Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([CH2:16][NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].Br[CH2:32][CH:33]1[CH2:35][CH2:34]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH:33]1([CH2:32][N:17]([CH2:16][C:14]2[S:15][C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=3)=[CH:12][CH:13]=2)[S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:28])[F:29])(=[O:20])=[O:19])[CH2:35][CH2:34]1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CNS(=O)(=O)c3ccccc3C(F)(F)F)s2)c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)c1cccc(-c2ccc(CN(CC3CC3)S(=O)(=O)c3ccccc3C(F)(F)F)s2)c1

Procedure:
In analogy to example 10, step 3, N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide (example 27, step 1) was reacted with (bromomethyl)-cyclopropane and cesium carbonate in N,N-dimethylacetamide to give N-cyclopropylmethyl-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide as a light yellow oil. MS: 546.8 ([M+NH4]+)
Reaction SMILES: NC(N)=O.[CH3:5][O:6][CH2:7][CH2:8][N:9]([CH2:22][CH2:23][O:24][CH3:25])[S:10]([C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([NH2:20])[C:14]=1[OH:21])(=[O:12])=[O:11].[Cl:26][C:27]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=1[N:34]=[C:35]=[O:36]>>[Cl:19][C:18]1[CH:17]=[CH:16][C:15]([NH:20][C:35]([NH:34][C:28]2[CH:29]=[CH:30][CH:31]=[C:32]([Cl:33])[C:27]=2[Cl:26])=[O:36])=[C:14]([OH:21])[C:13]=1[S:10]([N:9]([CH2:8][CH2:7][O:6][CH3:5])[CH2:22][CH2:23][O:24][CH3:25])(=[O:11])=[O:12]
Reactant: COCCN(CCOC)S(=O)(=O)c1c(Cl)ccc(N)c1O
Reactant: O=C=Nc1cccc(Cl)c1Cl
Agent: NC(N)=O
Product: COCCN(CCOC)S(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2cccc(Cl)c2Cl)c1O
Yield: 87 %

Procedure:
Following the general procedure for urea formation outlined in example 15, N,N-di-(2-methoxyethyl)-3-amino-6-chloro-2-hydroxybenzenesulfonamide (40 mg, 0.12 mmol) and 2,3-dichlorophenylisocyanate (22mg, 0.12 mmol) were coupled to form the desired urea (55 mg, 87%). 1H NMR (MeOD-d4): 8δ 8.27 (m, 1H), 8.03 (m, 1H), 7.23 (m, 2H), 7.03 (m, 1H), 3.61 (m, 4H), 3.45 (m, 4H), 3.23 (s, 6H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7](Cl)([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[CH2:18]([O:20][CH:21]([O:24][CH2:25][CH3:26])[CH2:22][NH2:23])[CH3:19]>C(OCC)(=O)C>[CH2:18]([O:20][CH:21]([O:24][CH2:25][CH3:26])[CH2:22][NH:23][C:7](=[O:8])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:19]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(CN)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(CNC(=O)OCc1ccccc1)OCC
Reaction time: 6 h
Yield: 98 %

Procedure:
An aqueous solution (400 ml) of sodium carbonate (31.8 g) and carbobenzoxy chloride (51.2 g) were added to a solution of 2,2-diethoxyethylamine (42.0 g) in ethyl acetate (300 ml) under ice-cooling, and the mixture was stirred for 6 hours. After separating the mixture into layers, the organic layer was washed successively with 0.5N hydrochloric acid, an aqueous sodium bicarbonate solution and an aqueous saturated sodium chloride solution, dried and concentrated to give pale orange oily benzyl 2,2-diethoxyethylcarbamate (78.6 g).
Reaction SMILES: C([Li])CCC.[C:6]([Si:10]([O:13][CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]1[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[C:28]([F:34])=[CH:27][C:26]=1[O:35][CH3:36])([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:7].B(OC)(OC)[O:38]C.C(O)(=O)C.OO>C1COCC1.O>[Si:10]([O:13][CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:18]=[CH:17][C:16]=1[C:25]1[CH:30]=[C:29]([CH:31]([CH3:32])[CH3:33])[C:28]([F:34])=[C:27]([OH:38])[C:26]=1[O:35][CH3:36])([C:6]([CH3:7])([CH3:8])[CH3:9])([CH3:12])[CH3:11]
Reactant: COB(OC)OC
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CO[Si](C)(C)C(C)(C)C
Agent: OO
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: COc1c(-c2ccc(C(F)(F)F)cc2CO[Si](C)(C)C(C)(C)C)cc(C(C)C)c(F)c1O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
n-Butyllithium (1.6M in hexanes, 261 μL, 0.417 mmol) was added dropwise over 30-45 min with a syringe pump to a stirred solution of tert-butyl{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methoxy}dimethylsilane (200 mg, 0.438 mmol) in dry THF (0.5 mL) at −78° C. under N2. The reaction was stirred for a further 2 h at −78° C. after the addition to give a violet colored solution. Trimethyl borate (43.4 mg, 47 μL, 0.417 mmol) was added dropwise and the reaction was stirred at −78° C. for 3 h. The reaction mixture was warmed to 0° C. and acetic acid (25.1 mg, 24 μL, 0.626 mmol) was added quickly followed by 30% aqueous hydrogen peroxide (52 μL, 0.459 mmol) dropwise. The reaction was stirred at room temperature overnight, diluted with water (10 mL) and extracted with Et2O (3×20 mL). The combined extracts were washed with 50% saturated FeSO4 (20 mL), dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-100% EtOAc in hexanes gradient) to afford 2′-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl-3-ol. Rf=0.32 (10% EtOAc in hexanes). LCMS calc.=473.1; found=473.2 (M+1)+. 1H NMR (600 MHz, CDCl3) δ 7.95 (s, 1H), 7.56 (d, J=7.8 Hz, 1H), 7.35 (d, J=7.9 Hz, 1H), 6.53 (d, J=7.8 Hz, 1H), 5.65 (s, 1H), 4.68 (br s, 1H), 4.54 (br s, 1H), 3.42 (s, 3H), 3.26-3.20 (m, 1H), 1.25 (d, J=6.9 Hz, 6H), 0.90 (s, 9H), 0.02 (s, 6H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][C@H:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4]1.C(Cl)Cl.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C([O-])(O)=O.[Na+]>>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:1][CH2:2][C@@H:3]2[CH2:7][C@H:6]([NH:8][C:9]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:15])[CH:5]=[CH:4]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@H](CO)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2C=C[C@@H](NC(=O)OC(C)(C)C)C2)cc1
Temperature: 0 °C
Yield: 70.9 %

Procedure:
To a stirred solution of tert-butyl (1S,4R)-4-(hydroxymethyl)cyclopent-2-enylcarbamate (Intermediate 6-step 2, about 4.5 g, 21.12 mmol) in DCM (50 ml) triethyl amine (about 9.5 ml, 68.1 mmol) was added at room temperature and cooled to about 0° C. After ten minutes, 4-methylbenzene-1-sulfonyl chloride (about 6.0 g) was added and stirred the reaction at room temperature for about 6 hours and completion of the reaction was monitored by TLC. Reaction mixture was neutralized with saturated NaHCO3 and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure to furnish the title compound (5.5 g) as a light yellow liquid. 1H NMR (300 MHz, CDCl3): 1.45 (s, 9H); 246-2.55 (m, 4H); 2.90-2.91 (m, 1H); 3.95-3.98 (m, 2H); 4.59-4.70 (m, 2H); 5.66-5.77 (m, 2H); 7.34-7.37 (d, J=9 Hz, 2H); 7.77-7.80 (d, J=9 Hz, 2H).
Reaction SMILES: [CH:1]([N:4]1[C:8](=[O:9])[CH2:7][CH2:6][C:5]1=[O:10])=[CH:2][CH3:3].[ClH:11]>>[Cl:11][CH:1]([N:4]1[C:8](=[O:9])[CH2:7][CH2:6][C:5]1=[O:10])[CH2:2][CH3:3]
Reactant: Cl
Reactant: CC=CN1C(=O)CCC1=O
Product: CCC(Cl)N1C(=O)CCC1=O
Reaction time: 240 h

Procedure:
Anhydrous hydrogen chloride is bubbled through a mixture of 10 g. (0.072 mole) of N-propenylsuccinimide and 1.04 g. of stannic chloride for 6 hours. The solution is allowed to stand at room temperature for 10 days, the solution being saturated again with hydrogen chloride gas after 3 days and 4 days. Solvents are removed under reduced pressure at 30° - 40°C. to give 1-chloro-1-succinimidopropane as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][N:3]=1.ClC1C=CC(CCl)=CN=1.[C:19]1(=[O:29])N[C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.[OH-].[K+]>C(O)C.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:22](=[O:24])[C:21]3=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]3[C:19]2=[O:29])=[CH:4][N:3]=1
Reactant: NCc1ccc(Cl)nc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: ClCc1ccc(Cl)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(Cl)nc1

Procedure:
It is known that 2-chloro-5-aminomethyl-pyridine, an intermediate for the preparation of insecticides, is obtained when, in a first step, 2-chloro-5-chloromethyl-pyridine is reacted with phthalimide in the presence of potassium hydroxide, dimethylformamide and ethanol to give N-(2-chloro-pyridin-5-yl-methyl)-phthalimide and, in a second step, the desired 2-chloro-5-aminomethyl-pyridine is liberated from this using hydrazine hydrate in ethanol (cf. EP-A 302,389, p. 23).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)CCO1.[H-].[Na+].[CH2:14]([O:21][C:22]1[C:31]2[C:26](=[CH:27][C:28](F)=[C:29]([Cl:32])[CH:30]=2)[CH:25]=[CH:24][N:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:34][C:35](N(C)C)=[O:36]>>[CH2:14]([O:21][C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:11][CH:8]3[CH2:7][CH2:6][C:5]4([O:1][CH2:34][CH2:35][O:36]4)[CH2:10][CH2:9]3)=[C:29]([Cl:32])[CH:30]=2)[CH:25]=[CH:24][N:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OC1CCC2(CCOO2)CC1
Reactant: CC(=O)N(C)C
Reactant: Fc1cc2ccnc(OCc3ccccc3)c2cc1Cl
Agent: [H-]
Agent: [Na+]
Product: Clc1cc2c(OCc3ccccc3)nccc2cc1OC1CCC2(CC1)OCCO2

Procedure:
1.26 g (8.34 mmol) of dioxa-spiro[4.5]decan-8-ol were dissolved in 50 ml of dimethyl acetamide and 695.2 mg (17.4 mmol) of sodium hydride (60%) were added. After stirring 30 minutes at room temperature a solution of 2.0 g (6.95 mmol) of 1-benzyloxy-7-chloro-6-fluoro-isoquinoline (103) in 50 ml of dimethyl acetamide was added and stirring was continued at room temperature. After 1 h the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane and washed with water. The organic layer was dried with magnesium sulfate and evaporated, which gave 3.30 g of the crude product, which was used without further purification. Rt=2.05 min (Method C). Detected mass: 426.5 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:11]=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:13]([O-])([O-])=O.[K+].[K+].CI.CCOCC>CN(C=O)C>[CH3:13][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[CH:11]=[O:12]
Reactant: O=Cc1ccc(Cl)cc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1cc(Cl)ccc1C=O
Reaction time: 4 h
Yield: 64.9 %

Procedure:
To a heterogeneous mixture of 5-chloro-2-formyl-benzoic acid (1.0 g, 5.42 mmol) and K2CO3 (1.12 g, 8.13 mmol) in DMF (7 ml) was added MeI (0.41 ml, 6.5 mmol) at RT. The reaction mixture was stirred for 4 h then diluted into Et2O and washed with water (2×). The organic layer was dried over Na2SO4, filtered and evaporated to dryness to yield the crude title compound (700 mg, 3.52 mmol, 65%) as a light yellow solid, which was used without further purification. HPLC: AtRet=1.84 min; LC-MS: m/z 199.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6): 3.91 (s, 3H), 7.84-7.94 (m, 3H), 10.33 (s, 1H).
Reaction SMILES: [C:1]([N:9]1[C@H:13]([C:14]([O-:16])=[O:15])[CH2:12][S@:11](=[O:17])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1([NH2+]C2CCCCC2)CCCCC1>C(O)C>[C:1]([N:9]1[C@H:13]([C:14]([OH:16])=[O:15])[CH2:12][S@:11](=[O:17])[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[C@@H]1C[S@](=O)CN1C(=O)c1ccccc1
Agent: C1CCC([NH2+]C2CCCCC2)CC1
Solvent: CCO
Product: O=C(O)[C@@H]1C[S@](=O)CN1C(=O)c1ccccc1
Yield: 88.1 %

Procedure:
To the alcoholic mother liquor, from which fractional recrystallization had been effected in step (c), a small excess of dicyclohexylamine was added, and then the mixture was allowed to stand at room temperature for 2 hours. The crystals which precipitated were recrystallized from ethanol to give 3.95 g of dicyclohexylammonium (1S,4R)-3-benzoyl-1-oxothiazolidine-4-carboxylate, melting at 186°-198° C. (with decomposition). 3.0 g of the cyclohexyl amine salt thus obtained were dissolved in 50 ml of 50% v/v aqueous ethanol, and the solution was passed through a column containing 50 ml of a cation-exchange resin (Dowex 50H+, trade mark), and eluted with 50% v/v aqueous ethanol. The solvent was distilled off and the residue was recrystallized from a 1:3 by volume mixture of ethanol and diethyl ether, to give 1.54 g of (1S,4R)-3-benzoyl-1-oxothiazolidine-4-carboxylic acid melting at 174°-175° C. (with decomposition).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[S:14])[NH:12][NH2:13])=[CH:6][CH:5]=1)([OH:3])=[O:2].[Br:15][C:16]1[C:17]([OH:25])=[C:18]([CH:21]=[C:22]([Br:24])[CH:23]=1)[CH:19]=O.CN(C)C=O.S(NN)(C1C=CC(C)=CC=1)(=O)=O>CS(C)=O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[S:14])[NH:12][N:13]=[CH:19][C:18]2[CH:21]=[C:22]([Br:24])[CH:23]=[C:16]([Br:15])[C:17]=2[OH:25])=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Reactant: O=Cc1cc(Br)cc(Br)c1O
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: O=C(O)c1ccc(NC(=S)NN=Cc2cc(Br)cc(Br)c2O)cc1
Reaction time: 24 h
Yield: 42.3 %

Procedure:
A solution of 4-(4-carboxyphenyl)-3-thiosemicarbazide (25 mg, 0.12 mmol) and 3,5-dibromo-2-hydroxybenzaldehyde (40 mg, 0.144 mmol) in dimethylsulfoxide (1 mL) was shaken with 4 Å molecular sieves for 18 h. Dimethylformamide (1 mL) was added, followed by PS-TsNHNH2 resin (80 mg, 0.230 mmol), shaking continued for 24 h, then the resin filtered off. The solution was chromatographed by reverse phase HPLC (CombiPrep ODS-A, 10–90% acetonitrile/water+0.1% trifluoroacetic acid) to give the title compound (24 mg, 42%) as a solid. MS (ES−) m/e 470, 472, 474 [M−H]−.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]([OH:6])=O.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:46]([O:53][C:54]1[CH:59]=[C:58]([NH:60][C:61]2[N:66]=[C:65]([N:67]3[CH2:72][C@@H:71]([NH:73][C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[CH2:70][C@@H:69]([NH:81][C:82]([O:84][C:85]([CH3:88])([CH3:87])[CH3:86])=[O:83])[CH2:68]3)[N:64]=[C:63]([N:89]3[CH2:94][C@@H:93]([NH:95][C:96]([O:98][C:99]([CH3:102])([CH3:101])[CH3:100])=[O:97])[CH2:92][C@@H:91]([NH:103][C:104]([O:106][C:107]([CH3:110])([CH3:109])[CH3:108])=[O:105])[CH2:90]3)[N:62]=2)[CH:57]=[CH:56][C:55]=1[NH2:111])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CN(C=O)C>[CH2:46]([O:53][C:54]1[CH:59]=[C:58]([NH:60][C:61]2[N:66]=[C:65]([N:67]3[CH2:72][C@@H:71]([NH:73][C:74]([O:76][C:77]([CH3:78])([CH3:79])[CH3:80])=[O:75])[CH2:70][C@@H:69]([NH:81][C:82]([O:84][C:85]([CH3:88])([CH3:87])[CH3:86])=[O:83])[CH2:68]3)[N:64]=[C:63]([N:89]3[CH2:90][C@@H:91]([NH:103][C:104]([O:106][C:107]([CH3:110])([CH3:109])[CH3:108])=[O:105])[CH2:92][C@@H:93]([NH:95][C:96]([O:98][C:99]([CH3:102])([CH3:101])[CH3:100])=[O:97])[CH2:94]3)[N:62]=2)[CH:57]=[CH:56][C:55]=1[NH:111][C:4](=[O:6])[C:3]1[C:7]([O:11][CH3:12])=[CH:8][CH:9]=[CH:10][C:2]=1[OH:1])[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: COc1cccc(O)c1C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2nc(Nc3ccc(N)c(OCc4ccccc4)c3)nc(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)n2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(O)c1C(=O)Nc1ccc(Nc2nc(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)nc(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)n2)cc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 0.42 h
Yield: 34.5 %

Procedure:
2-Hydroxy-6-methoxy-benzoic acid (87) (0.067 g=0.4 mmol), iPr2EtN (0.6 mmol) and HBTU (0.44 mmol) were dissolved in DMF (2 mL) and shaken in a sealed vial for 25 min. 2-Benzyloxy-N4-(4,6-bis-((3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piperidin-1-yl)-[1,3,5]triazin-2-yl)-benzene-1,4-diamine (83) (0.184 g, 0.2 mmol) was added and the mixture was heated to 80° C. for 3 h. LC-MS indicated complete coupling at this point. Upon concentrating, the crude product was dissolved in CHCl3 (4 mL), washed with aqueous sat. NaHCO3 (2×2 mL), water (2×2 mL) and concentrated to dryness. Purification by ISCO (15–100% EtOAc/hexanes) gave the desired product (88) (0.073 g, 0.069 mmol, 34.5% yield). LC-MS (ESI): (exact mass: 1069.56) m/e═1070.9 [M+1]+ (100%).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH:31]2[CH2:35][CH2:34][O:33][C:32]2=[O:36])(O)[C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[F:12][C:13]1[CH:18]=[CH:17][C:16](/[C:19](=[C:31]2\[C:32](=[O:36])[O:33][CH2:34][CH2:35]\2)/[C:20]2[CH:21]=[CH:22][C:23]([S:26]([CH3:29])(=[O:27])=[O:28])=[CH:24][CH:25]=2)=[CH:15][CH:14]=1
Reactant: CS(=O)(=O)c1ccc(C(O)(c2ccc(F)cc2)C2CCOC2=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(/C(=C2\CCOC2=O)c2ccc(F)cc2)cc1
Yield: 43.6 %

Procedure:
A few mg of toluene-4-sulfonic acid are added to a solution of 7 g of 3-[1-(4-fluorophenyl)-1-hydroxy-1-(4-methanesulfonylphenyl)methyl]dihydrofuran-2-one, prepared in Example 3, in 100 ml of toluene and the mixture is refluxed for 10 hours in a Dean-Stark apparatus. The solvent is then evaporated off to dryness under vacuum and the residue is chromatographed using a 9/1 dichloromethane/acetone mixture as the eluent to give an oil, which is chromatographed using t-butyl methyl ether as the eluent to give 2.9 g of (E)-3-[1-(4-fluorophenyl)-1-(4-methanesulfonylphenyl)methylidene]dihydrofuran-2-one (second product eluted) in the form of crystals melting at 187°-9° C. 1.5 g of (Z)-3-[1-(4-fluorophenyl)-1-(4-methanesulfonylphenyl)methylidene]dihydrofuran-2-one (first product eluted) are recovered in the form of crystals melting at 157°-158° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([OH:10])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.N1C=CC=CC=1.[C:17](Cl)(=[O:19])[CH3:18]>ClCCl>[C:17]([O:10][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[CH2:1][CH2:2][CH2:3]2)(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: Oc1ccc2c(c1)CCC2
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.2 %

Procedure:
5-Indanol (500 mg) was dissolved in dichloromethane (5 ml) to prepare a solution. Pyridine (439 mg) and acetyl chloride (349 mg) were added to the solution, and the mixture was stirred at room temperature for 6 hr. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform to give indan-5-yl acetate (599 mg, yield 92%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[O:38]1[CH:42]=[CH:41][CH:40]=[C:39]1[CH2:43][NH:44][CH3:45]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:44]([CH2:43][C:39]3[O:38][CH:42]=[CH:41][CH:40]=3)[CH3:45])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CNCc1ccco1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: CN(Cc1ccco1)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and furan-2-ylmethylmethylamine according to conditions described in general procedure C. Mp: 155-156° C.; 1H NMR (400 MHz, CDCl3) δ 1.61-1.69 (m, 6 H), 3.05 (s, 3 H), 3.25-3.28 (m, 4 H), 4.49 (s, 2 H), 6.12-6.18 (m, 2 H), 6.75 (d, J=11.1 Hz, 1 H), 6.98 (d, J=8.0 Hz, 1 H), 7.25-7.31 (m, 3H), 7.46-7.57 (m, 3 H), 7.88-7.97 (m, 3 H), 8.16-8.21 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:29])[C:5]2[N:10]=[C:9]([C:11]3[N:15]([C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=4)[N:14]=[C:13]([C:23]([F:26])([F:25])[F:24])[CH:12]=3)[O:8][C:7](=[O:27])[C:6]=2[CH:28]=1.[CH:30]([NH2:33])([CH3:32])[CH3:31]>O1CCCC1>[Cl:1][C:2]1[CH:28]=[C:6]([C:7]([NH:33][CH:30]([CH3:32])[CH3:31])=[O:27])[C:5]([NH:10][C:9]([C:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[C:13]([C:23]([F:26])([F:24])[F:25])[CH:12]=2)=[O:8])=[C:4]([CH3:29])[CH:3]=1
Reactant: CC(C)N
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc(C(=O)NC(C)C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reaction time: 0.08 h

Procedure:
To a solution of the benzoxazinone product of Step D (5.0 g, 11.3 mmol) in tetrahydrofuran (35 mL) was added dropwise isopropylamine (2.9mL, 34.0mmol) in tetrahydrofuran (10 mL) at room temperature. The reaction mixture was then warmed until all solids had dissolved and stirred an additional five minutes, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was purified by chromatography on silica gel, followed by trituration with ether/hexane to afford the title compound, a compound of the present invention, as a solid (4.6 g), melting at 195-196° C.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[C:18]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:19]([C:23]([F:26])([F:25])[F:24])[O:20]2)=[CH:15][CH:14]=1)([CH3:12])[CH3:11])=O)(C)(C)C.[Cl:32]Cl>CC(O)=O>[ClH:32].[Cl:32][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:13]=1[C:10]([CH3:12])([CH3:11])[CH2:9][NH2:8])[O:20][CH:19]([C:23]([F:26])([F:25])[F:24])[C:18]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:17]2
Reactant: ClCl
Reactant: CCOC(=O)C1=Cc2ccc(C(C)(C)CNC(=O)OC(C)(C)C)cc2OC1C(F)(F)F
Solvent: CC(=O)O
Product: CCOC(=O)C1=Cc2cc(Cl)c(C(C)(C)CN)cc2OC1C(F)(F)F
Product: Cl
Reaction time: 4 h

Procedure:
Into a solution of the title product of Example 120 Step 4 (3.47 g, 7.83 mmoles) in 50 mL of HOAc was bubbled Cl2 gas. After 4 h, N2 gas was bubbled through, Zn dust (2.1 g, 32.1 mg-atm) was added, and the mixture stirred for 1 h. The mixture was concentrated, and the residue chromatographed over silica gel using 10% MeOH—DCM as eluent to give the title compound, 3.61 g, as a white foam.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:17]O>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5]([O:7][CH3:17])=[O:6]
Reactant: Cc1cc(C(=O)O)ccc1I
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(I)c(C)c1

Procedure:
24.4 g (0.093 mol) of 3-methyl-4-iodobenzoic acid and 250 ml of methanol were introduced into a round-bottomed flask and 2.5 ml of concentrated sulfuric acid were added dropwise. The mixture was heated at reflux for 12 hours, the reaction medium evaporated, taken up in ethyl acetate and water, the organic phase decanted off, dried over magnesium sulfate and evaporated. The residue was triturated in methanol, filtered and 21.9 g (85%) of the expected methyl ester of melting point 58-9° C. were recovered.