Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([SiH2:14][CH2:15][CH2:16][P:17]([O:20][C@@H:21]2[C@@H:25]([CH2:26][O:27][C:28]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[O:24][C@@H:23]([N:51]3[C:68]4[N:67]=[CH:66][N:65]=[C:55]([NH:56][C:57](=[O:64])[C:58]5[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=5)[C:54]=4[N:53]=[CH:52]3)[CH2:22]2)(=O)[OH:18])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:69]([NH:72][CH:73]([CH3:75])[CH3:74])([CH3:71])[CH3:70].BrC1C=C(Br)C=C(Br)C=1OP(OC1C(Br)=CC(Br)=CC=1Br)(OC1C(Br)=CC(Br)=CC=1Br)(Cl)Cl>C(#N)C>[C:1]1([CH:7]([SiH2:14][CH2:15][CH2:16][PH:17]([O:20][C@@H:21]2[C@@H:25]([CH2:26][O:27][C:28]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[O:24][C@@H:23]([N:51]3[C:68]4[N:67]=[CH:66][N:65]=[C:55]([NH:56][C:57](=[O:64])[C:58]5[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=5)[C:54]=4[N:53]=[CH:52]3)[CH2:22]2)([N:72]([CH:73]([CH3:75])[CH3:74])[CH:69]([CH3:71])[CH3:70])[OH:18])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)NC(C)C
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)C[C@@H]2OP(=O)(O)CC[SiH2]C(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: ClP(Cl)(Oc1c(Br)cc(Br)cc1Br)(Oc1c(Br)cc(Br)cc1Br)Oc1c(Br)cc(Br)cc1Br
Solvent: CC#N
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)C[C@@H]2O[PH](O)(CC[SiH2]C(c2ccccc2)c2ccccc2)N(C(C)C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 3 h

Procedure:
A 250 mL two necked flask equipped with a magnetic stirrer, a gas inlet for argon, and a septum is assembled under an argon atmosphere. All glassware are dried at 120° C. for 1 hour. The flask is charged with N6 -Benzoyl-5'-O-(4,4'dimethoxytrityl)-2'-deoxyadenosine- 3'-O-(2-diphenylmethylsilylethylphosphonate) (0.015 mole) and diisopropylamine (0.12 mole). Anhydrous acetonitrile (200 mL) is added. To this stirred mixture under argon at room temperature is added tris(2,4,6-tribromophenoxy)dichlorophosphorane (0.225 mole). After stirring for three hours, the reaction mixture is filtered, and concentrated under reduced pressure. The crude product is purified by flash chromatography using silica gel to afford the desired product. Triethylamine (1%) is used throughout the purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[C:13]1([CH:19]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:20][CH2:21][N:22]([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:24])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1>[C:42]1([CH:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:20][CH2:21][N:22]([CH:36]2[CH2:37][CH2:38][N:39]([S:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)(=[O:11])=[O:10])[CH2:40][CH2:41]2)[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:33])[F:35])[CH:27]=2)=[O:24])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)N(CCC(c1ccccc1)c1ccccc1)C1CCNCC1
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N2CCC(N(CCC(c3ccccc3)c3ccccc3)C(=O)Nc3cccc(C(F)(F)F)c3)CC2)cc1
Reaction time: 8 h
Yield: 55.2 %

Procedure:
27.5 mg (100 μmol, 2 eq.) of morpholinomethyl resin is preswollen in anhydrous tetrahydrofuran, then 4-methoxyphenylsulphonyl chloride (15.5 mg, 0.075 mmol, 1.5 eq.) then N-(3,3-diphenylpropyl)-N-(4-piperidinyl)-N′-[3-(trifluoromethyl)phenyl] urea (24.3 mg, 0.05 mmol) are added. The mixture is agitated overnight. The aminomethyl (20 mg) and SAX ion exchange resins are added and the mixture is agitated overnight. The resins are filtered and rinsed with dichloromethane. The oil obtained after evaporation is passed through a silica gel cartridge (500 mg, Interchim) eluting with ethyl acetate in order to obtain 18 mg (yield=56%) of a white solid after concentration.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:16])[C@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH2:8])([CH3:4])[CH3:3].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>C(#N)C.P([O-])([O-])([O-])=O>[CH3:4][C:2]([O:5][C:6](=[O:16])[C@H:7]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[NH:8][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
An emulsion of L-phenylalanine 1,1-dimethylethyl ester (compound prepared at point A) (53.53 g; 242 mol), tert-butyl bromoacetate (37.3 mL; 254 mol) in acetonitrile (400 mL) and 2M buffer phosphate pH 8 (200 mL) is vigorously stirred at room temperature for 16 hours. After separation, the organic phase is evaporated and the residue is taken up into EtOAc; the aqueous phase is extracted with EtOAc (3×200 mL). The combined organic phases are washed with water (2×300 mL), saline solution (200 mL) and finally dried over Na2SO4. The crude is purified by flash chromatography (n-hexane/EtOAc 9:1 to 75:25). After removing the solvents under vacuum, the desired compound is obtained as a colourless oil (66.04 g; 196.90 mol).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[C:8]12([N:18]=[C:19]=[O:20])[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2.Cl.[CH3:22]N(C=O)C>>[CH3:22][O:6][C:5](=[O:7])[CH2:4][CH2:3][CH2:2][NH:1][C:19]([NH:18][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:20].[C:8]12([NH:18][C:19](=[O:20])[NH:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2
Reactant: CN(C)C=O
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Reactant: NCCCC(=O)O
Agent: Cl
Product: COC(=O)CCCNC(=O)NC12CC3CC(CC(C3)C1)C2
Product: O=C(O)CCCNC(=O)NC12CC3CC(CC(C3)C1)C2
Reaction time: 24 h
Yield: 100 %

Procedure:
The title compound was prepared by a procedure described in J. Med. Chem. 2004, 47, 2110. To a suspension of 4-aminobutyric acid (2.79 g, 27.1 mmol) in DMF (40 mL) was added 1-adamantyl isocyanate (1.20 g, 6.77 mmol) at room temperature. The reaction mixture was stirred for 24 h. Then 1 N HCl aqueous solution (40 mL) was added into the reaction, and the mixture was stirred for 30 min. The solid crystalline product was filtered and washed with water (20 mL) and ethyl acetate (20 mL). The resulting solid was dried in a vacuum oven to give 1.90 g (100%) of 4-(3-adamantan-1-yl-ureido)butyric acid 822 as a white solid: 1H NMR (CD3OD): 1.66-1.75 (8H, m), 1.94-1.97 (6H, m), 2.05-2.07 (3H, m), 2.30 (2H, t, J=6.9 Hz), 3.08 (2H, q, J=6.9 Hz), 3.32 (2H, s); LC-MS (ESI) m/z calcd for C15H24N2O3 [M+H]+ 281.18. found [M+H]+ 281.25; mp 165 C. Anal. (C15H24N2O3) C, H, N.
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][N:4]=1.BrCC1OC(C(F)(F)F)=CC=1.[F:24][C:25]1[C:30]([C:31]#[N:32])=[CH:29][C:28]2[C:33]3([CH2:43][O:44][C:27]=2[CH:26]=1)[C:41]1[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=1)[NH:35][C:34]3=[O:42].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1>>[F:24][C:25]1[C:30]([C:31]#[N:32])=[CH:29][C:28]2[C:33]3([CH2:43][O:44][C:27]=2[CH:26]=1)[C:41]1[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=1)[N:35]([CH2:2][C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][N:4]=1)[C:34]3=[O:42]
Reactant: N#Cc1cc2c(cc1F)OCC21C(=O)Nc2ccccc21
Reactant: FC(F)(F)c1cccnc1CCl
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: N#Cc1cc2c(cc1F)OCC21C(=O)N(Cc2ncccc2C(F)(F)F)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 2-(chloromethyl)-3-(trifluoromethyl)pyridine to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, and 6-fluoro-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, 6-fluoro-2′-oxo-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile was obtained (67%): mp 209-211° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 8.65 (d, J=6.0 Hz, 1H), 8.23 (d, J=6.0 Hz, 1H), 7.58-7.54 (m, 1H), 7.42-7.40 (m, 1H), 7.31-7.23 (m, 3H), 7.06-7.01 (m, 1H), 6.93-6.91 (m, 1H), 5.21 (s, 2H), 5.03 (s, 2H); MS (ES+) m/z 440.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][N:12]3[C:20]4[C:15](=[CH:16][C:17]([C:21]([O:23]C)=[O:22])=[CH:18][CH:19]=4)[C:14]([NH:25][CH3:26])=[N:13]3)[CH:10]=1)[N:7]([CH2:27][CH:28]([CH3:30])[CH3:29])[N:6]=[CH:5]2.[OH-].[Li+].O.CO>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][N:12]3[C:20]4[C:15](=[CH:16][C:17]([C:21]([OH:23])=[O:22])=[CH:18][CH:19]=4)[C:14]([NH:25][CH3:26])=[N:13]3)[CH:10]=1)[N:7]([CH2:27][CH:28]([CH3:30])[CH3:29])[N:6]=[CH:5]2
Reactant: CNc1nn(Cc2cc(Cl)cc3cnn(CC(C)C)c23)c2ccc(C(=O)OC)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CNc1nn(Cc2cc(Cl)cc3cnn(CC(C)C)c23)c2ccc(C(=O)O)cc12
Temperature: 100 °C

Procedure:
A mixture of compound 69 (0.021 g, 0.05 mmol), lithium hydroxide (0.09 g, 0.2 mmol) in a mixture of tetrahydrofuran (1 mL), water (0.5 mL) and methanol (0.5 mL) was heated at 100° C. under microwave conditions for 10 minutes. Then, the reaction was quenched by adding water and diluted with ethyl acetate. The organic layer was separated, washed with Brine, dried (MgSO4), filtered and the solvent was evaporated.
Reaction SMILES: [OH-].[Na+].CC(C)=O.O.Cl[C:9]1[CH:14]=[C:13]([Cl:15])[N:12]=[CH:11][N:10]=1.[OH:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[CH:20]2>CCOC(C)=O.O>[Cl:15][C:13]1[N:12]=[CH:11][N:10]=[C:9]([O:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][CH:21]=[CH:20]3)[CH:14]=1
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: Clc1cc(Cl)ncn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: Clc1cc(Oc2ccc3[nH]ccc3c2)ncn1
Temperature: 65 °C
Reaction time: 1.17 h

Procedure:
To a mixture of NaOH (720 mg, 18 mmol) and acetone/water 1:1 (72 ml), 4,6-dichloropyrimidine (2.4 g, 18 mmol) and 5-hydroxy-indole (2.68 g, 18 mmol) are added. After stirring for 70 min at 65° C., the brownish solution is cooled to rt and diluted with AcOEt and water. The aqueous layer is separated off and extracted twice with AcOEt. The organic layers are washed with water, saturated Na2CO3 solution, water and brine, dried (Na2SO4) and concentrated. The crude product can be used without further purification: m.p.: 137-138° C.; MS: [M+1]+=246.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:30]([F:33])([F:32])[F:31])[O:16][N:15]=[C:14]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([C:27](O)=[O:28])=[CH:19][CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:67][C:68]([F:78])([F:77])[CH2:69][CH2:70][N:71]1[C:75](=[O:76])[CH2:74][NH:73][CH2:72]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:30]([F:31])([F:32])[F:33])[O:16][N:15]=[C:14]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([C:27]([N:73]4[CH2:74][C:75](=[O:76])[N:71]([CH2:70][CH2:69][C:68]([F:67])([F:77])[F:78])[CH2:72]4)=[O:28])=[CH:19][CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: O=C1CNCN1CCC(F)(F)F
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)c2ccccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1CN(C(=O)c2ccc(C3=NOC(c4cc(Cl)cc(C(F)(F)F)c4)(C(F)(F)F)C3)c3ccccc23)CN1CCC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed N,N-dimethylformamide (10 mL), 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]naphthalene-1-carboxylic acid (70 mg, 0.14 mmol, 1.00 equiv), HATU (74 mg, 0.19 mmol, 4.00 equiv), DIEA (218 mg, 1.69 mmol, 4.00 equiv), 3-(3,3,3-trifluoropropyl)imidazolidin-4-one (31 mg, 0.17 mmol, 1.00 equiv). The resulting solution was stirred for 2 h at room temperature. The crude product was purified by Prep-HPLC. This resulted in 32 mg (34%) of 1-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]naphthalen-1-yl)carbonyl]-3-(3,3,3-trifluoropropyl)imidazolidin-4-one as a light brown solid. (ES, m/z): 693 [M+41]+; (300 MHz, CD3OD, ppm): δ 8.98-8.95 (m, 1H), 8.04-7.96 (m, 3H), 7.92-7.85 (m, 2H), 7.74-7.65 (m, 3H), 5.26 (s, 1H), 4.88-4.52 (m, 2H), 4.36-4.29 (m, 2H), 3.82 (s, 1H), 3.73 (t, J=6.6 Hz, 1H), 3.50 (t, J=7.5 Hz, 1H), 2.68-2.60 (m, 1H), 2.43-2.37 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.[CH3:17][N:18]([CH3:32])[C:19]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1.C(O)(=O)C>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH:22]2[CH2:21][CH2:20][C:19]([N:18]([CH3:32])[CH3:17])([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:24][CH2:23]2)[CH2:15][CH:16]=1
Reactant: Clc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(C)C1(c2ccccc2)CCC(N2CC=C(c3c[nH]c4ccc(Cl)cc34)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5-chloro-3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole (170 mg, 0.79 mmole) and 4-dimethylamino-4-phenylcyclohexanone (171 mg, 0.79 mmole) were dissolved in dry 1,2-dichloro-ethane (10 ml). Glacial acetic acid (0.79 mmole) and sodium triacetoxy boron hydride (300 mg, 1.4 mmole) were added to this mixture. The reaction mixture was then stirred for 24 hours at RT. The reaction mixture was worked up by distilling off the 1,2-dichloroethane and diluting with water (10 ml). The reaction mixture was adjusted to pH 11 with 5M NaOH and extracted with EE (4×20 ml). The organic phase was dried with Na2SO4 and concentrated by evaporation. The diastereoisomer mixture was obtained as a colourless solid in a yield of 340 mg (100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7](OC)=[N:6][S:5](=[O:11])(=[O:10])[N:4]=1.[CH3:12][N:13]([CH3:22])[CH2:14][C:15]#[C:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21]>>[CH3:1][O:2][C:3]1[C:7]([NH:21][CH2:20][CH2:19][CH2:18][CH2:17][C:16]#[C:15][CH2:14][N:13]([CH3:12])[CH3:22])=[N:6][S:5](=[O:11])(=[O:10])[N:4]=1
Reactant: CN(C)CC#CCCCCN
Reactant: COC1=NS(=O)(=O)N=C1OC
Product: COC1=NS(=O)(=O)N=C1NCCCCC#CCN(C)C

Procedure:
In a similar manner to Example 1, 3,4-dimethoxy-1,2,5-thiadiazole-1,1-dioxide (1.07 g) and 7-(dimethylamino)hept-5-ynylamine (0.92 g) were reacted to give a solution of 3-methoxy-4-[7-dimethylaminohept-5-ynylamino]-1,2,5-thiadiazole-1,1-dioxide. Reaction with ammonia gas and purification as in Example 1 gave the title compound (1.08 g), m.p. 172°-4° C. (recrystallisation from acetonitrile).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH2:10].[CH3:11][C:12]1([CH3:20])[O:17][C:16](=[O:18])[CH2:15][C:14](=[O:19])[O:13]1.[CH:21](OCC)(OCC)OCC>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH:10][CH:21]=[C:15]1[C:16](=[O:18])[O:17][C:12]([CH3:20])([CH3:11])[O:13][C:14]1=[O:19]
Reactant: COc1ccc(Br)c(N)c1
Reactant: CCOC(OCC)OCC
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: CCO
Product: COc1ccc(Br)c(NC=C2C(=O)OC(C)(C)OC2=O)c1
Temperature: 25 °C
Yield: 90.2 %

Procedure:
A solution of 2-bromo-5-methoxy-phenylamine (16.1 g, 80 mmol), 2,2-dimethyl-[1,3]dioxane-4,6-dione (Meldrum's acid) (13.7 g, 95 mmol) and triethyl orthoformate (14.1 g, 95 mmol) in ethanol (82 ml) was heated to reflux for 2 hours then allowed to cool to room temperature. Filtration and drying in vacuo afforded a white solid (25.7 g, 91%)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](OS(C(F)(F)F)(=O)=O)=[C:7]([Cl:19])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][NH2:29])=[CH:23][CH:22]=1.CN([CH:33]=[O:34])C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:33]([NH:29][CH2:28][CH2:27][C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)=[O:34])=[C:7]([Cl:19])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c1
Reactant: CN(C)C=O
Reactant: NCCc1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)c1ccc(C(=O)NCCc2ccc(F)cc2)c(Cl)c1
Temperature: 70 °C
Yield: 59 %

Procedure:
317 mg (1 mmol) of trifluoro-methanesulfonic acid 4-tert-butyl-2-chloro-phenyl ester and 281 mg (2 mmol) of 2-(4-fluoro-phenyl) ethyl amine were dissolved in 5 ml DMF. Under argon at rt 6.7 mg (0.03 mmol) of palladium acetate and 12.4 mg (0.03 mmol) of dppp were added. The reaction mixture was evacuated and charged with carbon monoxide gas three times. The reaction mixture was heated to 70° C. under a carbon monoxide atmosphere for 1 h. Water was added and the reaction mixture was extracted twice with EtOAc. The combined organic layers were washed with 1N aqueous HCl solution, once with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (45 g silica gel; heptane/EtOAc 7:3) to yield 198 mg (59%) of 4-tert-butyl-2-chloro-N-[2-(4-fluoro-phenyl)-ethyl]-benzamide as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 8.41 (t, 1H), 7.42 (s, 1H), 7.39 (d, 1H), 7.30 (d, 1H), 7.28 (t, 2H), 7.12 (t, 2H), 3.43 (q, 2H), 2.81 (t, 2H), 1.27 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[C:14]1(B(O)O)[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=1.C[O-:24].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CO>[C:14]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]([NH2:7])=[O:24])=[CH:4][C:3]=2[C:10]([F:13])([F:12])[F:11])[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=1
Reactant: OB(O)C1=CCCCC1
Reactant: N#Cc1ccc(Br)c(C(F)(F)F)c1
Reactant: C[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(C2=CCCCC2)c(C(F)(F)F)c1
Temperature: 80 °C
Yield: 78.9 %

Procedure:
4-bromo-3-(trifluoromethyl)benzonitrile (commercial) (1.2 g, 4.80 mmol), 1-cyclohexen-1-ylboronic acid (0.907 g, 7.20 mmol), sodium methoxide (0.778 g, 14.40 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.337 g, 0.480 mmol) were added to dry methanol (12 mL) and the mixture heated in the microwave at 80° C. for 10 minutes. The reaction mixture was partitioned between ethyl acetate (40 mL) and water (40 mL) and then the organic phase washed with further water (40 mL). The organic phase was dried (MgSO4), filtered and the solvent removed in vacuo. The crude product was purified by flash silica chromatography, eluting with 0-75% ethyl acetate in hexane to give the title compound as a white solid (1.02 g). δH (CDCl3, 400 MHz): 8.09 (1H, m), 7.90 (1H, dd), 7.32 (1H, d), 6.3-5.8 (2H, m) 5.61 (1H, s), 2.25-2.13 (4H, m), 1.80-1.60 (4H, m). MS (ES): C14H14F3NO requires 269; found 270 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:15][CH3:16])=[CH:5][C:6]2[O:10][C:9]([C:11](=[O:13])[CH3:12])=[CH:8][C:7]=2[CH:14]=1.C(O[K])(C)(C)C.[CH2:23](Br)/[CH:24]=[C:25](/[CH2:27][CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])\[CH3:26].O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([O:15][CH3:16])=[CH:5][C:6]2[O:10][C:9]([C:11](=[O:13])[CH2:12][CH2:23][CH:24]=[C:25]([CH3:26])[CH2:27][CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])=[CH:8][C:7]=2[CH:14]=1
Reactant: CC(C)=CCC/C(C)=C/CBr
Reactant: COc1cc2cc(C(C)=O)oc2cc1OC
Agent: CC(C)(C)O[K]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc2cc(C(=O)CCC=C(C)CCC=C(C)C)oc2cc1OC
Reaction time: 2 h

Procedure:
To a solution of 1-(5,6 dimethoxy benzofuran-2-yl)ethanone A2 (1 g, 4.545 mmol) in anhydrous Toluene added tBuOK (0.51 g, 4.545 mmol) at 0° C. under argon atmosphere and then stirred at the same temperature for 15 min to this reaction mixture geranyl bromide added drop wise. Resulting suspension stirred at the same temperature for 2 hrs. 50 ml water was added to the reaction mixture and layers were separated. Aqueous layer was extracted with ethylaectate. The combined organic extract were washed with brine and dried over Na2SO4, evaporated under reduced pressure. Chromatography of the residue on silica gel (5% EtOAc/hexanes) afforded the ketone A3 (1.69 g) in 70% yield pale yellow liquid: 1H NMR (500 MHz, CDCl3) δ 7.425 (s, 1H), 7.365 (s, 1H), 7.06 (s, 1H), 5.12-5.16 (m, 1H), 5.08-5.04 (m, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 2.97-2.89 (t, 2H), 2.50-2.40 (m, 2H), 2.17-2.00 (m, 4H), 1.66 (s, 3H), 1.63 (s, 3H), 1.64 (s, 3H), 1.58 (s, 3H), ppm. Mass: ESI [M+Na]+: 379.2; Elemental anal. calcd. for C22H28O4; C, 74.13; H, 7.92. found C, 74.0; H, 5.25.
Reaction SMILES: [CH3:1][C:2]([S:21]([CH3:24])(=[O:23])=[O:22])([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]=[CH:19][CH:18]=[N:17]2)=[CH:12][CH:11]=1)[C:3]([O:5]CC)=[O:4].O.[OH-].[Li+].O>O1CCCC1.CO.Cl>[CH3:1][C:2]([S:21]([CH3:24])(=[O:22])=[O:23])([CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH:20]=[CH:19][CH:18]=[N:17]2)=[CH:14][CH:15]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(CCc1ccc(-n2cccn2)cc1)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(CCc1ccc(-n2cccn2)cc1)(C(=O)O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-methyl-2-(methylsulfonyl)-4-[4-(1H-pyrazol-1-yl)phenyl]butanoate (316 mg, 0.902 mmol) in tetrahyrofuran/methanol (4:1, 10 mL) was added a solution of lithium hydroxide monohydrate in water (1.8 M, 3.61 mmol). The mixture was stirred at ambient temperature overnight. The mixture was diluted with aqueous 1N HCl and extracted with ether 2×. The combined organic extracts were washed with water, dried over magnesium sulfate, filtered and concentrated to dryness to afford 2-methyl-2-(methylsulfonyl)-4-[4-(1H-pyrazol-1-yl)phenyl]butanoic acid as an oil. 286 mg. LCMS: (M−1) 321.3.