Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]=[C:7]([C:9]([OH:11])=O)[S:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:44][CH:45]1[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][CH2:46]1>CN(C)C=O>[OH:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]=[C:7]([C:9]([NH:44][CH:45]3[CH2:46][CH2:47][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:49][CH2:50]3)=[O:11])[S:8][C:4]=2[CH:3]=1
Reactant: O=C(O)c1nc2ccc(O)cc2s1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2nc3ccc(O)cc3s2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
To a stirred mixture of 6-hydroxybenzo[d]thiazole-2-carboxylic acid (0.20 g, 1 mmol) in anhydrous N,N-dimethylformamide (2 mL) was added triethylamine (0.12 g, 1.2 mmol), 1-hydroxybenzotriazole hydrate (0.16 g, 1.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.23 g, 1.2 mmol), and tert-butyl 4-aminopiperidine-1-carboxylate (0.24 g, 1.2 mmol). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue obtained was purified by flash chromatography (silica gel, ethyl acetate/hexanes=1/1) to afford tert-butyl 4-(6-hydroxybenzo[d]thiazole-2-carboxamido)piperidine-1-carboxylate as a white solid (0.23 g, 62%). 1H-NMR (CDCl3, 300 MHz): δ 7.90 (m, 1H), 7.38 (m, 1H), 7.28 (m, 2H), 7.11 (m, 1H), 4.12 (m, 3H), 2.95 (m, 2H), 2.04 (m, 2H), 1.58 (m, 2H), 1.48 (s, 9H) ppm; MS (ESI): 379.1 (M+1).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]1([CH3:18])[O:15][C:14](=[O:16])[CH2:13][C:12](=[O:17])[O:11]1>>[CH:1](=[C:13]1[C:14](=[O:16])[O:15][C:10]([CH3:18])([CH3:9])[O:11][C:12]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=Cc1ccccc1
Product: CC1(C)OC(=O)C(=Cc2ccccc2)C(=O)O1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 120, Step 1 starting from benzaldehyde and 2,2-dimethyl-1,3-dioxane-4,6-dione.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]([C:10](=[O:23])[CH2:11][N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])[CH3:9])=[CH:6][CH:5]=[C:4]([Cl:24])[C:3]=1[CH3:25].[Br:26]N1C(=O)CCC1=O.N(C(C)(CC(C)(OC)C)C#N)=NC(C)(CC(OC)(C)C)C#N>ClCCl>[Br:26][CH2:25][C:3]1[C:2]([Cl:1])=[C:7]([CH:6]=[CH:5][C:4]=1[Cl:24])[N:8]([CH3:9])[C:10](=[O:23])[CH2:11][N:12]1[C:13](=[O:22])[C:14]2=[CH:21][CH:20]=[CH:19][CH:18]=[C:15]2[C:16]1=[O:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(Cl)ccc(N(C)C(=O)CN2C(=O)c3ccccc3C2=O)c1Cl
Agent: COC(C)(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)(C)OC
Solvent: ClCCl
Product: CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)c(CBr)c1Cl
Yield: 27.8 %

Procedure:
A mixture of 2,6-dichloro-3-[N-(phthalimidoacetyl)-N-methylamino]toluene (303 mg), N-bromosuccinimide (150 mg), 2,2'-azobis-(2,4-dimethyl-4-methoxyvaleronitrile) (30 mg) and dichloromethane (6 ml) was heated under reflux for 5 hours. N-Bromosuccinimide (75 mg) was added therein and the mixture was heated under reflux for additional 3 hours. The reaction mixture was washed with saturated sodium bicarbonate solution twice and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from diethyl ether to give 3-bromomethyl-2,4-dichloro-N-methyl-N-(phthalimidoacetyl)aniline (102 mg) as crystals. mp: 211° C. (dec.)
Reaction SMILES: [N+:1](=[CH2:3])=[N-:2].CC1C=CC(S(N(N=O)C)(=O)=O)=CC=1.[CH3:18][O:19][C:20](=[O:25])[C:21](Br)=[CH:22][CH3:23].C(O)(=O)C>C(OCC)C>[CH3:23][C:22]1[CH:3]=[N:1][NH:2][C:21]=1[C:20]([O:19][CH3:18])=[O:25]
Reactant: C=[N+]=[N-]
Reactant: CC=C(Br)C(=O)OC
Agent: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=O)c1[nH]ncc1C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of diazomethane (nominally 0.68 g—generated from DIAZALD® (5 g) in diethyl ether (45 ml)) at −78° C. was added a solution of E/Z methyl-2-bromo-2-butenoate (3.58 g) (available from Fluka) in diethyl ether (15 ml), dropwise, over 15 min. The mixture was maintained at −78° C. for 1 h then allowed to warm to 20° C. with stirring overnight. Acetic acid (1 ml) was added to destroy excess diazomethane and the mixture evaporated under reduced pressure. The residue was co-evaporated with toluene. Purification of the residue by column chromatography on silica gel eluting with ethyl acetate:cyclohexane (1:1) gave the title compound (1.12 g) as an orange solid.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].F[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26]>CS(C)=O>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:4]2[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:2]([NH:1][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N+:25]([O-:27])=[O:26])[S:6][C:5]=2[CH:7]=1
Reactant: CCOC(=O)c1c(N)sc2cc(OC)ccc12
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CS(C)=O
Product: CCOC(=O)c1c(Nc2ccccc2[N+](=O)[O-])sc2cc(OC)ccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 4 and using ethyl 2-amino-6-methoxybenzo[b]thiophene-3-carboxylate, 2-fluoronitrobenzene and dimethyl sulfoxide, ethyl 6-methoxy-2-(2-nitroanilino)benzo[b]thiophene-3-carboxylate is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH:13]1([NH:16][CH:17]=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1.C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([C:18](=[CH:17][NH:16][CH:13]1[CH2:14][CH2:15]1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:5]
Reactant: CCOC(=O)C=CNC1CC1
Reactant: O=C(Cl)c1cc(F)c(Cl)nc1Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(Cl)nc1Cl

Procedure:
In dry dioxane, 2,6-dichloro-5-fluoronicotinoyl chloride, prepared in Reference Example 10-(2), was allowed to react with ethyl β-cyclopropylaminoacrylate in the presence of triethylamine to give ethyl 2-(2,6-dichloro-5-fluoronicotinoyl)-3-cyclopropylaminoacrylate, m.p. 129°-130° C.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[OH:7][CH:8]([C:11]1[N:16]=[C:15]([C:17]2[N:22]=[CH:21][C:20]3[CH:23]=[N:24][N:25]([C:26]4[N:31]=[C:30]([N:32]5[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]5)[CH:29]=[CH:28][CH:27]=4)[C:19]=3[CH:18]=2)[CH:14]=[N:13][CH:12]=1)CO>O.O1CCCC1>[CH:8]([C:11]1[N:16]=[C:15]([C:17]2[N:22]=[CH:21][C:20]3[CH:23]=[N:24][N:25]([C:26]4[N:31]=[C:30]([N:32]5[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:36][CH2:37]5)[CH:29]=[CH:28][CH:27]=4)[C:19]=3[CH:18]=2)[CH:14]=[N:13][CH:12]=1)=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(-n3ncc4cnc(-c5cncc(C(O)CO)n5)cc43)n2)CC1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(-n3ncc4cnc(-c5cncc(C=O)n5)cc43)n2)CC1
Reaction time: 24 h

Procedure:
A solution of sodium periodate (260 mg 1.22 mmol) in 5 ml of water was added to a solution of tert-butyl 4-[6-[6-[6-(1,2-dihydroxyethyl)pyrazin-2-yl]pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]piperazine-1-carboxylate (315 mg, 0.61 mmol) in 25 ml of tetrahydrofuran and 5 ml of water. The mixture was stirred for 24 hours, concentrated, the residue partitioned between ethyl acetate and water, the organic extracts were washed with water, brine, dried over sodium sulfate and concentrated. The residue was purified on 12 g silica gel column eluting with ethyl acetate gradient in heptane to afford 245 mg (83%). MS (ESI) m/z: 505.2 [M+H2O+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][Si:19]([CH2:22][Mg]Cl)([CH3:21])[CH3:20].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C(O)(=O)C>C1COCC1>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc([N+](=O)[O-])c1
Reactant: C[Si](C)(C)C[Mg]Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nc1ccc(C[Si](C)(C)C)c([N+](=O)[O-])c1
Temperature: -70 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
A solution of (3-nitro-phenyl)-carbamic acid tert-butyl ester (1.20 g, 5.04 mmol) in THF (50 mL) was added ((trimethylsilyl)methyl)magnesium chloride (1.48 g, 10.1 mmol) at −70° C. under nitrogen gas. The solution was then stirred at −70° C. for one h. A solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (2.74 g, 12.1 mmol) in THF (30 mL) was added, the reaction was warmed to 0° C. and the reaction was allowed to stir at 0° C. for another hour. The reaction mixture is poured into an aqueous solution of acetic acid (50 mL, 5%v/v) and the aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown oil. Flash chromatography (80/20 hexanes/ethyl acetate) afforded (3-nitro-4-trimethylsilanylmethyl-phenyl)-carbamic acid tert-butyl ester (1.20 g, 73%) as a light oil.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[N:6]3[C:7](=[CH:12][C:13]([CH2:14][OH:15])=[C:5]3[C:4]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH:8]=[CH:9][CH:10]=2)[CH3:2].[Na].S(OC)(O[CH3:29])(=O)=O.O>O1CCCC1.C(OCC)C>[CH2:1]([C:3]1[C:11]2[N:6]3[C:7](=[CH:12][C:13]([CH2:14][O:15][CH3:29])=[C:5]3[C:4]=1[C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[CH:8]=[CH:9][CH:10]=2)[CH3:2]
Reactant: COS(=O)(=O)OC
Reactant: CCc1c(-c2ccc(OC)cc2)c2c(CO)cc3cccc1n32
Agent: [Na]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCc1c(-c2ccc(OC)cc2)c2c(COC)cc3cccc1n32
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
1-Ethyl-3-hydroxymethyl-2-(4-methoxyphenyl)pyrrolo[2,1,5-cd]indolizine (0.40 g, 1.31 mmol) was dissolved in 15 ml of dry tetrahydrofuran under a nitrogen atmosphere. Sodium hydrode (50% in oil) (0.06 g, 1.3 mmol) was added, and stirring was continued for 1/2 hour. Dimethyl sulfate (0.283 g, 2.25 mmol) was added, and the mixture was stirred at room temperature for 1day. 15 ml of water was added dropwise, and ther eaction mixture was diluted with 25 ml of diethyl ether. The organic material was extracted into diethyl ether, and the combined organic layers was washed with brine and dried over magnesium sulfate. The solvent was evaporated to afford 0.3 g (70%) of 1-ethyl-3-methoxymethyl-2-(4-methyoxyphenyl)pyrrolo[2,1,5-cd]indolizine. HPLC (Eluent: 65% CH3CN isocratic, 35% buffer H3PO4 pH=3): Rt=23.75 min (94% purity). 1H-NMR (CDCl3 /CD3OD, 200 MHz) δ: 1.42 (t, 3H); 3.16 (q, 2H); 3.41 (s, 3H); 3.88 (s, 3H); 4.78 (s, 2H); 7.07 (d, 2H); 7.21 (s, 1H); 7.56-7.69 (m, 3H); 7.81-7.91 (m, 2H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=O)(=[O:3])[CH3:2].C1(P(=[CH:38][C:39]([O:41][CH3:42])=[O:40])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH3:42][O:41][C:39](=[O:40])/[CH:38]=[CH:14]/[C:13]1[CH:16]=[CH:17][CH:18]=[C:11]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH:12]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)OCCCCCOc1cccc(C=O)c1
Product: COC(=O)/C=C/c1cccc(OCCCCCOC(C)=O)c1
Yield: 80 %

Procedure:
Using the procedure of example 28, the title compound was prepared in 80% yield, from 2.6 g (10.4 mmol) of 3-[[5-(acetyloxy)pentyl]oxy]benzaldehyde and 4.0 g (12 mmol) of methyl (triphenylphosphoranylidene)acetate, as a colorless solid, mp 65°-67° C.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[F:11][C:12]1[CH:13]=[C:14]([S:19]([C:22]([C:25]2[CH:30]=[C:29]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][C@@H:32]3[CH3:37])[N:28]=[C:27]([C:38]3[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=3)[N:26]=2)([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH:15]=[C:16]([F:18])[CH:17]=1.C(=O)([O-])O.[Na+]>O1CCOCC1>[F:18][C:16]1[CH:15]=[C:14]([S:19]([C:22]([C:25]2[CH:30]=[C:29]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][C@@H:32]3[CH3:37])[N:28]=[C:27]([C:38]3[CH:39]=[CH:40][C:41]([NH:42][C:2](=[O:3])[O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:43][CH:44]=3)[N:26]=2)([CH3:23])[CH3:24])(=[O:20])=[O:21])[CH:13]=[C:12]([F:11])[CH:17]=1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)c2cc(F)cc(F)c2)nc(-c2ccc(N)cc2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)c2cc(F)cc(F)c2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
Phenyl chloroformate (0.413 mL, 3.29 mmol) was added to 4-[4-[2-(3,5-difluorophenyl)sulfonylpropan-2-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (1.46 g, 2.99 mmol) and sodium hydrogen carbonate (0.377 g, 4.48 mmol) in dioxane (25 mL). The resulting slurry was stirred at RT for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic solution was dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was chromatographed on silica, eluting with 25%-80% ethyl acetate in isohexane, to give a colourless gum. This material was triturated with diethyl ether to give the desired material as a colourless crystalline solid (1.808 g).
Reaction SMILES: [CH3:1][C:2]12[CH2:17][CH:5]([C:6]3([CH3:16])[C:10]1([CH3:11])[C:9]1[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=1[O:7]3)[CH2:4][CH2:3]2.[Br:18]N1C(=O)CCC1=O>O1CCCC1.CN(C)C=O>[Br:18][C:13]1[CH:14]=[CH:15][C:8]2[O:7][C:6]3([CH3:16])[CH:5]4[CH2:17][C:2]([CH3:1])([C:10]3([CH3:11])[C:9]=2[CH:12]=1)[CH2:3][CH2:4]4
Reactant: CC12CCC(C1)C1(C)Oc3ccccc3C21C
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC12CCC(C1)C1(C)Oc3ccc(Br)cc3C21C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
11.42 g (50 mmol) of (-)-1,2,3,4-tetra-hydro-1,4a,9b-trimethyl-1,4-methanodibenzofuran obtained in Example 1 were dissolved in 110 ml of tetrahydrofuran and were treated dropwise with a solution containing 8.9 g of N-bromosuccinimide (NBS) in 50 ml of dimethylformamide (DMF). The reaction mixture was maintained under stirring at room temperature for 2 h, 30 min, and was then poured into ice-cold water and extracted with 500 ml of ethyl ether. After rinsing with water, drying over magnesium sulfate, filtering and evaporating, 13.8 g (90%) of the expected derivative, melting at 119.8° C., were isolated after chromatography on silica in hexane.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:7][C:8]1[CH:13]=[C:12](/[CH:14]=[C:15](\[O:20][CH3:21])/[C:16]([O:18]C)=[O:17])[CH:11]=[CH:10][C:9]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]([CH3:37])[C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:30])[CH:23]=1)[CH2:4][CH2:5][CH3:6].Cl.O.O1CC[CH2:42][CH2:41]1>C(OCC)(=O)C>[CH2:3]([O:7][C:8]1[CH:13]=[C:12](/[CH:14]=[C:15](\[O:20][CH3:21])/[C:16]([OH:18])=[O:17])[CH:11]=[CH:10][C:9]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]([CH3:37])[C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:41][CH3:42])=[O:30])[CH:23]=1)[CH2:4][CH2:5][CH3:6]
Reactant: C1CCOC1
Reactant: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OC)C(=O)OC)cc2OCCCC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OC)C(=O)O)cc2OCCCC)c1
Temperature: 68 °C
Reaction time: 6 h
Yield: 78 %

Procedure:
1.3 mL (1.3 mmol) of aqueous 1 M sodium hydroxide solution are added to a solution of 0.44 g (0.86 mmol) of methyl (Z)-3-[2-butoxy-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]-2-methoxyacrylate in 10 mL of tetrahydrofuran. The reaction mixture is stirred at 68° C. for 6 hours. After cooling, the reaction is worked up by addition of 3 mL (3 mmol) of aqueous 1 M hydrochloric acid solution and 10 mL of water and extraction with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution and then dried over magnesium sulfate. The solvents are evaporated off. The product is recrystallized from a pentane/acetone mixture to give 0.33 g (78%) of (Z)-3-[2-butoxy-3′-(1-methyl-3-heptylureido)biphenyl-4-yl]-2-methoxyacrylic acid in the form of a cream-colored solid with a melting point of 103° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10])([O-])=O.Cl[C:12]1[N:17]=[CH:16][N:15]=[C:14]([N:18]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=2)[C:19]([N:21]([C:30]2[C:35]([Cl:36])=[C:34]([O:37][CH3:38])[CH:33]=[C:32]([O:39][CH3:40])[C:31]=2[Cl:41])COCC[Si](C)(C)C)=[O:20])[CH:13]=1>>[Cl:41][C:31]1[C:32]([O:39][CH3:40])=[CH:33][C:34]([O:37][CH3:38])=[C:35]([Cl:36])[C:30]=1[NH:21][C:19](=[O:20])[N:18]([C:14]1[N:15]=[CH:16][N:17]=[C:12]([NH:1][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:10][C:34](=[O:37])[CH:33]=[CH2:32])[CH:13]=1)[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=1
Reactant: COc1cc(OC)c(Cl)c(N(COCC[Si](C)(C)C)C(=O)N(Cc2ccccn2)c2cc(Cl)ncn2)c1Cl
Reactant: Nc1ccccc1[N+](=O)[O-]
Product: C=CC(=O)Nc1ccccc1Nc1cc(N(Cc2ccccn2)C(=O)Nc2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Yield: 13 %

Procedure:
The compound was synthesized following the approach outlined in Procedure 2G (Example 123), substituting 2-nitro-phenylamine and 1-(6-chloro-pyrimidin-4-yl)-3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-pyridin-2-ylmethyl-3-(2-trimethylsilanyl-ethoxymethyl)-urea (preparation shown below) in step (d) to afford the title compound (35 mg, yield: 13% over five steps). 1H NMR (300 MHz, DMSO-d6) δ 12.15 (s, 1H), 9.65 (s, 1H), 8.83 (s, 1H), 8.50 (s, 1H), 8.39 (s, 1H), 7.80 (t, 1H), 7.66 (d, 1H), 7.31-7.25 (m, 3H), 7.17 (t, 1H), 7.09 (t, 1H), 6.91 (s, 1H), 6.45 (dd, 1H), 6.39 (s, 1H), 6.23 (d, 1H), 5.74 (d, 1H), 5.17 (s, 2H), 3.94 (s, 6H); MS (ESI): 594 [M+H]+.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([C:15](=O)[CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:28][C:29]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:30]=1[C:31](=[S:34])[NH:32][NH2:33]>CCO.C(Cl)Cl>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2([CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[NH:33][N:32]=[C:31]([C:30]3[CH:35]=[C:36]([F:39])[CH:37]=[CH:38][C:29]=3[F:28])[S:34]2)[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)c1cccc(O[Si](C)(C)C(C)(C)C)c1
Reactant: NNC(=S)c1cc(F)ccc1F
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCC1(c2cccc(O[Si](C)(C)C(C)(C)C)c2)NN=C(c2cc(F)ccc2F)S1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of tert-butyl 4-(3-(tert-butyldimethylsilyloxy)phenyl)-4-oxobutylcarbamate (1.400 g, 3.55 mmol) in 20 mL of a 3:1 EtOH/DCM mixture was added 2,5-difluorobenzothiohydrazide (0.704 g, 3.74 mmol). The reaction was stirred overnight at room temperature, then heated to 45° C. for 10 hours. The reaction mixture was then concentrated in vacuo, loaded directly to Biotage (45), followed by flash column chromatography (20-50% ethyl acetate/hexanes), yielding the desired product as a yellow semi-solid (1.742 g, 82%).
Reaction SMILES: Br.[Br:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[NH:8])=[CH:5][CH:4]=1.[C:12](OCC)(=[O:19])[CH2:13][C:14](OCC)=[O:15]>>[Br:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]2[NH:9][C:12](=[O:19])[CH2:13][C:14](=[O:15])[N:8]=2)=[CH:5][CH:4]=1
Reactant: N=C(N)c1ccc(Br)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Br
Product: O=C1CC(=O)NC(c2ccc(Br)cc2)=N1

Procedure:
In a similar manner, reacting p-bromobenzamidine hydrobromide with diethyl malonate produces 2-(4-bromophenyl)-4,6-(1H,5H)-pyrimidinedione, which is reacted with phosphoryl chloride to afford 2-(4-bromophenyl)-4,6-dichloropyrimidine.
Reaction SMILES: C([S:4][CH:5]1[CH2:8][N:7]([C:9]2[S:10][CH:11]=[C:12]([C:14]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[N:13]=2)[CH2:6]1)(=O)C.C(O)(=O)C.NN.C1(P(O[C:43]2[C@H:44]([CH3:67])[C@H:45]3[C@@H:62]([C@H:63]([OH:65])[CH3:64])[C:61](=[O:66])[N:46]3[C:47]=2[C:48]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=2)=[O:49])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C.C(OCC)(=O)C>[N:16]1([C:14]([C:12]2[N:13]=[C:9]([N:7]3[CH2:8][CH:5]([S:4][C:43]4[C@H:44]([CH3:67])[C@@H:45]5[C@@H:62]([C@H:63]([OH:65])[CH3:64])[C:61](=[O:66])[N:46]5[C:47]=4[C:48]([O:50][CH2:51][C:52]4[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=4)=[O:49])[CH2:6]3)[S:10][CH:11]=2)=[O:15])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Reactant: CC(=O)SC1CN(c2nc(C(=O)N3CCCCC3)cs2)C1
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)N5CCCCC5)cs4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a solution of 3-acetylthio-1-(4-piperidinocarbonyl-1,3-thiazol-2-yl)azetidine (276 mg, 0.85 mmol) (obtained as described in Reference Example 27) in dimethylformamide (20 ml) was added hydrazine acetate (94 mg, 1.02 mmol) at room temperature under an atmosphere of nitrogen and the mixture was stirred for 2 hours. After checking the completion of the reaction, a solution of p-nitrobenzyl (1R,5S,6S)-2-(diphenylphosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (505 mg, 0.85 mmol) in acetonitrile (20 ml) was added dropwise to the resulting mixture in an ice bath under an atmosphere of nitrogen, followed by the addition of diisopropylethylamine (0.59 ml, 3.40 mmol). The mixture was stirred overnight while gradually raising the temperature to room temperature. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with 0.5 M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate and ethyl acetate: methanol (9:1) as the eluant to afford p-nitrobenzyl (1R,5S,6S)-2-[1-(4-piperidinocarbonyl-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (464 mg, yield 87%) as a pale yellow solid.
Reaction SMILES: [C:1]([O:14][CH2:15][C:16]1[C:17](=[O:22])[O:18][CH:19]([OH:21])[CH:20]=1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].N1C=CC=CC=1.[C:29](Cl)(=[O:41])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>O1CCCC1>[C:29]([O:21][CH:19]1[O:18][C:17](=[O:22])[C:16]([CH2:15][O:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:20]1)(=[O:41])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCCCCCCCCC(=O)OCC1=CC(O)OC1=O
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(=O)OCC1=CC(OC(=O)CCCCCCCCCCC)OC1=O
Temperature: 25 °C

Procedure:
To a stirred solution of 3-dodecoyloxymethyl-5-hydroxy-2(5H)-furanone (0.098 g., 0.313 mmol) and pyridine (0.026 g., 0.313 mmol) in 3 ml anhydrous tetrahydrofuran at 0° was added lauroyl chloride (0.082 g., 0.376 mmol). The solution was allowed to warm to room temperature, stirred until starting material was no longer visible by TLC, and partitioned between ethyl ether and a 5% ammonium chloride solution. The organic portion was washed twice with 5% sodium bicarbonate solution, twice with aqueous cupric sulfate solution, water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give a solid residue. This material was further purified by recrystallization (acetone/methanol) to give the desired ester.