc1Cl)c1ccc(O)cc1
Agent: [Na+]
Solvent: CO
Product: COc1ncc(Br)cc1NC(=O)c1ccc(O)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 8 %

Procedure:
N-(5-Bromo-2-chloropyridin-3-yl)-4-hydroxybenzamide (600 mg, 1.83 mmol) was suspended in a solution of sodium methoxide 25% in methanol (12 ml, 55 mmol and the reaction mixture was stirred at 50° C. overnight. The solvent was removed and the crude poured into water. The precipitate was filtered off and discarded and the filtrate was brought to pH7 by adding hydrogen chloride 2N. The precipitate was then filtered and washed with water and was purified using SP1® Purification System (0% to 25%, hexane-ethyl acetate) to give 74 mg (8% yield) of the title compound. Purity 62%.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1.Cl.[NH:17]1[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[CH:33]=[CH:32][C:31]([CH2:34][NH2:35])=[CH:30][CH:29]=2)=[N:20][N:19]=[N:18]1.C([O-])(=O)C.[Na+]>C(O)CCC.CO>[NH:20]1[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[CH:33]=[CH:32][C:31]([CH2:34][NH:35][C:2]3[C:11]4[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=4[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=3)=[CH:30][CH:29]=2)=[N:17][N:18]=[N:19]1
Reactant: NCc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: FC(F)(F)c1nc(Cl)c2c(n1)CCCC2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Solvent: CO
Product: FC(F)(F)c1nc2c(c(NCc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)n1)CCCC2
Temperature: 25 °C
Yield: 49.8 %

Procedure:
To 10 mL of a 5:1 mixture of n-butanol/methanol were added 1.42 g of 4-chloro-5,6,7,8-tetrahydro-2-trifluoromethylquinazoline, 1.73 g of N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]amine hydrochloride and 2.7 g of sodium acetate. The resulting mixture was heated at reflux for 5 days and then cooled to room temperature. All solvents were removed by evaporation and the resulting residue was purified on silica to yield 1.35 g (50%) of the desired product. The compound was characterized as its potassium salt: 1H NMR (DMSO-d6, 400 MHz) δ 7.78 (t, J=6.0 Hz, 1H), 7.50 (m, 1H), 7.32 (m, 3H), 7.15 (m, 2H), 7.03 (m, 2H), 4.57 (d, J=6.0 Hz, 2H), 2.61 (m, 2H), 2.38 (m, 2H, 1.75 (m, 4H); negative FAB-MS m/e 488(M-H), 450(M-K). Anal. calcd for C23H19F3KN7.0.5H2O: C, 55.41; H, 4.04; N, 19.67. Found: C, 55.66; H, 4.09; N, 19.46.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]1[N:12]2[CH:13]=[C:14]([O:17][C@H:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C@@H:21]([NH2:28])[CH2:20][CH2:19]3)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1)[CH3:2].CCN(C(C)C)C(C)C.ClC(Cl)(Cl)C[O:41][C:42](=O)[NH:43][C:44]1[N:45]([C:53]2[CH:58]=[CH:57][C:56]([CH3:59])=[CH:55][CH:54]=2)[N:46]=[C:47]([C:49]([CH3:52])([CH3:51])[CH3:50])[CH:48]=1>O1CCOCC1>[C:49]([C:47]1[CH:48]=[C:44]([NH:43][C:42]([NH:28][C@@H:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:18]([O:17][C:14]3[CH:15]=[CH:16][C:11]4[N:12]([C:8]([C@@H:4]5[CH2:5][CH2:6][CH2:7][N:3]5[CH2:1][CH3:2])=[N:9][N:10]=4)[CH:13]=3)[CH2:19][CH2:20]2)=[O:41])[N:45]([C:53]2[CH:58]=[CH:57][C:56]([CH3:59])=[CH:55][CH:54]=2)[N:46]=1)([CH3:52])([CH3:50])[CH3:51]
Reactant: CCN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(C)cc4)c4ccccc43)cn12
Temperature: 60 °C

Procedure:
To a solution of Intermediate 61c (72.0 mg, 0.19 mmol) in 1,4-dioxane (2.00 mL) was added DIPEA (66 μL, 0.38 mmol) and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 77.0 mg, 0.19 mmol). The reaction was heated to 60° C. overnight then cooled and partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-7.5% MeOH in DCM. Further purification by HPLC (C18 X-select column, 20-70% MeCN in H2O, 0.1% HCO2H) gave the title compound as a white powder after freeze-drying (37 mg, 31%). LCMS (Method 5): Rt 3.73 min, m/z 633.2 [MH+]. 1H NMR (400 MHz, d4-MeOD): 0.94 (3H, t, J 7.2), 1.30 (9H, s), 1.89-2.16 (6H, m), 2.22-2.31 (2H, m), 2.31-2.38 (2H, m), 2.38 (3H, s), 2.49 (1H, m), 3.32 (1H, m), 4.11 (1H, t, J 8.0), 4.90 (1H, dd, J 9.0, 5.6), 5.28 (1H, t, J 4.1), 6.33 (1H, s), 7.19-7.36 (9H, m), 7.65 (1H, dd, J 10.0, 0.7), 8.37 (1H, d, J 1.9).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)=[O:4].[CH:14]([O:17][CH2:18][CH2:19][CH2:20][NH2:21])([CH3:16])[CH3:15]>>[CH:14]([O:17][CH2:18][CH2:19][CH2:20][NH:21][C:11]([C:8]1[CH:7]=[CH:6][C:5]([C:3]([OH:2])=[O:4])=[CH:10][N:9]=1)=[O:13])([CH3:16])[CH3:15]
Reactant: CC(C)OCCCN
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Product: CC(C)OCCCNC(=O)c1ccc(C(=O)O)cn1

Procedure:
The title compound was synthesized in two steps. The first as described for Intermediate example I-97, starting from 5-(methoxycarbonyl)pyridine-2-carboxylic acid and 3-isopropoxypropylamine, and the second as described for Intermediate example I-98, starting from the product received in the first step which was first purified by column chromatography using a gradient of ethyl acetate in heptane. Total yield (two steps) 22%; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.06 (d, 1 H), 8.99 (t, 1 H), 8.43 (dd, 1 H), 8.13 (dd, 1 H), 3.48-3.56 (m, 1 H), 3.34-3.45 (m, 4 H, obscured by H2O), 1.70-1.80 (m, 2 H), 1.09 (d, 6 H); MS (APPI/APCI) m/z 267[M+H+].
Reaction SMILES: Cl.[CH2:2]([N:6]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:8]([CH2:9][C@@H:10]([C:12]([O:14][CH3:15])=[O:13])[NH2:11])=[CH:7]1)[CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.[F:29][C:30]1[CH:40]=[CH:39][CH:38]=[CH:37][C:31]=1[CH:32]=[CH:33][C:34](O)=[O:35].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH2:2]([N:6]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:8]([CH2:9][C@@H:10]([C:12]([O:14][CH3:15])=[O:13])[NH:11][C:34](=[O:35])[CH:33]=[CH:32][C:31]2[CH:37]=[CH:38][CH:39]=[CH:40][C:30]=2[F:29])=[CH:7]1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCn1cc(C[C@H](N)C(=O)OC)c2ccccc21
Reactant: O=C(O)C=Cc1ccccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCn1cc(C[C@H](NC(=O)C=Cc2ccccc2F)C(=O)OC)c2ccccc21
Yield: 77.2 %

Procedure:
The same procedures as in Example 146 were carried out from the compound obtained in Example 145 (2.0 g), triethylamine (1.0 mL), 2-fluorocinnamic acid (1.2 g), WSC.HCl (1.4 g), and methylene chloride (60 mL), to give the captioned compound (2.1 g, 77%) as an oily product.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12](O)=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[S:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:17][C:3]1=2.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:37][C:38]1[NH:42][N:41]=[N:40][N:39]=1.Cl[Si](C)(C)C.C(N(CC)CC)C.[N-]1C=CN=C1>CN(C)C=O>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([NH:37][C:38]3[NH:42][N:41]=[N:40][N:39]=3)=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[S:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:17][C:3]1=2
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1ccc2nc3sc(-c4ccccc4)cc3c(=O)n2c1
Agent: C[Si](C)(C)Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1c[n-]cn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1nnn[nH]1)c1ccc2nc3sc(-c4ccccc4)cc3c(=O)n2c1
Reaction time: 2 h
Yield: 71.5 %

Procedure:
0.9 g (0.0028 mol) of 4-oxo-2-phenyl-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid (Example 5) and 0.7 g (0.0043 mol) of 1,1'carbonyldiimidazole (Aldrich Chemical Company) in 80 ml of dimethylformamide are stirred at 60°-70° C. for five hours. To 0.4 g (0.004 mol) of 5-aminotetrazole monohydrate (Aldrich Chemical Company) in 40 ml of dimethylformamide cooled to 0°-5° C. is added 1.5 ml (0.012 mol) of chlorotrimethylsilane (Aldrich Chemical Company) and 3 ml (0.022 mol) of triethylamine. After thirty minutes the mixture is allowed to reach room temperature and is stirred for an additional two hours. The mixture is combined with the previous imidazolide mixture and stirred for fourteen hours at room temperature. The resulting precipitate is collected, slurried in boiling glacial acetic acid, and mixture is cooled and filtered to give 0.78 g of 4-oxo-2-phenyl-N-1H-tetrazol-5-yl-4H-pyrido[ 1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide; mp 324°-328° C. (dec).
Reaction SMILES: CC1N=CNC=1.BrCCCC[N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22].C(N(CC)CC)C>CN(C)C=O>[C:16]1(=[O:17])[NH:12][C:13](=[O:22])[C:14]2=[CH:21][CH:20]=[CH:19][CH:18]=[C:15]12
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: Cc1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccccc21
Temperature: 120 °C
Reaction time: 3 h
Yield: 3.6 %

Procedure:
4-Methylimidazole (5.0 g) and N-(4-bromobutyl)phthalimide (17.2 g) were dissolved in dimethylformamide (250 ml), triethylamine (25.5 ml) was added to the solution, and the resulting mixture was stirred at 120° C. for 3 hours. The reaction mixture was left to cool to room temperature, then ethyl acetate and distilled water were added to the reaction mixture, and the layers were separated. The organic layer was washed with distilled water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was dissolved in ethyl acetate. The reaction mixture was stirred, the deposited solid was removed by filtration, and the resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:methanol=20:1). A mixed solution of ethyl acetate and hexane was added to the resulting roughly purified product, and the resulting mixture was stirred with heating to dissolve the roughly purified product, and then gradually cooled to room temperature to deposit a solid. The deposited solid was collected by filtration to obtain a phthalimide compound (324 mg). (2) By using the compound obtained in (1) mentioned above (324 mg) as a starting material, the title compound (183 mg) was obtained in the same manner as that of Reference Example 9, (2).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][Cl:19])=[CH:13][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(OCc2ccccc2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: ClCc1ccc(OCc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 87 %

Procedure:
To a dichloromethane (4.00 mL) solution of (6-benzyloxy-pyridin-3-yl)-methanol (1.80 g, 8.36 mmol) described in Manufacturing Example 191-1-1 was added dropwise thionyl chloride (732 μL, 10.0 mmol) on an ice bath (0° C.) under nitrogen atmosphere, which was stirred for 5 minutes at room temperature. Aqueous sodium bicarbonate was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure to obtain the title compound (1.70 g, 87.0%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[OH:10])[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].Br[CH:19]([CH3:21])[CH3:20]>CC#N>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[O:10][CH:19]([CH3:21])[CH3:20])[CH:5]=[O:6]
Reactant: O=Cc1cc(F)c(O)c(F)c1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)Oc1c(F)cc(C=O)cc1F
Temperature: 65 °C
Reaction time: 24 h

Procedure:
To a suspension of 3,5-difluoro-4-hydroxy-benzaldehyde as a colourless solid (0.81 g) and K2CO3 (2.14 g; 15.4 mmol) in MeCN (15 ml) is added 2-bromopropane (1.45 ml) dropwise. The mixture is stirred at 65° C. for 24 h. After evaporation of the solvent the residue is taken-up in Et2O and water. The organic layer is separated and extracted with brine, dried over MgSO4 and evaporated to give 3,5-difluoro-4-isopropoxy-benzaldehyde (0.14 g).