Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[F:7][C:8]([F:15])([CH2:12][CH:13]=[CH2:14])[C:9](O)=[O:10]>CN(C)C=O>[F:7][C:8]([F:15])([CH2:12][CH:13]=[CH2:14])[C:9]([Cl:4])=[O:10]
Reactant: C=CCC(F)(F)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: C=CCC(F)(F)C(=O)Cl
Reaction time: 2 h
Yield: 86 %

Procedure:
Add oxalyl chloride (17.6 mL, 201.8 mmol) to compound 8c (25 g, 183.7 mmol) and dimethylformamide (3 drops) under neat conditions at room temperature. Observe gas evolution for approximately 2 h. After 5 h, treat the reaction mixture with an additional 0.08 eq of oxalyl chloride (1.2 mL) and stir for 18 h. Use fractional distillation (88°-91° C.) to obtain 24.4 g, 158 mmol of the title compound 8a as an oil in 85% yield. 19F NMR (CDCl3) δ -101.9 (t); 13C NMR (CDCl3) δ 167.3 (t, CO2H), 125.5 (s, C=C), 123.1 (s, C=C), 115.6 (t, CF2), 38.3 (t, CH2); 1H NMR (CDCl3) δ 2.90 (m, 2H), 5.33 (d, 1H), 5.36 (s, 1H), 5.74 (m, 2H).
Reaction SMILES: [C:1]([Si:3]([CH3:6])([CH3:5])[CH3:4])#[CH:2].Br[C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1>[Cu]I>[CH3:4][Si:3]([C:1]#[C:2][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)([CH3:6])[CH3:5]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1ccc(Br)cc1
Agent: [Cu]I
Product: COC(=O)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
Ethynyltrimethylsilane (82.4 g, 0.84 mol) was added dropwise over 10 min under a nitrogen atmosphere to a solution of methyl 4-bromobenzoate (150 g, 0.7 mol), PdCl2 (PPh3)2 (15 g, 0.021 mol) and CuI (13 g, 0.07 mol) in TEA (1.5 L) and the reaction was stirred at 90° C. for 30 minutes. Solids were collected by filtration and washed with EtOAc (5×500 mL). The filtrate was concentrated under reduced pressure to give a residue, which was distilled under reduced pressure to yield methyl 4-((trimethylsilyl)ethynyl)benzoate (INT-1.2) as an off-white solid (156 g, 96%).
Reaction SMILES: Cl.Cl.[O:3]=[C:4]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]3[CH:20]=[N:21][CH:22]=[C:23]([CH:27]=3)[C:24]([OH:26])=[O:25])[CH:17]=2)[O:12][C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5]1.[CH:28]1([C:31]2[CH:32]=[CH:33][CH:34]=[C:35]3[C:40]=2[N:39]=[C:38]([C:41](N2C=CN=C2)=[O:42])[CH:37]=[C:36]3[O:48][CH3:49])[CH2:30][CH2:29]1.Cl>CN(C=O)C.O>[CH:28]1([C:31]2[CH:32]=[CH:33][CH:34]=[C:35]3[C:40]=2[N:39]=[C:38]([C:41]([N:9]2[CH2:10][CH2:11][C:6]4([CH2:5][C:4](=[O:3])[C:18]5[C:13](=[CH:14][CH:15]=[C:16]([C:19]6[CH:20]=[N:21][CH:22]=[C:23]([CH:27]=6)[C:24]([OH:26])=[O:25])[CH:17]=5)[O:12]4)[CH2:7][CH2:8]2)=[O:42])[CH:37]=[C:36]3[O:48][CH3:49])[CH2:29][CH2:30]1
Reactant: O=C(O)c1cncc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)c1
Reactant: COc1cc(C(=O)n2ccnc2)nc2c(C3CC3)cccc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cncc(C(=O)O)c4)ccc2O3)nc2c(C3CC3)cccc12
Temperature: 70 °C
Reaction time: 19 h

Procedure:
5-{4-oxospiro[chroman-2,4′-piperidin]-6-yl}nicotinic acid di-hydrochloride (4.93 g, 12.0 mmol), TEA (5.14 mL, 36.9 mmol) were suspended in DMF (49 mL) and (8-cyclopropyl-4-methoxy-quinolin-2-yl)-imidazol-1-yl-methanone (2.70 g, 9.22 mmol) was added thereto at room temperature, and the reaction mixture was stirred at 70° C. for 19 h. After cooled to room temperature, the mixture was poured into 1N HCl aq. (27.7 mL, 27.7 mmol) in H2O (367 mL) solution and the suspension was stirred for 2 h. The resulting precipitate was filtered, washed with H2O to give crude intended compound as a pale brown solid. This solid was washed with EtOAc-MeOH (1:1), then EtOH, and dried to afford the intended compound as a colorless solid. 1H-NMR (400 MHz, DMSO-d6) δ: 9.08 (1.0H, d, J=2.4 Hz), 9.03 (1.0H, d, J=2.0 Hz), 8.41 (1.0H, dd, J=2.0, 2.4 Hz), 8.07-8.03 (2.0H, m), 7.94 (1.0H, dd, J=8.3, 1.5 Hz), 7.49 (1.0H, dd, J=8.3, 7.6 Hz), 7.30-7.23 (2.0H, m), 7.20 (1.0H, s), 4.40-4.33 (1.0H, m), 4.07 (3.0H, s), 3.94-3.87 (1.0H, m), 3.57-3.48 (1.0H, m), 3.39-3.24 (1.0H, m), 3.11-3.04 (1.0H, m), 2.98 (2.0H, s), 2.15-2.07 (1.0H, m), 2.03-1.79 (3.0H, m), 1.10-1.04 (2.0H, m), 0.87-0.72 (2.0H, m). MS [M+H]+=564.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:12][C:13](=[O:24])[C:14]2[N:19]([CH3:20])[N:18]=[C:17]([CH2:21][CH2:22][CH3:23])[C:15]=2[N:16]=1)C=C.C1(O)C=CC=CC=1.N1CCCCC1>C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:12][C:13](=[O:24])[C:14]2[N:19]([CH3:20])[N:18]=[C:17]([CH2:21][CH2:22][CH3:23])[C:15]=2[N:16]=1
Reactant: C=CCOc1ccccc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Oc1ccccc1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3ccccc3O)nc12
Yield: 9.2 %

Procedure:
A mixture of 5-(2-allyloxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (0.25 g, 0.0008 mol), phenol (0.145 g, 0.0015 mol), piperidine (0.131 g, 0.0015 mol) and tetrakis(triphenylphosphine)palladium(O) (0.046 g, 0.00004 mol) in absolute ethanol (5 ml) was refluxed overnight under nitrogen. The mixture was allowed to cool, the solvent evaporated under vacuum and the residue dissolved in ethyl acetate (40 ml). This solution was washed with water (3×10 ml), 1M HCl (3×10 ml) and brine (1×10 ml). After drying (Na2SO4) and filtration, the filtrate was evaporated under vacuum to give the crude product. The title phenol (0.021 g, 10%) was obtained after trituration with diethyl ether and crystallisation from ethyl acetate/pentane, m.p. 233°-238° C. Found: C,63.17; H,5.65; N, 19.52. C15 H16N4O2 requires C,63.36; H, 5.67; N, 19.71%.
Reaction SMILES: [CH3:1][C@:2]1([CH2:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])[O:19][C:18](=[O:20])[C:17]2[N:21]=[C:14]([S:15][CH:16]=2)[S:13][CH2:12][CH2:11][N:10]2[C@H:6]([CH2:7][O:8][C:9]2=[O:22])[CH:5]=[CH:4][CH2:3]1.[OH:30][C@@H](C(C)(C)CCCC)/C=C/[C@H]1COC(=O)N1CCSC1SC=C(C(OCC)=O)N=1.O1CCCC1>CO>[O:22]=[C:9]1[N:10]([CH2:11][CH2:12][S:13][C:14]2[S:15][CH:16]=[C:17]([C:18]([OH:19])=[O:20])[N:21]=2)[C@@H:6](/[CH:5]=[CH:4]/[CH2:3][C@@:2]([OH:30])([CH3:1])[CH2:23][CH2:24][CH2:25][C:26]([F:27])([F:29])[F:28])[CH2:7][O:8]1
Reactant: C[C@@]1(CCCC(F)(F)F)CC=C[C@H]2COC(=O)N2CCSc2nc(cs2)C(=O)O1
Reactant: CCCCC(C)(C)[C@H](O)/C=C/[C@H]1COC(=O)N1CCSc1nc(C(=O)OCC)cs1
Solvent: C1CCOC1
Solvent: CO
Product: C[C@](O)(C/C=C/[C@H]1COC(=O)N1CCSc1nc(C(=O)O)cs1)CCCC(F)(F)F

Procedure:
By the same procedure as the reaction of Example 8 using the compound 64-1 (Less polar) instead of the compound 7 and using a mixture of tetrahydrofuran and methanol instead of methanol, the title compound having the following physical data was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([CH3:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[C:5]([C:20]([F:23])([F:22])[F:21])[CH:4]=1)#[N:2].[NH2:24][OH:25]>C(O)C>[OH:25][N:24]=[C:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([CH3:17])[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])=[C:5]([C:20]([F:21])([F:23])[F:22])[CH:4]=1)[NH2:2]
Reactant: NO
Reactant: CN(CC(=O)OC(C)(C)C)Cc1ccc(C#N)cc1C(F)(F)F
Solvent: CCO
Product: CN(CC(=O)OC(C)(C)C)Cc1ccc(C(N)=NO)cc1C(F)(F)F
Yield: 77 %

Procedure:
A solution of tert-butyl 2-((4-cyano-2-(trifluoromethyl)benzyl)(methyl)amino)acetate (0.541 g, 1.65 mmol) and 50% aqueous hydroxylamine (0.50 mL) in ethanol (2 mL) was heated at 75° C. for 2 hours. The solvent was evaporated in vacuo. The residue was partitioned between DCM and water. The organic phase was passed through a hydrophobic frit and evaporated in vacuo to afford the title compound (0.460 g, 77%). 1H NMR (CDCl3, 400 MHz,) δ 7.97 (1H, d, J=8.1 Hz), 7.89 (1H, s), 7.78 (1H, d, J=8.1 Hz), 4.86 (2H, br s), 3.86 (2H, s), 3.23 (2H, s), 2.37 (3H, s), 1.48 (9H, s).
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:16]=2)=[CH:10][CH:9]=1.[C:26](OCC)(=[O:28])[CH3:27]>CCCCCC.O1CCCC1>[C:20]1([N:17]2[CH2:18][CH2:19][C:15]([N:14]([C:11]3[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:13][CH:12]=3)[C:26](=[O:28])[CH3:27])=[N:16]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(C)=O
Reactant: COc1ccc(NC2=NN(c3ccccc3)CC2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(N(C(C)=O)C2=NN(c3ccccc3)CC2)cc1
Reaction time: 2 h

Procedure:
1.7M n-butyl lithium in hexane (7.0 ml) was added dropwise to a solution of 4,5-dihydro-N-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-amine (2.67 g) in tetrahydrofuran (150 ml) at -25° under N2. After 40 minutes ethyl acetate was added and the solution was allowed to reach room temperature. After being stirred for 2 hours, the solution was evaporated to dryness and the residue chromatographed on silica gel eluting with ethyl acetate in dichloromethane to give an oil which crystallised on trituration with ether. The solid was recrystallised from ether and hexane to give the title compound (0.82 g) mp 83°-5° (dec).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:25])=[N:12][CH:13]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:15]=1.C[O:27][C:28]([C@@H:30]1[CH2:34][C@H:33]([N:35]2[CH:39]=[C:38](I)[CH:37]=[N:36]2)[CH2:32][N:31]1C(OCC1C=CC=CC=1)=O)=[O:29].[F-].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:25][C:11]1[N:12]=[CH:13][C:14]([C:38]2[CH:37]=[N:36][N:35]([C@@H:33]3[CH2:32][NH:31][C@H:30]([C:28]([OH:29])=[O:27])[CH2:34]3)[CH:39]=2)=[CH:15][C:10]=1[C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1
Reactant: CC1(C)OB(c2cnc(N)c(-c3nc4ccccc4s3)c2)OC1(C)C
Reactant: COC(=O)[C@@H]1C[C@H](n2cc(I)cn2)CN1C(=O)OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ncc(-c2cnn([C@@H]3CN[C@H](C(=O)O)C3)c2)cc1-c1nc2ccccc2s1
Temperature: 60 °C

Procedure:
A mixture of 3-benzothiazol-2-yl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (BB8) (200 mg, 0.566 mmol), (2S,4S)-4-(4-iodopyrazol-1-yl)-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (309.0 mg, 0.679 mmol), Pd(PPh3)4 (60 mg, 0.06 mmol), potassium fluoride (98.7 mg, 1.70 mmol), and 4:1 dioxane:water (5 mL) was heated in the microwave reactor at 85° C. for 30 min. The material was concentrated in vacuo, then dry-loaded onto silica gel for column chromatography. The product was eluted with 2→5% MeOH/DCM, and the fractions containing the product were concentrated in vacuo. The material was dissolved in conc. HCl, transferred to a sealed tube and heated at 60° C. for 2 h. The solvent was removed using the corrosive pump to afford the title compound as a brown solid. 1H NMR (400 MHz, CD3OD): δ=2.73 (ddd, J=14.0, 6.5, 4.5 Hz, 1H), 3.07 (ddd, J=14.1, 10.0, 7.5 Hz, 1H), 3.81-3.93 (m, 2H), 4.68 (dd, J=10.0, 6.7 Hz, 1H), 5.36 (ddd, J=6.8, 3.8, 3.5 Hz, 1H), 7.56-7.63 (m, 2H), 8.05 (s, 1H), 8.08-8.11 (m, 1H), 8.16 (d, J=7.6 Hz, 1H), 8.32-8.36 (m, 2H), 8.72 (d, J=2.0 Hz, 1H). MS (ES′): m/z=407.13 (100) [MH+]. HPLC: tR=2.28 min (ZQ2, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@@H:8]([CH2:12][NH:13][C:14](=[O:24])[CH2:15][S:16][C:17]2[S:18][CH:19]=[C:20]([CH:22]=O)[N:21]=2)[CH2:7]1.C(O)(=O)[CH2:30][C:31]([OH:33])=[O:32].N1CCCCC1.Cl>N1C=CC=CC=1.O>[C:31](/[CH:30]=[CH:22]/[C:20]1[N:21]=[C:17]([S:16][CH2:15][C:14]([NH:13][CH2:12][C@@H:8]2[O:9][CH2:10][CH2:11][N:6]([CH2:5][C:4]3[CH:25]=[CH:26][C:27]([Cl:28])=[C:2]([Cl:1])[CH:3]=3)[CH2:7]2)=[O:24])[S:18][CH:19]=1)([OH:33])=[O:32]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1csc(SCC(=O)NC[C@H]2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)n1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCNCC1
Product: O=C(O)/C=C/c1csc(SCC(=O)NC[C@H]2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)n1
Temperature: 100 °C
Reaction time: 3.5 h

Procedure:
The resultant product (643 mg) of (70-2) was dissolved in pyridine (5 mL), malonic acid (291 mg) and piperidine (14 μL) were added, and the mixture was stirred at 100° C. for 3.5 hrs. The reaction mixture was poured into water, 1M hydrochloric acid was added to adjust to pH=4, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (618 mg) as a white amorphous solid.
Reaction SMILES: [NH2:1][CH:2]1[CH:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[C:10]2[CH:9]=[C:8]([CH2:20][CH2:21][CH2:22][NH:23][S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>ClCCl>[F:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][CH:11]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:20][CH2:21][CH2:22][NH:23][S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[CH:9]=2)[CH2:4][CH2:3][CH:2]1[NH:1][C:37](=[O:39])[CH3:38]
Reactant: CCCS(=O)(=O)NCCCc1ccc2c(c1)C(Cc1cccc(F)c1)C(N)CC2
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)NCCCc1ccc2c(c1)C(Cc1cccc(F)c1)C(NC(C)=O)CC2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
N-(3-(7-Amino-8-(3-fluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl)propyl)propane-1-sulfonamide (cf. example 209: 45 mg, 0.108 mmol) and triethylamine (15 μL, 0.108 mmol) were dissolved in dichloromethane (2 mL). Acetylchloride (7.64 μL, 0.108 mmol) were added. The reaction mixture was stirred for 12 hours at room temperature. The reaction mixture was diluted with dichloromethane and successively washed with hydrochloric acid, water and saturated sodium chloride solution. The organic layer was dried and concentrated in vacuo. The crude product was purified by flash-chromatography (silica gel, dichloromethane, methanol). Yield: 37 mg (0.08 mmol, 75%).
Reaction SMILES: [C:1]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:6]=[CH:5][C:4]([C:7]2(C3C=CC=CC=3)[NH:11][C:10]([CH2:12][CH2:13][S:14][C:15]3[CH:27]=[CH:26][C:18]([O:19][C:20]([CH3:25])([CH3:24])[C:21]([OH:23])=[O:22])=[CH:17][CH:16]=3)=[C:9]([CH3:28])[O:8]2)=[CH:3][CH:2]=1.CO.[OH2:43].OOS([O-])=O.[K+].C[OH:51]>>[C:1]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:9]([CH3:28])=[C:10]([CH2:12][CH2:13][S:14]([C:15]3[CH:27]=[CH:26][C:18]([O:19][C:20]([CH3:25])([CH3:24])[C:21]([OH:23])=[O:22])=[CH:17][CH:16]=3)(=[O:51])=[O:43])[N:11]=2)=[CH:3][CH:2]=1
Reactant: CC1=C(CCSc2ccc(OC(C)(C)C(=O)O)cc2)NC(c2ccccc2)(c2ccc(-c3ccccc3)cc2)O1
Reactant: O
Reactant: CO
Agent: O=S([O-])OO
Agent: [K+]
Product: Cc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCS(=O)(=O)c1ccc(OC(C)(C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-{4-[2-(2-biphenyl-4-yl-5-methyl-2-phenyl-oxazol-4-yl)-ethylsulfanyl]-phenoxy}-2-methylpropionic acid (31 mg, 0.078 mmol) was mixed with 8 mL 1/1 methanol/water. Solid oxone (100 mg, 0.16 mmol) was added and the reaction was stirred at room temperature for 2 h. The methanol was allowed to evaporate overnight and the white precipitate was collected and washed with water. After drying in a vacuum oven the product was obtained as a light tan solid. 1H NMR (CDCl3) δ 1.67 (s, 6H), 2.38 (s, 3H), 3.05 (t, 2H), 3.55 (t, 2H), 6.96 (d, 2H), 7.48 (m, 3H), 7.81 (d, 2H), 7.92 (m, 2H); MS (EI+) 506.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:26]=1)[O:7][CH2:8][C:9]1[N:25]=[CH:24][CH:23]=[CH:22][C:10]=1/[C:11]/2=[C:12](\[C:15]1[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=1)/[CH2:13][CH3:14].N1C=CC=CC=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:26]=1)[O:7][CH2:8][C:9]1[N:25]=[CH:24][CH:23]=[CH:22][C:10]=1/[C:11]/2=[C:12](\[C:15]1[CH:16]=[C:17]([NH:21][S:34]([CH3:33])(=[O:36])=[O:35])[CH:18]=[CH:19][CH:20]=1)/[CH2:13][CH3:14]
Reactant: CS(=O)(=O)Cl
Reactant: CC/C(=C1\c2ccc(Cl)cc2OCc2ncccc21)c1cccc(N)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC/C(=C1\c2ccc(Cl)cc2OCc2ncccc21)c1cccc(NS(C)(=O)=O)c1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
A 50 L three neck round bottom flask is equipped with a mechanical stirrer, nitrogen inlet, thermocouple and drying tube placed in a cooling tub. (E)-3-[1-(8-chloro-11H-10-oxa-1-aza-dibenzo[a,d]cyclohepten-5-ylidene)-propyl]-phenylamine (1800 g, 4.96 mol) (prepared essentially as described for Intermediate 10 using the Alternate Procedure) dichloromethane (18 L) and pyridine (588.5 g, 7.44 mol) are added to the flask. The reaction mixture is cooled to 0 to 5° C. and neat methanesulfonyl chloride (681.8 g, 5.952 mol) is added dropwise over about 20-30 min, maintaining the temperature ≦5° C. After the addition is complete, the reaction mixture is stirred at 0 to 5° C. for one hour. The cooling bath is removed and the reaction stirred at room temperature for a minimum of 12 h. The progress of the reaction is followed by TLC (straight EtOAc). Once the reaction is deemed complete, the reaction mixture is washed with a 10% aqueous citric acid solution (14 L) using a 40 L separatory funnel. The aqueous layer is back extracted with dichloromethane (1.5 L). The combined organic layers are washed with a 10% aqueous citric acid solution (2 L). The aqueous layer is back extracted with dichloromethane (1.5 L). The combined organic layers are washed with a 15% aqueous sodium chloride solution (5 L) and the aqueous layer back extracted with dichloromethane (1.5 L). The combined organic layers are washed with a half saturated aqueous sodium bicarbonate solution (5 L). The sodium bicarbonate wash should be performed for a minimum of 30 min. The aqueous layer is back extracted with dichloromethane (1.5 L). The combined organic layers are dried over sodium sulfate and filtered. A 50 L three neck round bottom flask is equipped with a mechanical stirrer, nitrogen inlet, thermocouple and drying tube placed in a cooling tub. The dichloromethane solution containing the product is charged to the flask, followed by trithiocyanuric acid, trisodium salt (630 g, 0.35 g/g of starting material), sodium sulfate (3.6 kg, 2 g/g of starting material) and charcoal (180 g, 0.1 g/g of starting material) to the flask. The suspension is stirred for 12 h at room temperature. The suspension is filtered and the filter cake slurried with dichloromethane (3×3 L). The filtrates are combined and concentrated to an off white solid. The product is dried in a vacuum oven at 40° C. overnight.
Reaction SMILES: C1([O:4][S:5](=[O:8])(=[O:7])[NH2:6])CC1.[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1[OH:17]>>[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1[NH:6][S:5](=[O:7])(=[O:4])[O-:8].[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1[O:17][S:5](=[O:7])(=[O:4])[NH2:6]
Reactant: NS(=O)(=O)OC1CC1
Reactant: Cc1cccc(C)c1O
Product: Cc1cccc(C)c1NS(=O)(=O)[O-]
Product: Cc1cccc(C)c1OS(N)(=O)=O

Procedure:
2,6-Dimethylphenylsulfamate was synthesized according to the method presented in the synthesis of sulfamic acid cyclopropyl ester in Example 1 with the exception of utilizing 2,6-dimethylphenol to obtain sulfamic acid 2,6-dimethyl-phenyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH:19]=[CH:18][C:11]3[C:12](O)=[N:13][S:14](=[O:16])(=[O:15])[C:10]=3[CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.O=P(Cl)(Cl)Cl.[C:25]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C>O1CCCC1>[C:25]([C:29]1[CH:30]=[CH:31][C:32]([NH:33][C:12]2[C:11]3[CH:18]=[CH:19][C:8]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=4)=[CH:9][C:10]=3[S:14](=[O:16])(=[O:15])[N:13]=2)=[CH:34][CH:35]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: O=S1(=O)N=C(O)c2ccc(-c3ncccc3Cl)cc21
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(NC2=NS(=O)(=O)c3cc(-c4ncccc4Cl)ccc32)cc1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
A suspension of the product of Example 1B (0.1507 g, 0.51 mmol) in POCl3 (4.0 mL, 42.9 mmol) was stirred at 90° C. for 90 minutes, cooled to room temperature and excess POCl3 was removed under vacuum. The resulting residue was treated with 4-tert-butylaniline (0.1027 g, 0.69 mmol) in tetrahydrofuran (3 mL), followed by the addition of a solution of triethylamine (0.25 mL, 1.79 mmol) in tetrahydrofuran (2 mL), and stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated NaHCO3 (5 mL) and diluted with dichloromethane (5 mL). The isolated aqueous phase was extracted with dichloromethane (2×10 mL). The combined organic fractions were dried (MgSO4), filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with ethyl acetate/dichloromethane to afford the title compound. MS (ESI+) m/z 426 (M+H)+; (ESI−) m/z 424 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 1.32 (s, 9H), 7.55 (m, 3H), 7.79 (m, 2H), 8.16 (dd, J=8.3, 1.5 Hz, 1H), 8.22 (d, J=8.1 Hz, 1H), 8.30 (s, 1H), 8.60 (d, J=8.1 Hz, 1H), 8.71 (dd, J=4.7, 1.4 Hz, 1H), 10.94 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[C:8]([CH3:20])=[C:9]([CH3:19])[C:10]([CH:17]=C)=[C:11]([CH:16]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:3]=1[O:23][CH3:24].CC(C)=[O:27].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[C:8]([CH3:20])=[C:9]([CH3:19])[C:10]([CH:17]=[O:27])=[C:11]([CH:16]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:3]=1[O:23][CH3:24]
Reactant: C=Cc1c(C(=O)OC)cc(Cc2ccc(F)c(OC)c2)c(C)c1C
Reactant: CC(C)=O
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cc(Cc2ccc(F)c(OC)c2)c(C)c(C)c1C=O
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of methyl 5-(4-fluoro-3-methoxybenzyl)-3,4-dimethyl-2-vinylbenzoate (0.39 g) in a mixed solvent of acetone (9.00 mL)-acetonitrile (9.00 mL)-water (9.00 mL) were added osmium oxide (fixed catalyst I) (0.15 g) and sodium periodate (1.27 g), and the mixture was stirred at room temperature for 2.5 days. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate to give the title compound (0.39 g). This compound was used in the next step without an additional purification.