Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][NH2:14])=[C:11]([CH3:15])[O:10][N:9]=2)=[CH:4][CH:3]=1.Cl[C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][N:18]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH3:24][O:23][C:21](=[O:22])[C:20]1[CH:25]=[CH:26][C:17]([NH:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:15])=[N:18][CH:19]=1
Reactant: Cc1onc(-c2ccc(F)cc2)c1CN
Reactant: COC(=O)c1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)c1ccc(NCc2c(-c3ccc(F)cc3)noc2C)nc1
Temperature: 160 °C
Yield: 32.7 %

Procedure:
A mixture of C-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methylamine (620 mg, 3.0 mmol), methyl 6-chloronicotinate (516 mg, 3.0 mmol), N,N-diisopropyl ethyl amine (1.0 mL, 6.0 mmol) and DMSO (6 mL) was heated in the microwave to 160° C. for 2 h. The mixture was then diluted with ice-water and extracted with ethyl acetate. The combined organic extracts were then washed with brine and dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1 then dichloromethane:methanol 97:3) afforded the title compound (335 mg, 33%) as a white foam. MS: m/e=342.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][Si:12]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.Br[C:30]([CH3:36])([CH3:35])[C:31]([O:33][CH3:34])=[O:32].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[Si:12]([O:11][CH2:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:30]([CH3:36])([CH3:35])[C:31]([O:33][CH3:34])=[O:32])=[CH:7][CH:6]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)[Si](OCCCc1ccc(O)cc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)Oc1ccc(CCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Temperature: 60 °C
Yield: 93 %

Procedure:
A solution of 3-(4-hydroxyphenyl)-1-(tert-butyldiphenylsilyloxy)propane (5.00 g, 12.8 mmol and methyl 2-bromo-2-methylpropionate (4.53 g, 25.0 mmol in dry acetonitrile (25 ml) was treated with cesium carbonate (8.3 g, 25.4 mmol and the resulting mixture was heated at 60° C. for 3.5 h. The cooled mixture was diluted with ethyl acetate, washed with water, brine and dried (magnesium sulfate). Evaporation of the solvent and chromatography of the residue on silica gel (elution toluene) gave 5.88 g (93%) of the title material as a clear oil.
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[CH:6]([CH:8]=[CH2:9])=[O:7]>>[CH3:5][C:3]1[CH2:4][CH2:9][CH:8]([CH2:6][OH:7])[CH2:1][CH:2]=1
Reactant: C=CC(=C)C
Reactant: C=CC=O
Product: CC1=CCC(CO)CC1

Procedure:
According to the well known Diels-Alder Reaction, using isoprene and acrolein as raw materials, 4-methyl-3-cyclohexenyl aldehyde was synthesized. The reaction was conducted under the conditions described in the literary documents of J. Amer, Chem. Soc., 119, 15, 1997, 3507-3512; and Tetrahedron Lett., 40, 32, 1999, 5817-5822. Subsequently, the compound was reduced to obtain 4-methyl-3-cyclohexenylmethanol at a high yield.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([O:9][C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:7][C:6]([N:20]=[C:21]2[S:25][C:24](=[O:26])[N:23](C=O)[NH:22]2)=[C:5]([F:29])[CH:4]=1>CO.CC(C)=O>[Cl:2][C:3]1[C:8]([O:9][C:10]2[C:15]([C:16]([F:18])([F:19])[F:17])=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:7][C:6]([N:20]=[C:21]2[S:25][C:24](=[O:26])[NH:23][NH:22]2)=[C:5]([F:29])[CH:4]=1
Reactant: O=Cn1[nH]c(=Nc2cc(Oc3ncccc3C(F)(F)F)c(Cl)cc2F)sc1=O
Agent: Cl
Solvent: CC(C)=O
Solvent: CO
Product: O=c1[nH][nH]c(=Nc2cc(Oc3ncccc3C(F)(F)F)c(Cl)cc2F)s1
Reaction time: 0.5 h
Yield: 32.4 %

Procedure:
A solution of 10% hydrochloric acid in methanol (8 ml) was added to a solution of 5-[4-chloro-2-fluoro-5-(3-trifluoromethyl-2-pyridyloxy)phenylimino]-3-formyl-1,3,4-thiadiazolidin-2-one (3.3 g) in acetone (60 ml). After stirring for 0.5 hour, the solvents were removed and the residue processed. A minimal amount of ethanol was used to dissolved the residue and hexane added to induce crystallization. The crystals were filtered off and dried to give the product (1.0 g, 36%).
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[OH:5][C:6]1[CH:15]=[C:14]([I:16])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[I:16][C:14]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([O:5][CH:2]([CH3:4])[CH3:3])[CH:15]=1
Reactant: CC(C)I
Reactant: COC(=O)c1ccc(I)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(I)cc1OC(C)C
Yield: 98.3 %

Procedure:
2-Iodopropane (6.42 g) was added at room temperature to a mixture of methyl 2-hydroxy-4-iodobenzoate (7.00 g), potassium carbonate (6.96 g), and DMF (100 mL), and the resultant mixture was stirred at 70° C. for 2 days in a nitrogen atmosphere. Water was added to the reaction mixture at room temperature, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (7.92 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.O.O.O.O.O.O.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>O>[ClH:1].[ClH:1].[O:11]([CH2:10][CH2:9][O:8][C:7]1[C:2]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:3][CH:4]=[CH:5][CH:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C1CNCCN1
Reactant: Clc1ncccc1OCCOc1ccccc1
Solvent: O
Product: Cl
Product: c1ccc(OCCOc2cccnc2N2CCNCC2)cc1
Temperature: 165 °C

Procedure:
A mixture of the product from Step 1 above (0.84 g, 3.1 mmol) and piperazine hexahydrate (5.3 g, 27.3 mmol) was heated in a sealed tube at 165° C. for 1 h. After cooling, the mixture was diluted with water (100 mL) and extracted twice with EtOAc. The combined and dried (MgSO4) organic phases were concentrated in vacuo and the residue was purified by chromatography on silica gel using CHCl3/MeOH/NH4OH (90:10:0.4) as eluent to give the free base of the title compound. The free base was treated with HCl/ether, and the resulting dihydrochloride salt was dried (80° C., 1 mmHg) to afford 0.598 g (52%) of the title compound as a light yellow solid: mp 91-120° C. Anal. (C17H21N3O2.2HCl) C, H, N.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH2:14][NH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[H][H].[CH3:28]I>O1CCCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH2:14][NH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([O:13][CH3:28])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1(CNCCc2ccccc2)CCN(Cc2ccccc2)C1
Reactant: CI
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(CNCCc2ccccc2)CCN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
26 g (83 mmol) of crude 1-benzyl-3-benzylmethylaminomethyl-3-hydroxypyrrolidine in 50 ml of absolute tetrahydrofuran are added dropwise to 4 g of 80% strength sodium hydride in 100 ml of absolute tetrahydrofuran and the mixture is heated under reflux during this. After completion of hydrogen evolution, 12.4 g (87 mmol) of methyl iodide are slowly added dropwise and the mixture is subsequently heated overnight under reflux. The product is poured into ice water and extracted using toluene, the extract is dried over K2CO3 and concentrated, and the residue is distilled.
Reaction SMILES: [F:1][C:2]1([F:18])C(=O)[CH2:6][CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH2:3]1.[CH3:19][O:20][CH:21](OC)[O:22][CH3:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:19][O:20][C:21]1([O:22][CH3:23])[CH2:6][CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH2:3][C:2]1([F:1])[F:18]
Reactant: COC(OC)OC
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC1(OC)CCN(c2ccc([N+](=O)[O-])cc2)CC1(F)F
Temperature: 45 °C
Yield: 84 %

Procedure:
The mixture of 4-(3,3-difluoro-4-oxo-piperidin-1-yl)-nitrobenzene (25 mmol), trimethylorthoformate (51 mmol), p-toluene-sulphonic acid monohydrate (27 mmol) in methanol was heated at 45° C. for 24 hours. Solvent was removed and residual mass was taken into ethyl acetate and saturated sodium bicarbonate solution mixture. The organic layer was dried and removal of the solvent afforded title compound as a solid in 84% yield.
Reaction SMILES: [CH2:1]1COCC1.CO.[CH:8]1([N:11]([CH2:44][C:45]2[CH:50]=[C:49]([O:51][CH2:52][CH2:53][CH2:54]SC)[N:48]=[C:47]([CH2:57][CH2:58][CH2:59][O:60][CH3:61])[CH:46]=2)[C:12](=[O:43])[CH:13]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][O:33][C:34]3[C:39]([Cl:40])=[CH:38][C:37]([CH3:41])=[CH:36][C:35]=3[Cl:42])=[CH:26][CH:25]=2)[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:10][CH2:9]1.O[O:63][S:64]([O-:66])=O.[K+]>O>[CH:8]1([N:11]([CH2:44][C:45]2[CH:50]=[C:49]([O:51][CH2:52][CH2:53][CH2:54][S:64]([CH3:1])(=[O:66])=[O:63])[N:48]=[C:47]([CH2:57][CH2:58][CH2:59][O:60][CH3:61])[CH:46]=2)[C:12](=[O:43])[CH:13]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][O:33][C:34]3[C:39]([Cl:40])=[CH:38][C:37]([CH3:41])=[CH:36][C:35]=3[Cl:42])=[CH:26][CH:25]=2)[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])[CH2:9][CH2:10]1
Reactant: COCCCc1cc(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCCSC)n1
Reactant: O=S([O-])OO
Reactant: C1CCOC1
Agent: [K+]
Solvent: CO
Solvent: O
Product: COCCCc1cc(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCCS(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 2:1:1 (v/v/v) THF:MeOH:water solution (0.1 M) of tert-butyl (3-[cyclopropyl({2-(3-methoxypropyl)-6-[3-(methylthio)propoxy]pyridin-4-yl]methyl)amino]-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from Example 100, Step 1 (1 eq.) was added Oxone™ (2.2 eq.) The resulting solution was stirred at RT for 2 h. The reaction was quenched with sat. aq. NaHCO3 and then extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 95:5 (v/v) CH2Cl2:EtOH) afforded the title compound as a colorless oil.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=[CH2:18])[N:12]=1.C(O)(=O)C>CO>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:18][CH2:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([CH3:10])[N:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: C=Cc1cccc(C)n1
Reactant: CC(=O)N1CCNCC1
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)N1CCN(CCc2cccc(C)n2)CC1
Temperature: 80 °C
Reaction time: 24 h
Yield: 72.8 %

Procedure:
To a stirring solution of N-acetylpiperazine (2.50 g, 20 mmol) in methanol (40 mL) at 0° C. under nitrogen was added 2-methyl-6-vinyl-pyridine (2.39 g, 20 mmol) and acetic acid (1.28 mL). The mixture was stirred for 24 hours at 80° C. and was then concentrated. The residue was partitioned between 10% aqueous K2CO3 /CH2Cl2. The organic phase was dried and concentrated to afford 3.60 g (73%) of 1-acetyl-4-[2-(6-methyl-2-pyridyl)ethyl]piperazine as a brown solid which was used directly in the next step: 1H NMR (CDCl3): δ 7.48 (m, 1H), 7.0 (d, 1H), 3.63 (t, 2H), 3.45 (t, 2H), 2.95-2.60 (m, 4H), 2.50 (m, s, 9H), 2.08 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].C(N(C(C)C)C(C)C)C.[C:20]([NH:37][CH2:38][C:39](Cl)=[O:40])([O:22][CH2:23][CH:24]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21].Cl>C1COCC1.C(Cl)Cl>[CH:26]1[C:25]2[CH:24]([CH2:23][O:22][C:20]([NH:37][CH2:38][C:39]([NH:1][C:2]3[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=3)[C:5]([OH:7])=[O:6])=[O:40])=[O:21])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]=2[CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)CNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: Nc1cccc(C(=O)O)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(CNC(=O)OCC1c2ccccc2-c2ccccc21)Nc1cccc(C(=O)O)c1
Yield: 43 %

Procedure:
A solution of 3-aminobenzoic acid (0.5 g; 3.8 mmol) and N-ethyldiisopropylamine (DIEA) (0.64 mL; 3.8 mmol) in THF (20 mL) was added dropwise to a solution of Fmoc-glycine chloride (1.2 g; 4.0 mmol) (3) in THF (10 mL) and CH2Cl2 (10 mL). After 24 h stirring at room temperature 1 M HCl (50 mL) was added (final pH: 1.5). The precipitate was filtered, washed with H2O (2×100 mL), vacuum dried and crystallised from CHCl3/CH3OH (1:1) to give B as a white solid (0.7 g; 1.6 mmol). Yield 43%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1F)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[NH:23]1[CH2:27][C@H:26]([OH:28])[C@@H:25]([OH:29])[CH2:24]1.Cl>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:23]1[CH2:27][C@H:26]([OH:28])[C@@H:25]([OH:29])[CH2:24]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6]
Reactant: O[C@H]1CNC[C@@H]1O
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(F)c(Br)c1
Agent: Cl
Solvent: CS(C)=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2C[C@H](O)[C@@H](O)C2)c(Br)c1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A solution of 3-bromo-4-fluoro-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 1.2, 500 mg, 1.322 mmol), (3S,4S)-pyrrolidine-3,4-diol (205 mg, 1.984 mmol) and TEA (553 μL, 3.97 mmol) in DMSO (994 μL) was stirred at 90° C. for 24 h. Additional (3S,4S)-pyrrolidine-3,4-diol, (68.2 mg, 0.661 mmol) and TEA (183 μL, 1.322 mmol) were added and mixture was stirred at 100° C. for 16 h. The cooled treated with 0.5 M HCl (20 mL) and extracted with TBME/EtOAc (1:1). The combined extracts were washed with 0.5 M HCl (20 mL) and brine, dried over MgSO4 and the solvent was evaporated off under reduced pressure to give a residue which was crystallized from cyclohexane/EtOAc to afford the title compound as an off-white solid. UPLC-MS (Condition 1) tR=2.41 min, m/z=460.9/462.9 [M+H]+, m/z=459.0/461.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.24 (d, J=10.76 Hz, 2H) 3.88 (dd, J=10.51, 3.67 Hz, 2H) 4.02 (br. s, 2H) 5.15 (d, J=3.18 Hz, 2H) 6.89 (d, J=8.80 Hz, 1H) 7.34 (d, J=8.31 Hz, 2H) 7.84 (dd, J=8.68, 2.08 Hz, 1H) 7.85-7.89 (m, 2H) 8.13 (d, J=2.20 Hz, 1H) 10.17 (s, 1H).
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[C:25]([O:27][CH3:28])=[O:26])[C:19](O)=[O:20].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.O>CN(C=O)C>[I:15][C:16]1[CH:17]=[C:18]([C:19](=[O:20])[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:22]=[CH:23][C:24]=1[C:25]([O:27][CH3:28])=[O:26]
Reactant: Nc1ccccc1Oc1ccccc1
Reactant: COC(=O)c1ccc(C(=O)O)cc1I
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)Nc2ccccc2Oc2ccccc2)cc1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
To a stirring solution of 2-phenoxyaniline 99 (0.813 g, 4.39 mmol) and 3-iodo-4-(methoxycarbonyl)benzoic acid 100 (1.28 g, 4.18 mmol) in DMF (15 mL) was added BOP (1.942 g, 4.39 mmol) and TEA (1.166 mL, 8.36 mmol), the reaction mixture was stirred at room temperature for 1 h then poured into water. The desired product was extracted with ethyl acetate and the combined organic layers were washed with water, brine, dried over Na2SO4, filtered and solvent evaporated to provide methyl 2-iodo-4-(2-phenoxyphenylcarbamoyl)benzoate 101 (1.382 g, 70% yield) as a red foam after purification by flash chromatography (0 to 40% ethyl acetate in hexane).
Reaction SMILES: [CH3:1][CH:2]([C:13]1[CH:32]=[CH:31][C:16]2[N:17]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][C:21](=[O:30])[N:20]=[C:18]3[S:19][C:15]=2[CH:14]=1)[C:3]([O:5][C:6]1([CH3:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:4].NC1S[C:36]2[CH:42]=C(C(C)C(OC34CC5CC(CC(C5)C3)C4)=O)C=C[C:37]=2N=1>>[CH3:1][CH:2]([C:13]1[CH:32]=[CH:31][C:16]2[N:17]3[C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][C:21](=[O:30])[N:20]=[C:18]3[S:19][C:15]=2[CH:14]=1)[C:3]([O:5][C:6]12[CH2:12][CH:36]3[CH2:42][CH:8]([CH2:9][CH:10]([CH2:37]3)[CH2:11]1)[CH2:7]2)=[O:4]
Reactant: CC(C(=O)OC12CC3CC(CC(C3)C1)C2)c1ccc2nc(N)sc2c1
Reactant: CC(C(=O)OC1(C)CCCCC1)c1ccc2c(c1)sc1nc(=O)cc(-c3ccccc3)n12
Product: CC(C(=O)OC12CC3CC(CC(C3)C1)C2)c1ccc2c(c1)sc1nc(=O)cc(-c3ccccc3)n12
Temperature: 160 °C
Yield: 39 %

Procedure:
Using a method similar to that used in the preparation of 1-methylcyclohexyl α-methyl-2-oxo-4-phenyl-2H-pyrimido[2,1-b]benzothiazole-8-acetate, 8.9 g of 1-adamantyl 2-amino-α-methylbenzothiazole-6-acetate were reacted with heating at 160° C. for 1 hour to obtain 4.73 g (39% yield) of 1-adamantyl α-methyl-2-oxo-4-phenyl-2H-pyrimido[2,1-b]benzothiazole-8-acetate as a yellow solid after crystallization from ethyl acetate/petroleum ether melting at 188°-190° C.
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][C:11]2[C:12]([C:22]([F:25])([F:24])[F:23])=[N:13][N:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:15]=2)[N:9]=1.[Cl-:26].[NH4+:27]>>[ClH:26].[C:16]1([N:14]2[CH:15]=[C:11]([CH2:10][CH:8]3[NH:9][C:3](=[NH:27])[CH2:4][CH2:5][CH2:6][CH2:7]3)[C:12]([C:22]([F:25])([F:24])[F:23])=[N:13]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC1=NC(Cc2cn(-c3ccccc3)nc2C(F)(F)F)CCCC1
Reactant: [NH4+]
Reactant: [Cl-]
Product: Cl
Product: N=C1CCCCC(Cc2cn(-c3ccccc3)nc2C(F)(F)F)N1

Procedure:
The title material of Example 141 is reacted with ammonium chloride by the method of Example 5 to generate the title compound.
Reaction SMILES: [Br:1][C:2]1[NH:11][C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:23]=1[CH2:24]Br.[K]>O.CS(C)=O.C(O)C>[Br:1][C:2]1[N:11]([CH2:24][C:23]2[C:26]([F:30])=[CH:27][CH:28]=[CH:29][C:22]=2[Cl:21])[C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1
Reactant: Cn1c(=O)c2[nH]c(Br)nc2n(C)c1=O
Reactant: Fc1cccc(Cl)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [K]
Solvent: O
Solvent: CCO
Solvent: CS(C)=O
Product: Cn1c(=O)c2c(nc(Br)n2Cc2c(F)cccc2Cl)n(C)c1=O
Temperature: 100 °C
Yield: 62.2 %

Procedure:
A solution of 8-bromotheophylline (10 g, 39 mmol) in 30 mL water was treated with potassium carbonate (2.6 g, 48 mmol). The reaction mixture was refluxed until dissolved. Ethanol (30 mL) was added to the hot reaction mixture and the resulting potassium salt was filtered, washed with acetone, and dried in a 100° C. vacuum oven. A solution of 2-chloro-6-fluorobenzyl bromide (5.3 g, 24 mmol) in 10 mL DMSO was treated with the solid potassium salt The reaction mixture was heated to 100° C. for 1 hour and cooled. Upon addition of 5 mL water, the mixture was collected by filtration and dried in a vacuum oven to yield a white solid (6.0 g, 89% yield): 1H NMR (CDCl3, 300 MHz) 7.37-7.21 (m, 2H), 7.07-6.96 (m, 1H), 5.87 (s, 2H), 3.60 (s, 3H), 3.42 (s, 3H); MS (ESP+) m/e 402 (MH+).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:11][CH3:12])=[CH:5][C:6]=1[C:7]([O:9]C)=O.ClC(Cl)(O[C:17](=[O:23])OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[CH3:32][C:33]1[O:37][N:36]=[C:35]([NH2:38])[CH:34]=1>C(Cl)Cl>[CH2:11]([C:4]1[S:3][C:2]2[NH:1][C:17](=[O:23])[N:38]([C:35]3[CH:34]=[C:33]([CH3:32])[O:37][N:36]=3)[C:7](=[O:9])[C:6]=2[CH:5]=1)[CH3:12]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(N)no1
Reactant: CCc1cc(C(=O)OC)c(N)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cc2c(=O)n(-c3cc(C)on3)c(=O)[nH]c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 228.6 %

Procedure:
To a solution (40 mL) of methyl 2-amino-5-ethylthiophene-3-carboxylate (0.63 g) in methylene chloride were added triphosgene (0.44 g) and triethylamine (0.76 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added 5-methylisoxazol-3-amine (1 g), and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (40 mL), sodium methoxide (28% methanol solution, 1.6 g) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was neutralized with hydrochloric acid (10% methanol solution), insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (0.94 g, 100%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=O)[CH2:2][CH3:3].[Br:11][C:12]1[CH:13]=[C:14]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=O)[CH:15]=[CH:16][C:17]=1[O:18][CH2:19][CH2:20][Br:21]>>[Br:11][C:12]1[CH:13]=[C:14]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=[C:1]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:2][CH3:3])[CH:15]=[CH:16][C:17]=1[O:18][CH2:19][CH2:20][Br:21]
Reactant: CCC(=O)c1ccccc1
Reactant: O=C(c1ccc(O)cc1)c1ccc(OCCBr)c(Br)c1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCBr)c(Br)c1)c1ccccc1
Yield: 35.8 %

Procedure:
Following general procedure of McMurry reaction as described in example 1, step B, propiophenone (0.2 g, 3.0 eq) was reacted with (3-bromo-4-(2-bromoethoxy) phenyl)(4-hydroxyphenyl)methanone (0.2 g, 1.0 eq) to give 0.09 g desired product (36% yield, Z/E=1/1). 1H NMR (400 MHz, CDCl3) δ 7.42 (s, 1H), 7.01-7.0 (m, 7H), 6.87 (d, J=8.4 Hz, 1H), 6.82 (d, J=8.4 Hz, 1H), 6.71 (d, J=8.4 Hz, 1H), 6.48 (d, J=8.4 Hz, 1H), 4.36 (t, J=6.8 Hz, 1H), 4.19 (t, J=6.4 Hz, 1H), 3.70 (t, J=6.4 Hz, 1H), 3.59 (t, J=6.8 Hz, 1H), 2.46 (q, J=6.4 Hz, 2H), 0.92 (t, J=6.0 Hz, 3H)
Reaction SMILES: [C:1]([OH:12])(=O)[CH:2]=[CH:3][CH2:4][CH2:5][CH:6]=[CH:7][CH:8]=[CH:9][CH3:10].CN(C=O)C.S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[C:1]([Cl:20])(=[O:12])[CH:2]=[CH:3][CH2:4][CH2:5][CH:6]=[CH:7][CH:8]=[CH:9][CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CC=CC=CCCC=CC(=O)O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC=CC=CCCC=CC(=O)Cl
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
In an atmosphere of nitrogen, a toluene solution of the above-mentioned 2,6,8-decatrienoic acid (7) and DMF (3.7 g, 0.05 mol) were added to a 100 ml capacity flask, followed by cooling to 5° C. Thionyl chloride (11.9 g, 0.10 mol) was added dropwise to this, followed by stirring at 5° C. for 0.5 hour to obtain a toluene solution of 2,6,8-decatrienoic acid chloride (8).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH:9]([NH:11][NH:12][CH:13]=O)=O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CN(C=O)C>[N:11]1[N:12]=[CH:13][N:1]([C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)[CH:9]=1
Reactant: O=CNNC=O
Reactant: Nc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Oc1ccc(-n2cnnc2)cc1

Procedure:
4-aminophenol (1 g, 9.16 mmol) and bisformyl hydrazine (888 mg, 10.08 mmol) were dissolved in a mixture of toluene (30 mL) and DMF (3 mL), followed by addition of pTSA (1.92 g, 10.08 mmol). The mixture was heated under reflux for 3 hours. Upon cooling, the mixture separated to two layers. The upper toluene layer was discarded. The lower dark DMF layer was directly purified by column chromatography using a 115 gram biotage silica gel cartridge eluting with 20-40 ethyl acetate/hexanes (gradient) to give the product as pale yellow solid. LRMS tale: 161.1; obs: 162.4 (M+1).