Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:11][CH2:12][C:13](=[O:39])[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31]CC1C=CC=CC=1)=[O:30])=[O:17])(OCC1C=CC=CC=1)=O.[ClH:40].[H][H]>[Pd].CC(O)C>[ClH:40].[NH2:11][CH2:12][C:13](=[O:39])[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:17]
Reactant: [H][H]
Reactant: O=C(CCC(=O)OCCCCCCCCCCC(=O)OCc1ccccc1)CNC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Product: NCC(=O)CCC(=O)OCCCCCCCCCCC(=O)O
Yield: 51.7 %

Procedure:
This compound was prepared from the product of 13b (0.60 g; 1.1 mmol), 12 M HCl (0.09 mL; 1.1 mmol), 10% Pd/C (100 mg), hydrogen gas, and 2-propanol (25 mL) using the procedure in Example 8d. 0.20 g (51%) product was obtained (white solid).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Cl:7][CH2:8][C:9](=O)[CH2:10][C:11](OCC)=[O:12].[OH-].[Na+]>>[Cl:7][CH2:8][C:9]1[N:1]=[C:2]2[S:3][CH:4]=[CH:5][N:6]2[C:11](=[O:12])[CH:10]=1
Reactant: Nc1nccs1
Reactant: CCOC(=O)CC(=O)CCl
Agent: [Na+]
Agent: [OH-]
Product: O=c1cc(CCl)nc2sccn12
Temperature: 110 °C
Yield: 25.9 %

Procedure:
A solution of 2-aminothiazole (5.0 g, 49.993 mmol) in polyphosphoric acid (40.0 g) was treated with ethyl chloroacetoacetate (11.176 g, 67.866 mmol) and heated at 110° C. for 5.0 h. The reaction mixture was cooled to room temperature and adjusted to pH 7 with 10% aq. NaOH. The solid formed was filtered and purified by column chromatography using ethyl acetate in dichloromethane as solvent to afford 2.6 g of the desired compound as a brown solid: 1H NMR (300 MHz, DMSO-d6) δ 4.59 (s, 2H), 6.41 (s, 1H), 7.56 (d, J=4.8 Hz, 1H), 8.03 (d, J=4.8 Hz, 1H); ESI-MS (m/z) 200.42 (M+H)+.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[C:8]([CH2:11][C:12]3[N:16]4[N:17]=[C:18]([C:21]5[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=5)[CH:19]=[CH:20][C:15]4=[N:14][CH:13]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH2:27]([Sn](CCCC)(CCCC)C=C)[CH2:28]CC>O1CCOCC1.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>[CH3:26][N:24]1[CH:25]=[C:21]([C:18]2[CH:19]=[CH:20][C:15]3[N:16]([C:12]([CH2:11][C:8]4[CH:9]=[CH:10][C:5]5[N:6]([C:2]([CH:27]=[CH2:28])=[CH:3][N:4]=5)[CH:7]=4)=[CH:13][N:14]=3)[N:17]=2)[CH:22]=[N:23]1
Reactant: Cn1cc(-c2ccc3ncc(Cc4ccc5ncc(Br)n5c4)n3n2)cn1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=Cc1cnc2ccc(Cc3cnc4ccc(-c5cnn(C)c5)nn34)cn12
Temperature: 150 °C

Procedure:
3-(3-Bromo-imidazo[1,2-a]pyridin-6-ylmethyl)-6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazine (Example 296, 50 mg, 0.122 mmol) was dissolved in dioxane (0.5 mL) in a microwave reactor. Then tributyl(vinyl)tin (36.9 μL, 0.122 mmol) and tetrakis(triphenylphosphine)palladium (1.4 mg, 0.001 mmol) were introduced. The RM was heated at 150° C. for 30 min under microwave irradiations. The solvent was removed and The residue was purified by preparative HPLC with acetonitrile and water (+0.1% TFA). The fractions were joined and were lyophilized. The residue was dissolved in MeOH and it was passed through an SPE cartridge of HCO3− to remove the TFA salt. The filtrate was evaporated to give the free salt of the title compound as a yellow solid (tR 0.7 min (conditions 2), MH+=356).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]([CH3:28])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13])[C:5](O)=[O:6].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:6])[CH:8]=[CH:9][C:10]=1[N:11]([CH3:28])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccc(C(=O)O)cc1Cl
Reactant: C1COCCN1
Product: CN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccc(C(=O)N2CCOCC2)cc1Cl

Procedure:
3-Chloro-4-(N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)benzoic acid and morpholine were reacted by a procedure similar to Example 47 to give 251. MS: (ESI+) 483.1
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:11]=[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:15]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH:28](B(O)O)=[CH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH:29]([C:30]1[CH:35]=[CH:34][C:33]([C:6]2[CH:7]=[CH:2][CH:3]=[C:4]([C:8]([C:10]3[CH:11]=[C:12]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:13]=[C:14]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:15]=3)=[O:9])[CH:5]=2)=[CH:32][CH:31]=1)=[CH2:28]
Reactant: O=C(c1cccc(Br)c1)c1cc(-c2ccccc2)cc(-c2ccccc2)c1
Reactant: OB(O)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=Cc1ccc(-c2cccc(C(=O)c3cc(-c4ccccc4)cc(-c4ccccc4)c3)c2)cc1
Temperature: 25 °C

Procedure:
25 g of (3-bromophenyl)-[1,1′;3′,1″]terphenyl-5′-ylmethanone and 8 g of styreneboronic acid [2156-04-9] are dissolved in 300 ml of toluene, and 100 ml of a 2M sodium carbonate solution are added. The reaction mixture is carefully degassed, and 200 mg of tetrakistriphenylphosphinepalladium are added, and the mixture is heated under reflux for 20 hours. The solution is cooled to room temperature. The phases are separated. The aqueous phase is extracted three times with toluene, the combined organic phases are subsequently washed twice with water, dried over magnesium sulfate, filtered, and the solvent is stripped off in vacuo.
Reaction SMILES: [O:1]=[C:2]([CH3:15])[CH2:3][CH2:4][CH2:5][C:6]#[C:7][CH2:8][C:9]#[C:10][CH2:11][C:12]([OH:14])=[O:13].[BH4-].[Na+].Cl>CCO.[Cl-].[Na+].O>[OH:1][CH:2]([CH3:15])[CH2:3][CH2:4][CH2:5][C:6]#[C:7][CH2:8][C:9]#[C:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: CC(=O)CCCC#CCC#CCC(=O)O
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC(O)CCCC#CCC#CCC(=O)O

Procedure:
Keto-acid 12 (1.8 g, 8.7 mmol) was dissolved in 25 mL absolute EtOH, and cooled to -20°. NaBH4 (0.456 g, 12 mmol) was added in one portion, and the solution was warmed to 0° over 15 min, then cooled to -20° again. The reaction mixture was then slowly acidified with 3.5N HCl, brine (25 mL) was added, and the solution was extracted with ether (4×25 mL). The combined ether extracts were washed with brine (2×20 mL), dried (MgSO4), and concentrated in vacuo, to give an orange oil, which rapidly darkened in colour. This was used immediately without purification in the next step.
Reaction SMILES: Br[C:2]1[C:3]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.[F:18][C:19]1[CH:24]=[C:23](B(O)O)[CH:22]=[C:21]([F:28])[N:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:18][C:19]1[CH:24]=[C:23]([C:2]2[C:3]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[N:4][N:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=23)[CH:22]=[C:21]([F:28])[N:20]=1
Reactant: Fc1ccc(-c2nn3ccccc3c2Br)cc1
Reactant: OB(O)c1cc(F)nc(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nn3ccccc3c2-c2cc(F)nc(F)c2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 25.1 %

Procedure:
A solution of 3-bromo-2-(4-fluorophenyl)-pyrazolo[1,5-a]pyridine (from Example le, 570 mg, 1.96 mmol), 2,6-difluoro-4-pyridyl-boronic acid (340 mg, 2.15 mmol) and dichlorobis(triphenylphosphine)palladium (137 mg, 0.196 mmol) in DMF (10.0 mL) was placed in a pre-heated oil bath at 110° C. To the reaction was added, in a dropwise manner, 2M sodium carbonate (2.00 mL, 4.00 mmol). The reaction was allowed to stir for 45 min before cooling to room temperature and filtering through a Celite 545 pad. The Celite filter was washed with ethyl acetate and the filtrate was concentrated to dryness at 50° C. under vacuum. The residue was dissolved in methylene chloride and dried (MgSO4). The drying agent was removed by filtration and the filtrate was concentrated and purified by silica gel chromatography to yield the title compound (160 mg, 0.492 mmol, 25%). 1H NMR (CDCl3) δ 8.53(d, 1H, J=6.8 Hz), 7.67(d, 1H, J=8.8 Hz), 7.53(dd, 2H, J=5.6, 8.0 Hz), 7.31(t, 1H, J=7.6 Hz), 7.11(t, 2H, J=8.4 Hz), 6.93(t, 1H, J=6.8 Hz), 6.75(s, 2H). MS (ES+ve): 326 (90, M+).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5](=[O:13])[C:4]2[CH:14]=[C:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:16]=[CH:17][C:3]1=2.[H-].[Na+].O.C(O)(=O)C.[CH3:30][C:31]1([CH3:38])[O:35][CH:34](CO)[CH2:33][O:32]1>>[CH3:30][C:31]1([CH3:38])[O:35][CH2:34][CH:33]([CH2:22][O:21][C:19](=[O:20])[CH2:18][C:15]2[CH:16]=[CH:17][C:3]3[N:2]([CH3:1])[CH2:8][C:7]4[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=4[C:5](=[O:13])[C:4]=3[CH:14]=2)[O:32]1
Reactant: CC1(C)OCC(CO)O1
Reactant: COC(=O)Cc1ccc2c(c1)C(=O)c1ccccc1CN2C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CN1Cc2ccccc2C(=O)c2cc(CC(=O)OCC3COC(C)(C)O3)ccc21

Procedure:
Methyl 5,6-dihydro-5-methyl-11-oxodibenz[b,e]azepine-2-acetate (1.5 g) was dissolved in Solketal (20 ml), and 50% oily sodium hydride (0.2 g) was added. The mixture was maintained at 80°-100° C. under reduced pressure using an aspirator. The reaction mixture was poured into water (150 ml) and acetic acid (0.5 ml), and the system was extracted with dichloromethane. The extract was dried over MgSO4, and then, the solvent was distilled off. The residual oily matter was subjected to liquid column chromatography using 100 g of Wakogel C-200 to afford the desired compound as a yellow oily material (0.950 g) eluted with a mixed liquid of benzene-dichloromethane (1:1).
Reaction SMILES: [C:1]([C:5]1[CH:23]=[CH:22][C:8]([CH2:9][NH:10][CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[CH2:30](Cl)[CH:31]=[CH2:32]>CN(C)C=O>[CH2:32]([N:10]([CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)[CH2:9][C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:23][CH:22]=1)[CH:31]=[CH2:30]
Reactant: C=CCCl
Reactant: CC(C)(C)c1ccc(CNCc2cccc3ccccc23)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN(Cc1ccc(C(C)(C)C)cc1)Cc1cccc2ccccc12
Temperature: 25 °C
Yield: 95 %

Procedure:
3.03 g (0.01 mole) of N-(4'-t-butylbenzyl)-1-naphthylmethylamine was dissolved in 50 ml of dry dimethylformamide, and 1.6 g (0.015 mole) of anhydrous sodium carbonate was added. With continued stirring at room temperature, 0.84 g (0.011 mole) of allyl chloride was added, and the mixture was reacted at 30° to 40° C. for 5 hours. The reaction mixture was mixed with ice water and extracted with toluene. The organic layer was washed with water, and toluene was evaporated. The residue was chromatographed on a silica gel column, and eluted with 5% ethyl acetate/n-hexane. The eluate was concentrated to give 3.26 g (yield 95%) of an oily substance.
Reaction SMILES: C[Si](C)(C)[O:3][CH:4]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]#[N:13])[CH:7]=1)[CH3:5].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si:34](Cl)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35].N1C=CN=C1>C1COCC1.O.C(OCC)C>[Si:34]([O:3][CH:4]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]#[N:13])[CH:7]=1)[CH3:5])([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(O[Si](C)(C)C)c1ccnc(C#N)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O[Si](C)(C)C(C)(C)C)c1ccnc(C#N)c1
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
To a solution of 4-[1-(trimethylsilyloxy)ethyl]-2-pyridinecarbonitrile (39.04 g, 0.1624 mol) in THF (200 ml) was added a solution of tetrabutylammonium fluoride in THF (1M, 178.6 ml, 0.1786 mol) at room temperature. After stirring for 0.5 h, the mixture was concentrated. The residue was diluted with ethyl acetate (300 ml) and washed with water (200 ml). The aqueous layer was then extracted with dichloromethane (200 ml×2). The combined organic layers were dried (MgSO4) and concentrated. The residual oil was dissolved in DMF (200 ml). To the solution was added tert-butyldimethylsilylchloride (36.72 g, 0.2436 mol) and imidazole (22.11 g, 0.3248 mol) at room temperture. After stirring for 19 h, diethyl ether (500 ml) and water (200 ml) were added to the mixture and the organic layer was separated. The organic layer was washed with water (100 ml×2), dried (MgSO4) and concentrated. The residue was purified by flash column chromatography eluting with ethyl acetate/hexane (1:20) to give 39.23 g (92%) of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[C:23]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)#[N:24].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([C:23]#[N:24])[CH:30]=2)=[CH:17][CH:16]=1)=[O:22]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)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: COCCOC
Solvent: O
Product: N#Cc1cccc(-c2ccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)cc2)c1
Yield: 31.3 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-cyanobiphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 3-cyanophenylboronic acid (0.027 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.022 g (31%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-cyanobiphenyl-4-carboxamide as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([NH2:21])[CH2:10][CH:11]([CH3:20])[N:12]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=1[O:22][CH3:23])=[O:4].C(O)(=O)C.[F:28][C:29]([F:43])([F:42])[C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH:33]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@H:9]([NH:21][CH2:33][C:32]3[CH:35]=[C:36]([C:38]([F:40])([F:41])[F:39])[CH:37]=[C:30]([C:29]([F:28])([F:42])[F:43])[CH:31]=3)[CH2:10][C@H:11]([CH3:20])[N:12]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=1[O:22][CH3:23])=[O:4]
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)N1c2cc(C(=O)OC)c(OC)cc2C(N)CC1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOC(=O)N1c2cc(C(=O)OC)c(OC)cc2[C@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 4-amino-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1,7-dicarboxylic acid 1-ethyl ester 7-methyl ester (208 mg, 0.64 mmol) in anhydrous 1,2-dichloroethane (5 mL) was added acetic acid (0.041 mL, 0.71 mmol), followed by 3,5-bis(trifluoromethyl)benzaldehyde (172 mg, 0.71 mmol) and sodium triacetoxyborohydride (0.205 g, 0.97 mmol). The reaction was stirred at room temperature for 2 h. The reaction mixture was partitioned between dichloromethane (45 ml) and water (100 ml) and the aqueous phase was adjusted to pH 9. The aqueous phase was extracted with dichloromethane (3×10 mL). The combined extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography using 20% acetone/hexanes as eluent afforded the title product (337 mg, 95%). MS m/z 567 (M++NH4); 1H NMR (CDCl3) δ 1.40 (d, 3H), 7.14 (s, 1H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]=[C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]1=[N:20]O)([OH:3])=[O:2].[CH:22](OC)=[O:23]>[Pt]=O.CO>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[NH:20][CH:22]=[O:23])([OH:3])=[O:2]
Reactant: CN1C(=O)C(=NO)C(=NCCCCCC(=O)O)N(C)C1=O
Reactant: COC=O
Agent: O=[Pt]
Solvent: CO
Product: Cn1c(NCCCCCC(=O)O)c(NC=O)c(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
A mixture of 15.8 g (0.05 mol) of the oxime (III), 200 ml of methanol, and 100 mg of platinum oxide was shaken under 4 atmospheres H2 for 15 minutes at room temperature. The catalyst was removed by filtration and the filtrate concentrated under reduced pressure (35° C.) to give a red oil. Methyl formate (200 ml) was added and the resulting mixture refluxed under argon for 20 hours. It was then cooled in an ice bath and the white solid collected by filtration. Recrystallization from methanol gave 9.82 g (63% yield) of the formamido uracil (IV) as white crystals, mp 152°-153° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][S:17][CH2:18][C@H:19]([O:35][C:36](=[O:48])[NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:20][O:21][C:22](=[O:34])[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:82][CH2:83][CH2:84][O:85][CH2:86][CH2:87][O:88][CH2:89][CH2:90][O:91][CH2:92][CH2:93][C:94]([O:96][C:97]([CH3:100])([CH3:99])[CH3:98])=[O:95]>C(Cl)Cl>[C:97]([O:96][C:94](=[O:95])[CH2:93][CH2:92][O:91][CH2:90][CH2:89][O:88][CH2:87][CH2:86][O:85][CH2:84][CH2:83][NH:82][C:13](=[O:14])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[CH2:16][S:17][CH2:18][C@H:19]([O:35][C:36](=[O:48])[NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:20][O:21][C:22](=[O:34])[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])([CH3:100])([CH3:99])[CH3:98]
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCN
Reactant: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OC(=O)NCCCCCCCCCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)NCCOCCOCCOCCC(=O)OC(C)(C)C)OC(=O)NCCCCCCCCCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-2-(benzyloxycarbonylamino)-3-((R)-2,3-bis(decylcarbamoyloxy)propylthio)propanoic acid (15, 1 eq) and HBTU (1.2 eq) in DCM (0.06 M) was added DIEA (2.4 eq), followed by tert-butyl 3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propanoate (1.2 eq). The reaction was stirred at room temperature for 4 hours. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-100% EtOAc/Hex to afford the title compound as an off-white solid.
Reaction SMILES: [C:1]([N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[O:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Br:21]Br.O.Cl>C(#N)C.C(O)C>[Br:21][C:12]1[CH:13]=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]2[O:7][CH2:6][N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:10][C:9]=2[CH:11]=1
Reactant: BrBr
Reactant: CC(C)(C)N1COc2c(cccc2-c2ccccc2)C1
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CC#N
Product: CC(C)(C)N1COc2c(cc(Br)cc2-c2ccccc2)C1
Temperature: 4 °C
Reaction time: 2.17 h

Procedure:
To a solution of 3-(tert-butyl)-8-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazine (9.420 g, 77.09 mmol) in acetonitrile (100 mL) was added dropwise bromine (1.8 mL, 1.0 equiv) at 5-10° C. After the addition, the mixture was stirred at 3-5° C. for 130 min. The resulting reaction mixture was allowed to stir at room temperature for 24 hours. To the reaction mixture was added water (200 mL) and the resulting mixture was concentrated under reduced pressure to remove most of the acetonitrile. The aqueous mixture was extracted with ethyl acetate and the combined organic layer was washed with water, dried (Na2SO4), filtered and concentrated under reduced pressure to give a yellow solid. The solid was dissolved in ethanol and treated with 37% HCl (3.65 g). The resulting mixture was concentrated to removed ethanol to give the product which was crystallized from MTBE-EtOH to give 6-bromo-3-(tert-butyl)-8-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazine (3.118 g).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.S(Cl)([Cl:16])=O>>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:16])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=C(O)c1ccc(I)cc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(I)cc1[N+](=O)[O-]

Procedure:
4-Iodo-2-nitrobenzoic acid piperidine amide. A suspension of 4-iodo-2-nitrobenzoic acid (1.0 g, 3.4 mmol) in thionyl chloride (10 mL) was heated to reflux for 45 min. The reaction mixture became homogeneous. The mixture was cooled and concentrated in vacuo to give 4-iodo-2-nitrobenzoyl chloride as a yellow oil, which was used immediately in the following reaction. 1H NMR (500 MHz, CDCl3): 8.38 (d, J=1.6 Hz, 1H), 8.12 (dd, J=8.1, 1.6 Hz, 1H), 7.48 (d, J=8.1 Hz, 1H). To a solution of 4-iodo-2-nitrobenzoyl chloride (3.4 mmol) in DCM (10 mL) at ambient temperature was added piperidine (1.3 mL, 13.1 mmol). The reaction mixture was stirred for 0.5 h then poured into 1 N HCl and extracted with DCM (2×). The combined organic extracts were dried (Na2SO4), and concentrated in vacuo affording the title amide as a white solid (1.2 g, 98%). MS (ESI): m/z 361 [M+H]+, 383 [M+Na]+. 1H NMR (400 MHz, CDCl3): (rotameric broadening) 8.51 (d, J=1.6 Hz, 1H), 8.01 (dd, J=8.0, 1.6 Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 3.85-3.65 (bm, 2H), 3.16 (t, J=5.6 Hz, 2H), 1.90-1.35 (bm, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]#[N:25])=[C:6]([C:8]2[C:13]([O:14][CH:15]([F:17])[F:16])=[CH:12][N:11]([CH:18]([CH3:22])[C:19](O)=[O:20])[C:10](=[O:23])[CH:9]=2)[CH:7]=1.[NH2:26][C:27]1[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:29][CH:28]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]#[N:25])=[C:6]([C:8]2[C:13]([O:14][CH:15]([F:16])[F:17])=[CH:12][N:11]([CH:18]([CH3:22])[C:19]([NH:26][C:27]3[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])=[CH:29][CH:28]=3)=[O:20])[C:10](=[O:23])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: CC(C(=O)O)n1cc(OC(F)F)c(-c2cc(Cl)ccc2C#N)cc1=O
Product: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(OC(F)F)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
270 mg (purity 63%, 0.46 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-(difluoromethoxy)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) and 98 mg (0.51 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 100 mg (40% of theory)