Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH2:8][O:9][C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3]1.[H-].[Na+].I[CH2:23][C:24]1[N:25]=[C:26]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)[O:27][C:28]=1[CH2:29][CH3:30].C(OCC)(=O)C>CC(OC)(C)C>[CH2:29]([C:28]1[O:27][C:26]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)=[N:25][C:24]=1[CH2:23][O:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH2:8][O:9][C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3]1)[CH3:30]
Reactant: CCc1oc(-c2cccc(OC)c2)nc1CI
Reactant: CC(C)(C)OC(=O)C(C)(C)OC[C@@H]1CCC[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CCOC(C)=O
Product: CCc1oc(-c2cccc(OC)c2)nc1CO[C@H]1CCC[C@@H](COC(C)(C)C(=O)OC(C)(C)C)C1

Procedure:
200 mg of tert-butyl 2-((1R,3S)-3-hydroxycyclohexylmethoxy)-2-methylpropionate are added dropwise as solution in MTBE to a suspension of 65 mg of sodium hydride (60% by weight in mineral oil) in 10 ml of MTBE. After gas evolution ceases, 503 mg of 4-iodomethyl-5-ethyl-2-(3-methoxyphenyl)oxazole are added as solution in MTBE, and the suspension is heated under reflux overnight. Ethyl acetate (MTBE can also be used) is added to the reaction mixture, and the mixture is washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is chromatographed on silica gel (heptane/ethyl acetate gradient), resulting in 323 mg of tert-butyl 2-{(1R,3S)-3-[5-ethyl-2-(3-methoxyphenyl)oxazol-4-ylmethoxy]cyclohexylmethoxy}-2-methylpropionate as yellow oil.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:24])[CH2:18][CH2:19][C:20]([O:22]C)=[O:21])=[CH:13][CH:12]=1>>[C:1]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:17](=[O:24])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:16]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Product: O=C(O)CCC(=O)c1ccc(NC(=O)c2ccccc2)cc1
Yield: 53.8 %

Procedure:
In a manner similar to that described in Example 3, benzoyl chloride (0.047 g, 0.00033 mol) was allowed to react with 4-(4- amino-phenyl)4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.040 g of 4-[4-(benzoylamino)-phenyl]-4-oxo-butyric acid as an off-white solid; MS-(AP+) MH+332.
Reaction SMILES: [Br-].[CH:2]1([C:8]#[CH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:10]=[O:11]>CCOCC>[CH:2]1([C:8]#[C:9][CH2:10][OH:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C#CC1CCCCC1
Reactant: C=O
Agent: [Br-]
Solvent: CCOCC
Product: OCC#CC1CCCCC1
Temperature: 25 °C

Procedure:
To a solution of ethyl ma gesium bromide (prepared from 2.5 g of magnesium turning and 11.3 g of bromoethane) in ether was added dropwise a solution of 10.2 g of cyclohexylacetylene in ether and the reaction mixture was refluxed for 2 hours. The reaction mixture was cooled to ambient temperature and anhydrous formaldehyde (prepared from the thermal decomposition of 50 g of paraformaldehyde for 20 minutes) was bubbled into the mixture. After cooling, the reaction was quenched with saturated ammonium chloride and extracted with ether (2×100 ml). The combined ether extracts were washed with brine, dried over magnesium sulfate and evaporated to yield the product which was distilled under high vacuum at 68°-74° C. to yield 6.4 g as a colorless liquid.
Reaction SMILES: [C:1]([N:8]1[CH2:15][C:14](=[CH2:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:17][C:18]([F:28])([F:27])[O:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:15][C:14](=[CH2:16])[CH2:13][C@H:9]1[C:10](=[O:12])[NH:23][C:22]1[CH:24]=[CH:25][CH:26]=[C:20]([O:19][C:18]([F:17])([F:27])[F:28])[CH:21]=1)=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: Nc1cccc(OC(F)(F)F)c1
Reactant: C=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
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: C=C1C[C@@H](C(=O)Nc2cccc(OC(F)(F)F)c2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of N-Boc-4-methylene-L-proline (1 g, 4.4 mmol) in CH2Cl2 (40 mL) was added 3-(trifluoromethoxy)aniline (0.71 mL, 5.28 mmol), HBTU (1.14 g, 6.6 mmol) and diisopropylethylamine (1.51 mL, 8.8 mmol). The reaction mixture was stirred at RT for 2 days. The mixture was successively washed with 30 mL of a saturated aqueous NaHCO3 solution and an HCl 1M solution. The organic layers were dried (phase separator) and concentrated under vacuum. The crude residue was purified by flash column chromatography on silica gel (eluent: c-hexane/EtOAc:65/35) to give the title compound. TLC, Rf (c-hexane/EtOAc: 1:1)=0.55; MS (LC/MS): 287.0 [M-Boc]+, 385.0 [M−H]−.
Reaction SMILES: [CH2:1]([O:3][CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:15][CH2:16][CH2:17][CH2:18][P:19](=[O:31])([O-:30])[O:20]CCCC3C=CC=CC=3)[C:10](=[O:32])[N:9]([CH3:33])[C:8]=2[N:7]=[CH:6]1)[CH3:2].N>C(O)C.[Pd]>[CH2:1]([O:3][CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:15][CH2:16][CH2:17][CH2:18][P:19](=[O:20])([O-:31])[O-:30])[C:10](=[O:32])[N:9]([CH3:33])[C:8]=2[N:7]=[CH:6]1)[CH3:2].[CH2:13]([NH3+:5])[CH3:8].[CH2:13]([NH3+:5])[CH3:8]
Reactant: CCOCn1cnc2c1c(=O)n(CCCCP(=O)([O-])OCCCc1ccccc1)c(=O)n2C
Agent: [Pd]
Agent: N
Solvent: CCO
Product: CCOCn1cnc2c1c(=O)n(CCCCP(=O)([O-])[O-])c(=O)n2C
Product: CC[NH3+]

Procedure:
6.3 g (0.013 mol) of benzylethyl 4-(7-ethoxymethyl-3-methylxanthin-1-yl)-butylphosphonate were hydrogenated in 100 ml of ethanol over 0.5 g of palladium (10%) on active carbon at room temperature in the course of 4 hours. The catalyst was filtered off, the filtrate was concentrated under reduced pressure, the solution obtained was treated with methanolic ammonia and the residue which remained after evaporating the solvent was then crystallized from diisopropyl ether.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][CH3:11])[CH2:5][CH2:6][CH2:7][CH2:8]O)[CH3:2].CS([Cl:16])(=O)=O.N1C=CC=CC=1>CN(C)C=O>[Cl:16][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([O:3][CH2:1][CH3:2])[CH2:10][CH3:11]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(CC)CCCCO
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCOC(CC)CCCCCl

Procedure:
As shown in Reaction 4, Compound III may be reacted with lithium aluminum hydride (LAH) in tetrahydrofuran (THF) to produce 5-ethoxyheptanol (Compound IV). Compound IV may be produced at a yield of from approximately 90% to approximately 99%. The reaction may be conducted at a temperature of from approximately −50° C. to approximately room temperature (from approximately 20° C. to approximately 25° C.). To control the reaction, in some embodiments, the reaction is conducted at room temperature. As shown in Reaction 5, Compound IV may be reacted with methanesulfonyl chloride (MSCl) and pyridine in dimethylformamide (DMF) to produce 1-chloro-5-ethoxyheptane (Compound V) at a yield of from approximately 75% to approximately 95%.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[CH:23])[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)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.[Cu]I>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[C:23][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[O:27][CH2:26][CH2:25][OH:24])[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: OCCOc1ccccc1I
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCCC(=O)C1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C#Cc3ccccc3OCCO)CCCC(=O)C2)cc1OC1CCCC1
Temperature: 80 °C
Yield: 13.9 %

Procedure:
To a solution of the compound from Example 3 (E1) (0.25 g, 0.8 mmol) and 2-hydroxyethoxy-1-iodobenzene (0.21 g, 0.8 mmol) in triethylamine (5 mL) under an argon atmosphere was added trace tetrakis(triphenylphosphine)palladium(0), copper(I) iodide and triphenylphosphine. The mixture was heated at 80° C. for 1 h, was cooled to room temperature and was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, was dried (MgSO4) and was evaporated. Purification by flash chromatography, eluting with 1:1 hexanes/ethyl acetate, provided the tide compound as a white solid (0.05 g, 14%), m.p. 93°-94° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[N:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=O)=[CH:4][CH:3]=1.O.NN.[OH-].[K+].O.C(O)[CH2:25][OH:26]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:25][OH:26])=[N:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)c2ccc(Br)cc2)cn1
Reactant: OCCO
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: OCCOc1ccc(Cc2ccc(Br)cc2)cn1
Temperature: 140 °C
Reaction time: 0.33 h
Yield: 41 %

Procedure:
(4-Bromophenyl)(6-methoxypyridin-3-yl)methanone (0.88 g, 3.0 mmol), hydrazine monohydrate (1.5 mL, 30 mmol) and potassium hydroxide (0.60 g, 12 mmol) were dissolved in ethylene glycol (10 mL), followed by stirring at 140° C. for 20 minutes. After the reaction solution was cooled to room temperature, water was added, followed by extraction with diethyl ether. After the organic layer was concentrated under reduced pressure, the resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.30 (hexane/ethyl acetate=1/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (0.38 g, 1.2 mmol) as a colorless oil (yield 41%).
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:22]([O:24]C)=O)[C:15](=[CH:20][CH:21]=1)[C:16]([O:18]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26](#[N:28])[CH3:27].[H-].[Na+]>CCOCC>[C:26]([CH:27]1[C:22](=[O:24])[C:14]2[C:15](=[CH:20][CH:21]=[C:12]([O:11][CH2:10][CH2:9][CH2:8][O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:13]=2)[C:16]1=[O:18])#[N:28]
Reactant: CC#N
Reactant: COC(=O)c1ccc(OCCCOc2ccccc2)cc1C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: N#CC1C(=O)c2ccc(OCCCOc3ccccc3)cc2C1=O
Reaction time: 6 h
Yield: 86 %

Procedure:
A mixture of dimethyl 4-(3-phenoxypropoxy)phthalate (6.5g; 0.019 mole), acetonitrile (10ml) and sodium hydride (0.69g of 100%) was stirred at 100° for 6 hours and dry ether added to the cooled yellow product. The solid which separated was filtered off, dissolved in water and the solution strongly acidified with concentrated hydrochloric acid. Filtration of the precipitated solid gave the title compound which recrystallised from ethanol dilute hydrochloric acid with mp 148°-150° (dec) and in 86% yield. (Found; C, 69.00; H, 4.90; N, 4.41; C19H15NO4 0.5H2O requires; C, 69.08; H, 4.88; N, 4.24%).
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[C@H:3]([NH:6][CH3:7])[CH2:4][OH:5].[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1.[C:19]([O-:22])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([O:5][CH2:4][C@@H:3]([N:6]([CH3:7])[C:19](=[O:22])[C:13]2[CH:17]=[CH:18][C:10]([Cl:9])=[CH:11][CH:12]=2)[CH:2]([CH3:8])[CH3:1])=[O:15])=[CH:12][CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CN[C@H](CO)C(C)C
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)[C@@H](COC(=O)c1ccc(Cl)cc1)N(C)C(=O)c1ccc(Cl)cc1
Yield: 98.5 %

Procedure:
TEA (4.73 mL, 34.1 mmol) was added to (S)-3-methyl-2-(methylamino)butan-1-ol (Compound B2.1) (1 g, 8.5 mmol) in DCM (10 mL). The mixture was cooled on an ice-bath and 4-chlorobenzoyl chloride (3.14 g, 17.9 mmol) in DCM (10 mL) was dropwise (over 10 min) added. The resultant mixture was stirred at rt for 2 h. The organic phase was washed with Na2CO3 (8 wt %, 40 mol) and concentrated under reduced pressure to give the title compound (3.3 g, 98%). The obtained crude product was used without further purification. LCMS (M+H)+: 394. Mixture of rotamers: 1H NMR (600 MHz, CD3OD) δ 0.93-1.04 (m), 1.13 (d), 1.98-2.13 (m), 2.87 (s), 3.02 (s), 3.60-3.74 (m), 4.43-4.73 (m), 7.16-7.64 (m), 7.87-8.19 (m). Total number of protons: 21.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:13]([CH2:22][OH:23])=[N:12][C:11]=2[CH:24]([CH3:26])[CH3:25])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH:27]([C:31]([O-:33])=[O:32])[C:28]([O-:30])=O.[C:34]1(O)[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1.C(=O)=NC(Cl)=O>>[NH:27]([C:28]([O:23][CH2:22][C:13]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[C:10]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:11]([CH:24]([CH3:26])[CH3:25])[N:12]=1)=[O:30])[C:31]([O:33][C:42]1[C:43]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:39]=[CH:40][CH:41]=1)=[O:32]
Reactant: Oc1cccc2ccccc12
Reactant: O=C([O-])NC(=O)[O-]
Reactant: CC(C)c1nc(CO)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Agent: O=C=NC(=O)Cl
Product: CC(C)c1nc(COC(=O)NC(=O)Oc2cccc3ccccc23)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Yield: 45 %

Procedure:
The compound 89 (245 mg, 0.6 mmol) was converted to the iminodicarboxylate with N-1-naphthyloxycarbonyl isocyanate prepared from 1-naphthol (158 mg, 1.1 mmol) and N-chlorocarbonylisocyanate (106 mg, 1 mmol) in the same manner as the example 82 to give the compound 104 (169 mg, 45%). Mp 166-167° C. Rf 0.38 (EtOAc). 1H-NMR (CDCl3): δH1.33 (6 H, d, J 6.8 Hz, (CH3)2CH), 3.21 (1 H, sep, J 6.9 Hz, (CH3)2CH), 5.33 (4 H, s, NCH2 and OCH2), 6.72 (2 H, d, J 1.6 Hz, arom 2- and 6-H), 6.78 (2 H, d-like, 4-pyridyl 2- and 6-H), 7.05 (1 H, t, J 1.6 Hz, arom 4-H), 7.30 - 7.91 (7 H, m, 1-naphthyl), 8.04 (1 H, bs, NH), 8.45 (2 H, d-like, 4-pyridyl 3- and 5-H). IR(CHCl3)cm-1 : 3418 (NH), 1820 and 1748 (OOCNCOO). Elementary analysis (for C31H26N4O4SCl2) Calcd.: C, 59.91% H, 4.22% N, 9.01% S, 5.16% Cl, 11.41% Found: C, 59.34% H, 4.12% N, 9.27% S, 5.24% Cl, 11.16%
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:13][CH2:12][O:11][C:9](=[O:10])[CH2:8][CH2:7]1.N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].O>CN(C)C=O>[Si:19]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:13][CH2:12][O:11][C:9](=[O:10])[CH2:8][CH2:7]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: O=C1CCC(CCCCO)CCO1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCCCC1CCOC(=O)CC1
Reaction time: 16 h

Procedure:
To a solution of 8.77 g (47 mmol) of 4-(4-hydroxybutyl)-epsilon-caprolactone (example 28) in 52 ml dry dimethylformamide is added 6.16 g (90 mmol) of imidazole followed by 11.1 g (71 mmol) of t-butyldimethylsilyl chloride (97% pure) and then the mixture is stirred for 16 h. The reaction mixture is poured into water and extracted twice with ether. The combined organic extracts are washed twice with water, brine, dried, filtered and concentrated to give an oil which is purified by flash chromatography using 3:2 hexane/ether to yield 4-(4-t-butyldimethylsilyloxybutyl)-epsilon-caprolactone as an oil; NMR (CDCl3): delta 4-4.3 (m,2H), 3.6 (t,2H), 0.88 (s,9H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[S:11][C:12]3[CH2:19][CH2:18][O:17][C:16]4[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=4[C:13]=3[N:14]=2)[CH2:5][CH2:4]1.[C:24](Cl)(=[O:27])[CH2:25][CH3:26].O>N1C=CC=CC=1.C(N(C(C)C)CC)(C)C>[N:14]1[C:13]2[C:15]3[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:12]=2[S:11][C:10]=1[NH:9][CH:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:24](=[O:27])[CH2:25][CH3:26])[CH2:4][CH2:5]1
Reactant: NCC1CCC(Nc2nc3c(s2)CCOc2ccccc2-3)CC1
Reactant: CCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: c1ccncc1
Product: CCC(=O)NCC1CCC(Nc2nc3c(s2)CCOc2ccccc2-3)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70 %

Procedure:
To a stirred solution of N2-[4-(aminomethyl)cyclohexyl]-4,5-dihydrobenzo[2,3]-oxepino[4,5-d][1,3]thiazol-2-amine (0.600 g, 1.49 mmol) in anhydrous pyridine (3 ml) and diisopropylethylamine (3 ml) was added propionyl chloride (0.144 ml, 1.66 mmol) dropwise. The solution was stirred for 20 minutes at room temperature and then poured into water (50 ml) and extracted with EtOAc. The solvent was removed and the residue chromatographed on silica-gel eluting with EtOAc to yield 70% (402 mg) of the product as a light yellow solid: 1H-NMR (CDCl3) δ 1.12 (6H, m), 1.50 (1H, m), 1.65 (1H, m), 1.85 (2H, d, J=12.1 Hz), 2.22 (4H, m), 3.16 (4H, t, J=5.3 Hz), 3.32 (1H, m), 4.33 (2H, t, J=5.2 Hz), 4.81 (1H, m), 5.49 (1H, m), 7.00 (1H, d, J=8.5 Hz), 7.15 (2H, m), 8.25 (1H, d, J=8.1 Hz). m.p. 56-60° C. FAB+ m/z=386 (MH+).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:12]=[CH:11][C:10](I)=[CH:9][C:6]=1[CH:7]=[O:8])(=[O:3])[CH3:2].C(N(CC)CC)C.[C:21]([OH:25])(=[O:24])[CH:22]=[CH2:23].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:7]([C:6]1[CH:9]=[C:10]([CH:11]=[CH:12][C:5]=1[O:4][C:1](=[O:3])[CH3:2])[CH:23]=[CH:22][C:21]([OH:25])=[O:24])=[O:8]
Reactant: C=CC(=O)O
Reactant: CC(=O)Oc1ccc(I)cc1C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(C=CC(=O)O)cc1C=O
Temperature: 67.5 °C
Yield: 58.8 %

Procedure:
2-Acetyloxy-5-iodobenzaldehyde (0.2 g, 0.69 mmol) is dissolved in 25 ml of acetonitrile and oxygen is removed by bubbling nitrogen through the solution. Triethylamine (0.673 ml, 4.82 mmol) and acrylic acid (0.095 ml, 1.38 mmol) are added dropwise with stirring, followed by 0.016 g of tri-o-tolylphosphine (0.069 mmol) and 0.008 of palladium(II) acetate (0.047 mmol). The mixture is heated at 65-70° C. for 4 hours, volatiles are removed by distillation and the residue is purified by column chromatography on silica gel, eluting with mixtures of ethyl acetate-hexane of increasing polarity. 3-Formyl-4-acetyloxycinnamic acid (0.095 g) is obtained as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23]Cl.CN(C)C=O>O>[Cl:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: ClC/C=C\CCl
Reactant: O=C1CCc2ccc(O)cc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCc2ccc(OC/C=C\CCl)cc2N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.0 g of 7-hydroxy-3,4-dihydro-1H-quinolin-2-one, 1.7 g of potassium carbonate, 3.2 ml of cis-1,4-dichloro-2-butene and 50 ml of dimethylformamide was stirred at room temperature overnight. Water was added to the reaction solution, which was then extracted with ethyl acetate and, after washed with water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), and 7-(4-chloro-(Z)-2-butenyloxy)-3,4-dihydro-1H-quinolin-2-one (1.3 g) was obtained in the form of a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1)[CH2:26][NH2:27]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:27][CH2:26][C:25]2[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=[C:23]([O:22][CH3:21])[CH:24]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: COc1cc(CN)cc(OC)c1
Product: COc1cc(CNC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)cc(OC)c1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (145 mg, 0.41 mmol) and 3,5-dimethoxy benzylamine (65 mg, 0.39 mmol). The title compound was obtained as a solid (55 mg, 34% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.35 (1H, m), 8.98 (2H, m), 8.48 (1H, s), 6.43 (2H, m), 6.38 (1H, m), 4.32 (2H, m), 3.70 (6H, m). MS m/z: 498.16, 500.08 [M+H]+.
Reaction SMILES: C([CH:3]([CH:7]1[C:11]2=[C:12]([S:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[C:13]3[C:14]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][C:16]([F:19])=[CH:17][C:18]=3[N:10]2[C:9](=[O:32])[CH2:8]1)[C:4]([O-:6])=[O:5])C.Cl>CC(=O)CC.O>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([S:24][C:12]2[C:13]3[C:14]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][C:16]([F:19])=[CH:17][C:18]=3[N:10]3[C:9](=[O:32])[CH2:8][CH:7]([CH2:3][C:4]([OH:6])=[O:5])[C:11]=23)=[CH:26][CH:27]=1
Reactant: CCC(C(=O)[O-])C1CC(=O)n2c1c(Sc1ccc(Cl)cc1)c1c(S(C)(=O)=O)cc(F)cc12
Agent: Cl
Solvent: CCC(C)=O
Solvent: O
Product: CS(=O)(=O)c1cc(F)cc2c1c(Sc1ccc(Cl)cc1)c1n2C(=O)CC1CC(=O)O
Temperature: 80 °C
Reaction time: 3 h
Yield: 60.8 %

Procedure:
To the compound of Step 7 (40 mg) in 2-butanone (4 mL) was added 6N HCl (0.5 mL). The mixture was stirred at 80° C. for 3 hours, cooled to r.t., diluted with H2O and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with 40% EtOAc/hexane containing 1% AcOH to give 23 mg of the title compound as a white solid.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7](B(O)O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1>>[F:20][C:19]([F:22])([F:21])[C:16]1[CH:17]=[CH:18][C:13]([C:7]2[S:8][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=2)=[CH:14][CH:15]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CC(=O)c1ccc(B(O)O)s1
Product: CC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)s1

Procedure:
1-(5-(4-(Trifluoromethyl)phenyl)thien-2-yl)ethanone is prepared from 5-acetyl-2-thiopheneboronic acid and 4-bromobenzotrifluoride according to general procedure A.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12](OC)(OC)OC.C(O)(=O)C.[NH2:23][C:24]1[CH:25]=[C:26]([CH:33]=[CH:34][C:35]=1[CH3:36])[C:27]([NH:29][CH:30]1[CH2:32][CH2:31]1)=[O:28]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH:30]1([NH:29][C:27](=[O:28])[C:26]2[CH:33]=[CH:34][C:35]([CH3:36])=[C:24]([N:23]3[C:4](=[O:6])[C:3]4[C:2](=[CH:10][CH:9]=[C:8]([I:11])[CH:7]=4)[N:1]=[CH:12]3)[CH:25]=2)[CH2:31][CH2:32]1
Reactant: Nc1ccc(I)cc1C(=O)O
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N
Reactant: COC(OC)OC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(I)cc2c1=O

Procedure:
A stirred mixture of 2-amino-5-iodobenzoic acid (1.0 g), trimethyl orthoformate (0.83 ml), and acetic acid (0.022 ml) in toluene (15 ml) was heated under reflux for 2 hours. 3-Amino-N-cyclopropyl-4-methylbenzamide (0.65 g) was added to the reaction mixture and stirred at reflux for 16 hours. The reaction mixture was allowed to cool and diluted with ethyl acetate. The organic solution was then washed with 1N HCl solution, 2N NaOH solution (x 2), brine, dried (magnesium sulfate), and concentrated to give N-cyclopropyl-3-(6-iodo-4-oxoquinazolin-3(4H)-yl)-4-methylbenzamide (AZ12233711) (1.22 g) as an off white solid; NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.70 (m, 2H), 2.14 (s, 3H), 2.85 (m, 1H), 7.52 (d, 1H), 7.58 (d, 1H), 7.88 (s, 1H), 7.92 (d, 1H), 8.20 (d, 1H), 8.34 (s, 1H), 8.42 (d, 1H), 8.49 (s, 1H); Mass Spectrum: M+H+ 446.