Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[O:31]1[CH2:36][CH2:35][N:34]([C:37]([C:39]2[CH:44]=[CH:43][C:42](B3OC(C)(C)C(C)(C)O3)=[CH:41][CH:40]=2)=[O:38])[CH2:33][CH2:32]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:42]2[CH:41]=[CH:40][C:39]([C:37]([N:34]3[CH2:35][CH2:36][O:31][CH2:32][CH2:33]3)=[O:38])=[CH:44][CH:43]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: CC1(C)OB(c2ccc(C(=O)N3CCOCC3)cc2)OC1(C)C
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
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: O
Solvent: C1COCCO1
Product: CCN(c1cc(-c2ccc(C(=O)N3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 67.6 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (300 mg, 0.63 mmol) and morpholino(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone (260 mg, 0.82 mmol) in dioxane (10 mL), aqueous 2M Na2CO3 solution (1.13 mL, 2.27 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (72 mg, 0.06 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 100° C. for 4 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the title compound (250 mg, 68%). LCMS: 587.35 (M+1)+; HPLC: 93.85% (@254 nm) (Rt; 4.535; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 1.46 (bs, 1H), 8.21 (t, 1H), 7.69-7.71 (m, 2H), 7.45-7.49 (m, 3H), 7.26 (s, 1H), 5.86 (s, 1H), 4.29 (d, 2H, J=4 Hz), 3.82-3.84 (m, 2H), 3.48-3.60 (m, 8H), 3.23-3.25 (m, 2H), 3.09-3.11 (m, 3H), 2.26 (s, 3H), 2.21 (s, 3H), 2.11 (s, 3H), 1.52-1.68 (m, 4H), 0.83 (t, 3H, J=6.8 Hz).
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].[CH3:14][S:15](Cl)(=[O:17])=[O:16]>ClCCl.[Ag]=O>[CH3:14][S:15]([O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:13])(=[O:17])=[O:16]
Reactant: OCCOCCOCCOCCO
Reactant: CS(=O)(=O)Cl
Agent: O=[Ag]
Solvent: ClCCl
Product: CS(=O)(=O)OCCOCCOCCOCCO
Temperature: 25 °C
Reaction time: 48 h
Yield: 68.5 %

Procedure:
250 mL of dichloromethane was added to 25 g of tetraethylene glycol and 32.8 g of silver oxide, and then a solution of 17.7 g of methanesulfonyl chloride in 50 ml of dichloromethane was added dropwise. After stirring the reaction solution at room temperature for 2 days, the solution was filtered with a celite, and then the filtrate was concentrated under reduced pressure. The residue was purified with silica gel column chromatography to obtain 24 g of the objective compound.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH:10]=[O:11])=[CH:4][CH:3]=1.[CH:17]([C:19]([CH3:21])=[O:20])=[CH2:18].C(N(CC)CC)C>C(O)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([C:10](=[O:11])[CH2:18][CH2:17][C:19](=[O:20])[CH3:21])[CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: C=CC(C)=O
Reactant: O=Cc1cccc(Oc2ccc(F)cc2)c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)CCC(=O)c1cccc(Oc2ccc(F)cc2)c1
Reaction time: 6 h
Yield: 66.5 %

Procedure:
To a stirred solution of 3-(4-fluorophenoxy)benzaldehyde (26.8 g; 0.124M) in ethanol (60 ml) was added methyl vinyl ketone (8.32 ml; 0.1M), 3-benzyl-5-(2-hydroxyethyl)-4-methylthizolium chloride (5.93 g; 0.022M), and triethylamine (27.88 ml; 0.2M) at room temperature. After stirring for 6 hrs, volatiles were removed. To the residue was added water (200 ml), and the whole was extracted with ethyl acetate (150 ml×2). The combined organic layers were washed with water (100 ml), brine (100 ml), dried over MgSO4, and concentrated in vacuo. The residual oil was purified by flash column (SiO2) eluting with ethyl acetate-n-hexane (1:5) to give 19.03 g (yield 66.5%) of the subtitle compound [C] as a pale yellow oil.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[CH:17])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[F:23][C:24]([F:30])([F:29])[C:25]([CH2:27][F:28])=[O:26].C(OCC)C>O1CCCC1>[F:23][C:24]([F:30])([F:29])[C:25]([OH:26])([CH2:27][F:28])[C:17]#[C:16][C:13]1[CH:12]=[CH:11][C:10]([S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])=[CH:15][CH:14]=1
Reactant: C#Cc1ccc(S(=O)(=O)c2ccccc2)cc1
Reactant: O=C(CF)C(F)(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)c1ccc(C#CC(O)(CF)C(F)(F)F)cc1
Reaction time: 0.08 h

Procedure:
To a cooled (-78° C.) solution of 4-phenylsulfonylphenylethyne (1.68 g) in anhydrous tetrahydrofuran (70 mL) was added n-butyl lithium (3.06 mL of a 2.5 M solution in hexanes). The solution was stirred for 15 minutes at -78° C. before 1,1,1,3-tetrafluoroacetone (2.96 mL of a 40% diethyl ether solution) was added. The reaction mixture was kept at -78° C. for five minutes before quenching with 2N hydrochloric acid. Diethyl ether was added and the aqueous layer extracted further with diethyl ether. The combined organic layers were dried, evaporated and the product purified by chromatography, with diethyl ether:chloroform (1:9) as eluent. This yielded the title compound as a white solid (1.64 g) mp 119-120.8; (300 MHz) (CDCl3): 3.77 (s,1, OH), 4.55-4.79 (m,2, CH2F), 7.48-7.61 (m,5, Ar), 7.86-7.94 (m,4, Ar); MS: m/z=373 (M+1). Analysis for C17H12F4O3S: Calculated: C, 54.84; H, 3.25; Found: C, 54.70; H, 3.37.
Reaction SMILES: [Cl-].[CH2:2](N(CC)CC)C.CO.[C:11]([C:14]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][C:16]([OH:24])([CH2:17]3)[CH2:15]1)[CH2:21]2)([OH:13])=[O:12]>CN(C=O)C>[CH3:2][O:12][C:11]([C:14]12[CH2:21][CH:20]3[CH2:19][CH:18]([CH2:17][C:16]([OH:24])([CH2:22]3)[CH2:15]1)[CH2:23]2)=[O:13]
Reactant: O=C(O)C12CC3CC(CC(O)(C3)C1)C2
Reactant: CCN(CC)CC
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)C12CC3CC(CC(O)(C3)C1)C2
Reaction time: 2 h
Yield: 95 %

Procedure:
In an atmosphere of nitrogen, 10 mmole of 1-carboxy-3-adamantanol obtained by the method of Example 2 was dissolved in 10 ml of DMF. To the mixture, 15 mmole of tionyl chloride was added dropwise over 30 minutes while heating the mixture to the reflux temperature so as to begin to reflux at about the time the addition is finished. After refluxing for 2 hours, the mixture was cooled. To the mixture, 20 mmole of triethylamine was added and 11 mmole of methanol was added dropwise over 30 minutes while keeping the temperature of the solution at 10° C. or below, and the mixture was stirred for another 2 hours. As a result, the conversion of 1-carboxy-3-adamantanol was 99%, and 1-methoxycarbonyl-3-adamantanol (yield 95%) was formed.
Reaction SMILES: [CH3:1]I.[Na].[NH2:4][C:5]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2[N:24]3[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]3)=[C:18]([O:25][CH3:26])[C:17]=2[CH3:27])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8].O>CN(C=O)C>[NH2:4][C:5]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2[N:24]3[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]3)=[C:18]([O:25][CH3:26])[C:17]=2[CH3:27])=[O:15])=[CH:10][C:6]=1[C:7]([O:9][CH3:1])=[O:8]
Reactant: COc1c(C)c(C(=O)c2ccc(N)c(C(=O)O)c2)n2ccccc12
Reactant: CI
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(C(=O)c2c(C)c(OC)c3ccccn23)ccc1N
Reaction time: 1 h

Procedure:
1.51 ml (24.26 mmol) of methyl iodide are added, under an inert atmosphere at ambient temperature, to 8 g (23.1 mmol) of the sodium salt of 2-amino-5-[(1-methoxy-2-methylindolizin-3-yl)carbonyl]benzoic acid (described in WO 03/084956) in 130 ml of DMF. After stirring for 1 hour, water is added. The precipitate formed is filtered off, rinsed with water, and then dried under reduced pressure at 50° C. overnight. 7.17 g of a yellow solid are obtained.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=1[N:20]1[N:24]=[CH:23][CH:22]=[N:21]1)=[O:11].F[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[F:19][C:15]1[C:16]([F:18])=[CH:17][C:12]([C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH:1][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=2)=[O:11])=[C:13]([N:20]2[N:24]=[CH:23][CH:22]=[N:21]2)[CH:14]=1
Reactant: C[C@@H]1CCCN(C(=O)c2cc(F)c(F)cc2-n2nccn2)[C@@H]1CN
Reactant: Fc1ccc(C(F)(F)F)cn1
Product: C[C@@H]1CCCN(C(=O)c2cc(F)c(F)cc2-n2nccn2)[C@@H]1CNc1ccc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(4,5-difluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 481 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 8.30-6.50 (m, 8H), 4.80-2.70 (m, 5H), 1.90-0.65 (m, 8H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][C:15](B(O)O)=[CH:16][CH:17]=2)[CH:12]=[N:11]1.C([O-])([O-])=O.[K+].[K+]>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>[Cl:8][C:6]1[CH:7]=[C:2]([C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][CH:16]=2)[N:10]([CH3:9])[N:11]=[CH:12]3)[N:3]=[N:4][CH:5]=1
Reactant: Clc1cnnc(Cl)c1
Reactant: Cn1ncc2cc(B(O)O)ccc21
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: [K+]
Product: Cn1ncc2cc(-c3cc(Cl)cnn3)ccc21
Temperature: 95 °C

Procedure:
3,5-dichloropyridazine (200 mg, 1.34 mmol), 1-methyl-1H-indazole-5-boronic acid (260 mg, 1.48 mmol), K2CO3 (556.6 mg, 4.03 mmol), and tetrakis(triphenylphosphine)palladium(0) (233, 0.20 mmol) were taken in a microwave vial, and the vial was vacuum pumped and flushed with argon three times. To this mixture was added degassed 1,4-dioxane (10 mL) and degassed water (2.5 mL). The reaction mixture was heated at 95° C. for 2 h then cooled to room temperature. The reaction mixture was filtered through Celite (ethyl acetate eluent) and concentrated. Purification by flash column chromatography on silica gel (hexanes/ethyl acetate eluent) provided the product. LCMS-ESI+: calc'd for C14H10ClN4: 245.1 (M+H+); Found: 245.2 (M+H+). 1H NMR (400 MHz, Chloroform-d) δ 9.15 (d, J=2.2 Hz, 1H), 8.44 (s, 1H), 8.21 (dd, J=8.8, 1.5 Hz, 1H), 8.11 (s, 1H), 7.97 (s, 1H), 7.56 (d, J=8.8 Hz, 1H), 4.14 (s, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[C:15]([CH:16]=[C:17]4[C:22]=2[CH:21]=[CH:20][CH:19]=[CH:18]4)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:5][CH:4]=1)=[O:2].C1C(=O)N([Br:30])C(=O)C1>CN(C=O)C.O>[Br:30][C:16]1[C:17]2[C:22]([C:9]([C:6]3[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:8][CH:7]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:21][CH:20]=[CH:19][CH:18]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: O=Cc1ccc(-c2c3ccccc3cc3ccccc23)cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(-c2c3ccccc3c(Br)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 90 %

Procedure:
9-(4-Formylphenyl)anthracene (3.3 g, 12 mmole) was suspended in anhydrous DMF (40 ml). To the resultant suspension, a solution (8 ml) of NBS (2.3 g, 13 mmole, 1.1 eq) in anhydrous DMF was added and the obtained mixture was stirred at the room temperature for 10 hours and left standing for one night. After the reaction mixture was diluted with water (50 ml), the solid was separated by filtration and washed with methanol and a yellow solid (3.9 g, 90%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4](F)[CH:3]=1.[CH3:11][O-:12].[Na+]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:12][CH3:11])[CH:3]=1
Reactant: C[O-]
Reactant: O=Cc1ccc(Cl)cc1F
Agent: [Na+]
Product: COc1cc(Cl)ccc1C=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 77.8 %

Procedure:
4-Chloro-2-Fluorobenzaldehyde (300 mg, 1.89 mmol) was diluted with NaOMe (3784 μL, 1.89 mmol) (solution in methanol), heated to 50° C. and stirred for 3 hours. The reaction was concentrated in half and loaded directly onto a biotage 25 cartridge eluting with 5% ethyl acetate/hexanes to yield 4-chloro-2-methoxybenzaldehyde (250 mg, 1.47 mmol, 77.5% yield).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9](Cl)([O:11]C(=O)OC(Cl)(Cl)Cl)Cl.[CH2:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][C:29]1[N:34]=[CH:33][C:32]([NH:35][C:36](=[O:40])[C@@H:37]([CH3:39])[NH2:38])=[CH:31][CH:30]=1)[CH3:21]>ClCCl.CN(C)C1C=CN=CC=1>[CH2:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][C:29]1[N:34]=[CH:33][C:32]([N:35]2[C:36](=[O:40])[C@@H:37]([CH3:39])[NH:38][C:9]2=[O:11])=[CH:31][CH:30]=1)[CH3:21]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCc1ccccc1Oc1ccc(NC(=O)[C@@H](C)N)cn1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1ccccc1Oc1ccc(N2C(=O)N[C@H](C)C2=O)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 168.5 %

Procedure:
In a 50 mL round-bottomed flask N1-{6-[(2-ethylphenyl)oxy]-3-pyridinyl}-D-alaninamide (Intermediate 48, 170.0 mg) was dissolved in dichloromethane (5 mL) to give a pale yellow solution. The reaction mixture was cooled at 0° C. N,N-dimethyl-4-pyridinamine (35.7 mg, 0.292 mmol), triethylamine (0.203 mL, 1.460 mmol) and triphosgene (87 mg, 0.292 mmol) were added. The reaction mixture was stirred at 0° C. After 20 min, the reaction mixture was evaporated in vacuo affording yellow solid that was purified by silica gel chromatography (Biotage system, 10 g SNAP column) eluting with a gradient Cyclohexane/EtOAc from 2:1 to 1:3 in 20 CV; then 1:3 for 5 CV. The collected fractions afforded the title compound as a colourless oil (153.2 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[C:20](=O)[CH2:19][C:17](=O)[NH:16][C:14]2=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:17]1[CH:19]=[C:20]2[C:6]3[C:5]([CH2:11][CH2:12][N:13]2[C:14](=[O:15])[N:16]=1)=[CH:4][C:3]([O:2][CH3:1])=[C:8]([O:9][CH3:10])[CH:7]=3
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(CCN2C(=O)CC(=O)NC2=O)cc1OC
Product: COc1cc2c(cc1OC)-c1cc(Cl)nc(=O)n1CC2

Procedure:
A mixture of 1-(3,4-dimethoxyphenylethyl)barbituric acid (20.2 g) and phosphorus oxychloride (100 ml) is refluxed for 2.5 hours at 100°-110° C. The excess of phosphorus oxychloride is distilled. The residue is poured onto crushed ice and made basic with a cold solution of 30% aqueous sodium hydroxide. A yellow gummy precipitate is separated and extracted with chloroform. The extract is washed with water, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue is purified by passage over a silica gel column using chloroform as eluent to give the desired compound.
Reaction SMILES: [O:1]=[C:2]1[O:6][CH2:5][C@@H:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3]1.CC(C)=[O:20].C([O-])([O-])=O.[Cs+].[Cs+]>O>[OH:20][CH2:5][C@@H:4]([NH:7][C:8]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:17])[CH2:3][C:2]([OH:6])=[O:1]
Reactant: CC(C)=O
Reactant: O=C1C[C@H](NC(=O)OCc2ccccc2)CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: O=C(O)C[C@@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In a 500 ml round-bottomed flask phenylmethyl [(3S)-5-oxotetrahydro-3-furanyl]carbamate (4.3 g, 18.28 mmol, available from Sigma-Aldrich # 419249) was dissolved in water (100 ml) and acetone (100 ml) and to this solution Cs2CO3 (10.72 g, 32.9 mmol) was added and the reaction left under stirring at room temperature for 5 hours. The solution was then transferred into a separatory funnel and washed with EtOAc (2×50 ml). The aqueous phase was then acidified to pH=2 by the addition of a 2 M HCl aqueous solution and then extracted with EtOAc (5×100 mls). The organic phase was dried (Na2SO4) and solvent removed under reduced pressure to give the title compound D1 (3.78 g) as a white solid. MS: (ES/+) m/z: 254 (M+1). C12H15NO5 requires 253. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 12.11 (bs, 1 H), 7.41-7.07 (m, 5 H), 5.17-4.92 (m, 2 H), 3.95-3.62 (m, 1 H), 3.42-3.22 (m, 2H), 2.55-2.40 (m, 1 H), 2.34-2.23 (m, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8][C:3]=1[C:4](OC)=[O:5].[CH:22]([NH2:24])=O.C(O)(=O)C>O>[CH2:15]([O:14][C:9]1[CH:8]=[C:3]2[C:2](=[CH:11][C:10]=1[O:12][CH3:13])[N:1]=[CH:22][NH:24][C:4]2=[O:5])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NC=O
Reactant: COC(=O)c1cc(OCc2ccccc2)c(OC)cc1N
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2nc[nH]c(=O)c2cc1OCc1ccccc1
Temperature: 130 °C

Procedure:
A mixture of methyl 2-amino-5-(benzyloxy)-4-methoxybenzoate (7.36 g, 0.025 mol), formamide (25 mL) and acetic acid (6.25 mL) was heated at 130° C. for 24 hr. After letting cooling down to room temperature, water was added and the resulting solid was filtered and washed with plenty of cold water. The solid was dried under vacuum at 120° C. for 3 hr to yield 6-(benzyloxy)-7-methoxyquinazolin-4(3H)-one. Yield: 7.45 g (100%). 1HNMR (DMSO-d6): δ 12.15 (1H, s), 8.05 (1H, s), 7.66 (1H, s), 7.44 (5H, m), 7.23 (1H, s), 5.28 (2H, s), 3.92 (3H, s). LC-MS (ESI) m/z 207 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[S:30][C:7]3[N:8]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([C:21]5[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=5)=[CH:17][C:16]=4[F:29])[C:9](=[O:13])[NH:10][C:11](=[O:12])[C:6]=3[CH:5]=2)[CH2:3][CH2:2]1.Br[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)=[O:34].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH:1]1([C:4]2[S:30][C:7]3[N:8]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([C:21]5[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=5)=[CH:17][C:16]=4[F:29])[C:9](=[O:13])[N:10]([CH2:32][C:33]([C:35]4[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=4)=[O:34])[C:11](=[O:12])[C:6]=3[CH:5]=2)[CH2:3][CH2:2]1
Reactant: N#Cc1ccccc1-c1ccc(Cn2c(=O)[nH]c(=O)c3cc(C4CC4)sc32)c(F)c1
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Cn2c(=O)c3cc(C4CC4)sc3n(Cc3ccc(-c4ccccc4C#N)cc3F)c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.7 %

Procedure:
To a mixture of 4′-[(6-cyclopropyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile (1.5 g), 2-bromo-1-(4-methoxyphenyl)ethanone (0.99 g) and N,N-dimethylformamide (40 mL) was added 60% sodium hydride (0.17 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.95 g, 47%).
Reaction SMILES: C1C(=O)N(Cl)C(=O)C1.[CH:9](=[N:16][OH:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Br:18][C:19]1[N:20]=[C:21]([C:40]#[CH:41])[C:22]([N:25]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[N:23][CH:24]=1.CCN(CC)CC>CN(C=O)C>[Br:18][C:19]1[N:20]=[C:21]([C:40]2[O:17][N:16]=[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:41]=2)[C:22]([N:25]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[N:23][CH:24]=1
Reactant: C#Cc1nc(Br)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: ON=Cc1ccccc1
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1cc(-c2ccccc2)no1
Temperature: 55 °C
Reaction time: 0.75 h
Yield: 44.3 %

Procedure:
NCS (12.19 g, 91.26 mmol) was added to a solution of benzaldehyde oxime (10.05 g, 82.96 mmol) in DMF (40.20 mL) and the mixture heated at 55° C. for 15 minutes. The reaction mixture was cooled to ambient temperature and tert-butyl N-(5-bromo-3-ethynyl-pyrazin-2-yl)-N-tert-butoxycarbonyl-carbamate (36.34 g, 91.26 mmol) and DMF (30.15 mL) were added followed by the dropwise addition of Et3N (10.07 g, 13.87 mL, 99.55 mmol). The reaction mixture was stirred at ambient temperature for 45 minutes and then heated to 65° C. for 1 hour. The reaction mixture was cooled to ambient temperature and the solvent removed under high vacuum. The residue was taken up in ethyl acetate (50 ml). Remaining solid was filtered off and the filtrate concentrated in vacuo and then purified by column chromatography on silica using the ISCO column companion system, eluting with ethyl acetate/petroleum ether (0-40% EtOAc). Product fractions were combined and concentrated in vacuo to give tert-butyl (5-bromo-3-(3-phenylisoxazol-5-yl)pyrazin-2-yl)-N-tert-butoxycarbonyl-carbamate as a pale yellow solid (19 g, 46%). LC/MS m/z 419 [M−100+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])=[CH:7][C:5]([NH2:6])=[C:4]([F:17])[CH:3]=1.Cl[C:19]([O:21][CH3:22])=[O:20].CN(C)C1C=CC=CC=1.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([F:17])[C:5]([NH:6][C:19]([O:21][CH3:22])=[O:20])=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16]
Reactant: Nc1cc(Oc2ccccc2O)c(Cl)cc1F
Reactant: COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)c1ccccc1
Product: COC(=O)Nc1cc(Oc2ccccc2O)c(Cl)cc1F
Temperature: 25 °C

Procedure:
Into a mixture of 4-chloro-2-fluoro-5-(2-hydroxyphenoxy)aniline [Intermediate Compound A3-4], methyl chloroformate and tetrahydrofuran is added dropwise N,N-dimethylaniline, and the mixture is stirred at room temperature. Dilute hydrochloric acid is added to the reaction solution, and this is extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated to obtain 2-(2-chloro-4-fluoro-5-methoxycarbonylaminophenoxy)phenol [Intermediate compound A9-4].
Reaction SMILES: [CH:1](=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Cl:11][CH2:12][C:13]([O:15][CH3:16])=[O:14].C([N-]C(C)C)(C)C.[Li+]>O1CCCC1>[Cl:11][CH:12]([CH:1]([OH:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COc1ccc(C=O)cc1
Reactant: COC(=O)CCl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(Cl)C(O)c1ccc(OC)cc1

Procedure:
Condensation reaction between p-anisaldehyde and methyl chloroacetate was effected in tetrahydrofuran at -78° C. in the presence of lithium diisopropylamide, and the methyl 2-chloro-3-hydroxy-3-(p-methoxyphenyl)propionate obtained was separated into anti isomer (a mixture of (2R, 3R) isomer and (2S, 3S) isomer) and syn isomer (a mixture of (2R, 3S) isomer and (2S, 3R) isomer) by silica gel chromatography (solvent: n-hexane/ethyl acetate=3/1). NMR of these isomers was measured to determine anti isomer and syn isomer. When these isomers were analyzed by high performance liquid chromatography by use of a chiralcel OJ 4.6 mmφ×250 mm manufactured by Dicel Chemical Industries, LTD. (mobile phase: n-hexane/i-propanol=7/3, flow rate: 1.0 ml/min, column temperature: 40° C.), a retention time of the anti isomer was 9.2 minutes and 9.9 minutes, and a retention time of the syn isomer was 11.7 minutes and 13.9 minutes.