Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[N:6][CH:5]=[CH:4][N:3]=1.CC#N.N1C=CC=CC=1.[C:18]1([O:24][C:25](Cl)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[CH3:8][C:7]1[C:2]([NH:1][C:25](=[O:26])[O:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccnc1N
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CC#N
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1nccnc1NC(=O)Oc1ccccc1
Reaction time: 18 h

Procedure:
A solution of 2-amino-3-methyl-pyrazine (1.50 g, 1.37 mmol) in a mix of 1:2 THF:MeCN (30 mL), and pyridine (0.664 g, 1.44 mmol) was treated dropwise with phenylchloroformate (1.3 g, 1.44 mmol) in THF (10 mL). After stirring for 18 h, the reaction mixture was concentrated in vacuo to a solid and was used without further purification.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11](Cl)(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.[C:15]([O:19][C:20]([NH:22][CH2:23][CH:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:25][CH2:26][NH2:27])=[O:21])([CH3:18])([CH3:17])[CH3:16]>C(N(CC)CC)C>[C:15]([O:19][C:20]([NH:22][CH2:23][CH:24]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:25][CH2:26][NH:27][S:11]([C:6]1[C:5]2[CH:4]=[CH:3][N:2]=[CH:1][C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:13])=[O:12])=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: CC(C)(C)OC(=O)NCC(CCN)c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(CCNS(=O)(=O)c1cccc2cnccc12)c1ccccc1
Yield: 82.5 %

Procedure:
The same procedure as described in Referential example 3 were repeated using 4.0 g of 5-isoquinolinesulfonyl chloride, 6.95 g of 4-t-butoxycarbonylamino-3-phenylbutylamine and 2.66 g of triethylamine, and there were obtained 6.6 g of N-(4-t-butoxycarbonylamino-3-phenylbutyl)-5-isoquinolinesulfonamide in a yield of 83%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[C:21]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)([OH:23])=[O:22].C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:9][O:8][C:6]1[N:7]=[C:2]([C:28]2[CH:29]=[C:24]([CH:25]=[CH:26][CH:27]=2)[C:21]([OH:23])=[O:22])[CH:3]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:5]=1
Reactant: COc1ccc(CCNc2cc(Cl)nc(OC)n2)cc1
Reactant: O=C(O)c1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(CCNc2cc(-c3cccc(C(=O)O)c3)nc(OC)n2)cc1
Temperature: 90 °C
Reaction time: 17 h
Yield: 90.4 %

Procedure:
Argon is bubbled through a mixture of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(4-methoxy-phenyl)-ethyl]-amine [300 mg, 1.02 mmol, Intermediate (8)], 3-carboxyphenyl boronic acid [339 mg, 2.04 mmol, Intermediate (20)], and Cs2CO3 (1.66 g, 5.1 mmol) in ethylene glycol dimethyl ether (8 mL) and water (2 mL), for a period of 5 minutes. To this mixture is added tetrakis(triphenylphosphine) palladium (0) (59 mg, 0.051 mmol) and the reaction vessel is sealed and heated to 90° C. After stirring for 17 hours the mixture is diluted with water (50 mL) and extracted with EtOAc (50 mL). The aqueous layer is acidified to pH 6 with 10% hydrochloric acid and extracted twice with EtOAc (50 mL). The organic extracts from the acidic solution are combined and dried over magnesium sulfate, filtered and concentrated to provide 3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzoic acid [350 mg, 90.4%, Example 35(a)] as a solid. LCMS: RT=2.69 minutes, MS: 380 (M+H). 1H NMR [(CD3)2SO]: δ 8.52 (1H, s), 8.28 (3H, m), 8 (2H, m), 7.61 (2H, t, J=0.027 Hz), 7.47 (1H, m), 7.17 (2H, d, J=0.027 Hz), 6.85 (2H, d, J=0.027 Hz), 6.69 (1H, s), 3.89 (3H, s), 3.71 (3H, s), 2.8 (2H, t, J=0.024 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[N:12]([N:21]=[C:22](S(C)(=O)=O)[C:23]=2[C:24](=[O:31])[NH:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.[N-:36]=[N+:37]=[N-:38].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[N:36]([C:22]1[C:23]([C:24](=[O:31])[NH:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[C:11]2[N:10]=[CH:9][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]2[N:21]=1)=[N+:37]=[N-:38]
Reactant: CS(=O)(=O)c1nn2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cnc2c1C(=O)NC1CCCC1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=Nc1nn2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cnc2c1C(=O)NC1CCCC1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a solution of the compound obtained in Example 33 (1.5 g) in dimethylformamide (20 mL) was added sodium azide (1.11 g) and the mixture was stirred at 110° C. overnight. After cooling to room temperature, to the reaction mixture was a saturated brine and the mixture was stirred and extracted with ethyl acetate. The organic layer was washed with water and concentrated in vacuo and the resultant crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=80/20 to 30/70) to give 2-azido-6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-(N-cyclopentylcarbamoyl)pyrazolo[1,5-a]pyrimidine (1.15 g, a yellow viscidity). To a solution of the product (870 mg) in tetrahydrofuran (16 mL) was added triphenylphosphine (896 mg) and the mixture was stirred at 40° C. for 1 hour. After cooling to room temperature, the reaction mixture was concentrated in vacuo and the resultant crude product was purified by a column chromatography on silica gel (solvent; chloroform/methanol=100/0 to 97/3) to give 6-(2-chlorophenyl)-7-(4-chlorophenyl)-2-triphenylphosphoranylidenamino-pyrazolo[1,5-a]pyrimidine (942 mg, yield: 58%) as a yellow solid MS (APCI)m/z; 726/728 M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH2:13]([SH:17])[CH2:14][CH2:15][SH:16].B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]1[S:17][CH2:13][CH2:14][CH2:15][S:16]1
Reactant: SCCCS
Reactant: COc1cccc(C=O)c1OC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cccc(C2SCCCS2)c1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
A solution of 49.5 g (298 mmol) of 2,3-dimethoxybenzaldehyde and 48.4 g (447 mmol) of propane-1,3-dithiol in 800 mL of methylene chloride was cooled to 0° C. Boron trifluoride etherate (7.5 mL, 61 mmol) was added dropwise to the cooled solution and the reaction mixture was stirred at 0° C. for 0.5 h, then at ambient temperature for 18 h. The methylene chloride solution was washed with 2×200 mL of 10% aqueous sodium hydroxide solution, 200 mL of water and 100 mL of brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 75 g (98% yield) of 2-(2',3'-dimethoxyphenyl)-1,3-dithiane, m.p. 119°-120° C.; 1H NMR (CDCl3) δ: 1.8-2.0 (m, 1H), 2.1-2.25 (m, 1H), 2.86 (t, 1H), 2.91 (t, 1H), 3.05-3.2 (m, 2H), 3.83 (s, 3H), 3.91 (s, 3H), 5.68 (s, 1H), 6.86 (dd, 1H), 7.07 (t, 1H), 7.19 (dd, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:12][C:11]2[C:10](I)=[N:9][NH:8][C:7]=2[CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[C:20]([O:24][C:25]([N:27]1[C:35]2[C:30](=[CH:31][C:32]([C:36]([CH3:44])([CH3:43])[O:37][SiH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:33][CH:34]=2)[CH:29]=[C:28]1C1C2SC=CC=2N(C(OC(C)(C)C)=O)N=1)=[O:26])([CH3:23])([CH3:22])[CH3:21].N#N>C(OCC)(=O)C.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]([O:24][C:25]([N:27]1[C:35]2[C:30](=[CH:31][C:32]([C:36]([CH3:44])([CH3:43])[O:37][SiH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:33][CH:34]=2)[CH:29]=[C:28]1[C:10]1[C:11]2[S:12][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][C:7]=2[NH:8][N:9]=1)=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)c1cc2[nH]nc(I)c2s1
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3cc(C(C)(C)O[SiH2]C(C)(C)C)ccc3n2C(=O)OC(C)(C)C)c2sccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2[nH]nc(-c3cc4cc(C(C)(C)O[SiH2]C(C)(C)C)ccc4n3C(=O)OC(C)(C)C)c2s1
Temperature: 120 °C

Procedure:
In two separate Smith process vials (10-20 mL capacity) are added 3-iodo-1H-thieno[3,2-c]pyrazole-5-carboxylic acid methyl ester [420 mg, 1.36 mmol, Intermediate (26)], 5-(tert-butyl-dimethyl-silanyloxymethyl)-1H-indole-2-boronic acid 1-carboxylic acid tert-butyl ester [912 mg, 2.25 mmol, Intermediate (8), prepared as described in Example 1-4 of International Patent Application Publication No. WO 02/32861], potassium carbonate (2M, aqueous, 2.25 mL) tetrakis(triphenylphosphine)palladium(0) (87 mg, 0.0752 mmol), and a mixture of toluene/ethanol (9:3 mL). The reaction tube is filled with N2 and sealed using capping device. The reaction mixture is heated to 120° C. using microwave (Personal chemistry optimizer) for 900 seconds. After reactions are over combined them into a flask, diluted with ethyl acetate (50 mL) and washed twice with water (10 mL), brine and dried over sodium sulfate. Purification by chromatography on 35 g silica gel cartridge (30-50% ethyl acetate gradient in heptane) gave two major fractions. The higher rising Rf fractions are combined and evaporated solvent in vacuo to give 5-(tert-butyl-dimethyl-silanyloxymethyl)-2-(5-methoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-indole-1-carboxylic acid tert-butyl ester [653 mg, Intermediate (27)] as light yellow solid. LC/MS: 542 (M+H). The lower rising Rf fractions are combined and evaporated in vacuo to give product 3-[5-(tert-butyl-dimethyl-silanyloxymethyl)-1H-indol-2-yl]-1H-thieno[3,2-c]pyrazole-5-carboxylic acid methyl ester [253 mg, Intermediate (28)] as light yellow solid; LC/MS: 442 (M+H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:13]#[N:14])=[CH:4][C:5]2[S:9][C:8]([S:10][CH3:11])=[N:7][C:6]=2[CH:12]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[F:1][C:2]1[C:3]([CH2:13][NH2:14])=[CH:4][C:5]2[S:9][C:8]([S:10][CH3:11])=[N:7][C:6]=2[CH:12]=1
Reactant: CSc1nc2cc(F)c(C#N)cc2s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CSc1nc2cc(F)c(CN)cc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
To a stirred mixture of 5-fluoro-2-(methylthio)benzo[d]thiazole-6-carbonitrile in anhydrous THF (20 mL) at −20° C. under argon was added dropwise lithium aluminum hydride (2 M solution in THF, 11.7 mL, 5.9 mmol). After 1 h, water (500 μL) and 1 M aq NaOH (500 μL) were added slowly to the reaction mixture. After 5 minutes, additional water (2 mL) was added and the mixture was stirred at rt for 30 minutes. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 5% MeOH in CH2Cl2 to afford (5-fluoro-2-(methylthio)benzo[d]thiazol-6-yl)methanamine (128 mg, 29%) as a colorless oil. 1H NMR (500 MHz, DMSO-d6) δ 8.07 (d, J=7.1 Hz, 1H), 7.64 (d, J=11.1 Hz, 1H), 3.83 (s, 2H), 2.78 (s, 3H), 1.80-2.06 (m, 2H); LCMS (ESI) m/z 229 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[S:7](=[O:9])(=[O:8])[C@@H:6]2[CH2:10][CH2:11][S:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=3[C@@:5]2([CH3:22])[N:4]=[C:3]1[N:23]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27].CCOC(C)=O>[Pd].CO>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]2[S:12][CH2:11][CH2:10][C@H:6]3[S:7](=[O:8])(=[O:9])[C:2]([CH3:38])([CH3:1])[C:3]([N:23]([C:24]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:30])[C:31](=[O:32])[O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[N:4][C@:5]3([CH3:22])[C:14]=2[CH:15]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(C)c3cc([N+](=O)[O-])ccc3SCC[C@H]2S(=O)(=O)C1(C)C
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(C)c3cc(N)ccc3SCC[C@H]2S(=O)(=O)C1(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.5 %

Procedure:
A flask was charged with tert-butyl N-[(4aR,11bR)-3,3,11b-trimethyl-10-nitro-4,4-dioxo-5,6-dihydro-4aH-[1]benzothiepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (1.18 g, 2.071 mmol), 10 wt. % Pd/C (0.220 g, 0.207 mmol), EtOAc (4.14 ml) and MeOH (4.14 ml). The flask was purged with nitrogen, evacuated, and filled with hydrogen. The reaction was stirred at RT under hydrogen atmosphere for 16 h. The reaction was incomplete, so another 100 mg of 10 wt. % Pd/C was added, and stirring under hydrogen was continued. After 8 h, the reaction was complete. The mixture was filtered through Celite and washed with EtOAc. The filtrate was concentrated to provide tert-butyl N-[(4aR,11bR)-10-amino-3,3,11b-trimethyl-4,4-dioxo-5,6-dihydro-4aH-[1]benzothiepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (1.00 g, 89%) as a dark foamy solid. LC/MS (ESI+) m/z=562.2 (M+Na). tert-Butyl N-[(4aS,11bR)-10-amino-3,3,11b-trimethyl-4,4-dioxo-5,6-dihydro-4aH-[1]benzothiepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate was prepared following the same hydrogenation procedure. The product was isolated as a dark foamy solid in 90% yield. LC/MS (ESI+) m/z=562.2 (M+Na).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16](O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[N:34]1[CH:39]=[CH:38][C:37]([C:40]([NH:42][NH2:43])=[NH:41])=[CH:36][CH:35]=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][CH2:15][C:16]2[NH:41][C:40]([C:37]3[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=3)=[N:42][N:43]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: N=C(NN)c1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCC(OCC(=O)O)CC1
Agent: CC(C)COC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(OCc2nnc(-c3ccncc3)[nH]2)CC1

Procedure:
A solution of 4-carboxymethoxypiperidine-1-carboxylic acid tert-butyl ester (Preparation 1, 255 mg, 0.952 mmol) and triethylamine (138 μl, 0.982 mmol) in toluene was cooled to 0° C. and isobutylchloroformate (127 μl, 0.982 mmol) added. After stirring at rt for 45 min 4-pyridinecarboximidic acid hydrazide (100 mg, 0.82 mmol) and 3 Å powdered molecular sieves (0.82 g) were added and the reaction heated under reflux for 18 h. On cooling, the mixture was filtered through celite, the filtrate evaporated and the residue dissolved in EtOAc (50 ml). After washing with saturated aqueous Na2CO3 (10 ml) and brine (10 ml), the solvent was removed and the residue purified by flash chromatography (EtOAc then 5% MeOH in EtOAc) to afford the title compound: RT=2.81 min; m/z (ES+)=360.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11](OS(C(F)(F)F)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)O1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>C1(C)C=CC=CC=1.C(O)C.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:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
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: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(N)cc2)CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 64.8 %

Procedure:
To a mixture of 4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (Synthesis, 993, (1991), 7.4 g, 22 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (4.0 g, 18 mmol) and Pd(PPh3)4 (2.3 g, 2.0 mmol) in 160 mL of toluene and 80 mL of absolute ethanol under Ar was added 2.0 M aq Na2CO3 solution (80 mL, 160 mmol). The resulting mixture was stirred at 80° C. for 3 h and then cooled to RT. After adding 600 mL of EtOAc, the mixture was washed with 1 M NaOH (250 mL), H2O (2×250 mL), brine (300 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (20% EtOAc/hexane) gave 3.20 g (63%) of the title compound as a hard yellow foam: Mass spectrum (ESI, m/z): Calcd. for C16H22N2O2, 275.2 (M+H), found 275.1.
Reaction SMILES: C[O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.[CH2:22]([C:24]1[O:28][C:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[N:26][C:25]=1[CH2:36][CH2:37]O)[CH3:23]>>[NH2:5][C@@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:37][CH2:36][C:25]2[N:26]=[C:27]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[O:28][C:24]=2[CH2:22][CH3:23])=[CH:18][CH:19]=1)[C:3]([OH:2])=[O:21]
Reactant: CCc1oc(-c2ccc(F)cc2)nc1CCO
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Product: CCc1oc(-c2ccc(F)cc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Yield: 88 %

Procedure:
Intermediate 58 was prepared as described above for the preparation of intermediate 52. From 230 mg of N-(Boc)-L-Tyrosine methyl ester and 200 mg of Intermediate 10B was prepared 350 mg of BOC-protected intermediate methyl ester (88% yield; 1H NMR (DMSO-d6, 300 MHz) δ8.07-8.01 (m, 2H), 7.15 (t, 2H, J=8.7), 7.04 (d, 2H, J=8.5), 6.84 (d, 2H, J=8.5), 4.50 (m, 1H), 4.24 (t, 2H, J=6.5), 3.72 (s, 3H), 3.04-2.99 (m, 2H), 2.77 (q, 2H, J=7.5), 1.44 (s, 9H), 1.33 (t, 3H, J=7.5); From 340 mg of BOC-protected ester intermediate was prepared 350 mg of intermediate 58 as a crude off-white colored solid. 1H NMR (DMSO-d6, 400 MHz) δ8.13 (br s, 2H), 7.91 (dd, 2H, J=8.8, 5.3), 7.3 (t, 2H, J=8.9), 7.10 (d, 2H, J=8.6), 6.85 (d, 2H, J=8.4), 4.13 (t, 2H, J=6.4), 4.08 (m, 1H), 2.98-2.95 (m, 2H), 2.88 (t, 2H, J=6.5), 2.70 (q, 2H, J=7.4), 1.19 (t, 3H, J=7.5); low resolution MS (ES+)m/e 399.13 (MH+).
Reaction SMILES: BrBr.[CH2:3]([O:5][C:6]([CH:8]1[CH2:19][N:18]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11]2[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=2[C:9]1=[O:27])=[O:7])[CH3:4].C(N(CC)CC)C.O>C(Cl)Cl>[CH2:3]([O:5][C:6]([C:8]1[C:9](=[O:27])[C:10]2[CH:15]=[N:14][C:13]([S:16][CH3:17])=[N:12][C:11]=2[N:18]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)C1CN(Cc2ccccc2)c2nc(SC)ncc2C1=O
Agent: BrBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccccc2)c2nc(SC)ncc2c1=O
Reaction time: 0.5 h
Yield: 25.6 %

Procedure:
Bromine (0.68 g, 4.3 mmol) was added to a solution of 8-benzyl-2-methylsulfanyl-5-oxo-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (1.53 g, 4.28 mmol) in DCM (20 mL). After 30 minutes, the reaction mixture was concentrated. The residue was redissolved in DCM (20 mL) and triethylamine (1.08 g, 10.7 mmol) was added. After 15 h, water (10 mL) was added, the organic layer separated, dried (MgSO4), and concentrated. Chromatography on silica (0-50% EtOAc/hexanes gradient) provided 0.39 g 8-benzyl-2-methylsulfanyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.26 (s, 1H), 8.51 (s, 1H), 7.21-7.29 (m, 5H), 5.45 (s, 2H), 4.27 (q, 2H, J=7.1 Hz), 2.48 (s, 3H), 1.30 (t, 3H, J=7.1 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=2)=[CH:6][N:7]=1.Cl[CH:18]([CH2:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[CH:34][CH:33]=[CH:32]2)[CH:19](N1C(=O)CCC1=O)O>C(O)CO>[F:16][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[N:7][C:2]3[N:3]([C:18]([CH2:28][C:29]4[CH:30]=[C:31]5[C:36](=[CH:37][CH:38]=4)[N:35]=[CH:34][CH:33]=[CH:32]5)=[CH:19][N:1]=3)[N:4]=2)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: O=C1CCC(=O)N1C(O)C(Cl)Cc1ccc2ncccc2c1
Reactant: N#Cc1ccc(-c2cnc(N)nn2)cc1F
Solvent: OCCO
Product: N#Cc1ccc(-c2cnc3ncc(Cc4ccc5ncccc5c4)n3n2)cc1F
Temperature: 135 °C
Reaction time: 3.5 h
Yield: 185.4 %

Procedure:
A 22 L reactor equipped with a overhead stirring, a thermocouple, a distillation apparatus, and a nitrogen inlet was purged with nitrogen before 4-(3-amino-1,2,4-triazin-6-yl)-2-fluorobenzonitrile (20, 300 g, 1.39 mol), 1-(2-chloro-1-hydroxy-3-(quinolin-6-yl)propyl)pyrrolidine-2,5-dione (11, 635 g, 1.99 mol, 1.43 equiv), and ethylene glycol (3.0 L) were charged to the reactor at room temperature. The resulting reaction mixture was heated to 130-140° C. with nitrogen bubbled through continuously. The distillate was collected with the distillation apparatus. After 3-4 h, HPLC indicated the reaction was deemed complete (presence of <1.5% of starting material 20). The reaction mixture was gradually cooled to room temperature. A 2.5% aqueous sodium carbonate solution (Na2CO3, 14.1 L) was added with stirring to the reactor over 60 min and the mixture was stirred at room temperature for 1-2 h. The mixture was then filtered, and the solid was washed with water (9.6 L) and dried under vacuum to afford the desired crude product (13, 980.4 g), which was combined with several other batches for purification as described below.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH2:13]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 101.1 %

Procedure:
To a solution of 1-(2-hydroxy-phenyl)-ethanone (5 g, 0.03672 mole) in DMF (75 mL) was added NaH (60% w/w dispersion in oil) (1.66 g, 0.0416 mole) and the resulting mixture was stirred at ambient temperature for 15 minutes. Benzyl bromide (7.23 g, 0.0422 mole) was then added and the mixture as stirred for an additional 4 hours. The reaction mixture was then quenched with cold aqueous NH4Cl solution and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with water, brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 8.4 g (100%) of 1-(2-benzyloxy-phenyl)-ethanone. LCMS: 227.1 (M+1)+, 84.14%. To a mixture of THF (200 mL) and NaH (60% w/w dispersion in oil) (4.4 g, 0.11 mole) cooled to 0° C. was added diethyl oxalate (10.73 g, 0.07345 mole). The resulting mixture was heated to reflux for 15 minutes. After cooing to ambient temperature, 1-(2-benzyloxy-phenyl)-ethanone (8.3 g, 0.0376 mole) was added dropwise over a period of 45 minutes. The resulting mixture was heated to 55° C. for 30 minutes. The reaction mixture was then quenched with cold aqueous NH4Cl solution and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with water, brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (4% ethyl acetate in hexane) to afford 8.7 g (71%) of 4-(2-benzyloxy-phenyl)-2,4-dioxo-butyric acid ethyl ester. LCMS: 327.12 (M+1)+, 78.6%. A solution of 4-(2-benzyloxy-phenyl)-2,4-dioxo-butyric acid ethyl ester (3.75 g, 0.01149 mole), acetic acid (20 mL) and hydrazine hydrate (0.632 g, 0.01264 mole) was heated to reflux for 3 hours. The reaction mixture was then poured into iced water basified with saturated aqueous NaHCO3 solution and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 3.703 g (100%) of 5-(2-benzyloxy-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester. LCMS: 323.13 (M+1)+, 97.14%.